Frequency of Symptomatic Adverse Events in Rheumatoid Arthritis: An Exploratory Online Survey.

Effects of Helicobacter pylori and Nonsteroidal Anti-Inflammatory Drugs on Peptic Ulcer Disease: A Systematic Review

Patient-reported outcomes are critical for assessing symptomatic adverse events in non-small-cell lung cancer (NSCLC) clinical trials, but these reports may not fully capture tyrosine kinase inhibitor-specific adverse events in patients with metastatic NSCLC. This study evaluated coverage of tyrosine kinase inhibitor-related symptomatic adverse events by commonly used patient-reported outcomes item libraries. We compiled a list of US Food and Drug Administration-approved tyrosine kinase inhibitors for NSCLC with alterations in EGFR, ALK, ROS1, RET, MET, and NTRK. Symptomatic adverse events were extracted from clinical trials reported in US prescribing information (ie, drug labels). The European Organisation for Research and Treatment of Cancer (EORTC), Patient-Reported Outcomes Measurement Information System (PROMIS), and Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) item libraries were searched for items corresponding to extracted adverse events. Items were classified according to the adverse event's physical, functional, and social or emotional impact. Data from 17 drug labels covering 29 clinical trials of 17 tyrosine kinase inhibitors were analyzed. By tyrosine kinase inhibitor, EORTC covered the highest average percentage of adverse events (99%), followed by PRO-CTCAE (86%) and PROMIS (47%). Of the 15 most common adverse events, 8 were covered by all 3 item libraries. The EORTC and PRO-CTCAE covered 15 adverse events, whereas PROMIS covered 8. Of the 8 adverse events covered by all 3 libraries, PROMIS included the most items assessing functional and social or emotional impact. The EORTC and PRO-CTCAE covered more symptomatic adverse events than PROMIS. For the adverse events it covered, PROMIS had the most items assessing functional and social or emotional impact. Our assessment is a starting point for improving patient-reported outcome coverage of adverse events associated with new treatments such as tyrosine kinase inhibitors.

To examine changes in rheumatoid arthritis (RA) medication prescriptions during the peri-delivery period, and to explore recent RA prescription trends using a Japanese claims database. This retrospective observational cohort study used an insurance claims database provided by JMDC Inc. We identified pregnant women with RA who delivered between April 2018 and October 2023. The outcome was the initiation or resumption of intensive treatment after delivery, defined as new or restarting of biologic disease modifying anti-rheumatic drugs (DMARDs), targeted synthetic DMARDs, oral corticosteroids (OCS), or methotrexate. We identified 229 mothers with RA and 246 deliveries. Intensive treatment was initiated in 55 (22.4%) deliveries. Continuation of the same prescription from before delivery was observed in 106 (43.1%) deliveries. The most frequent new prescription postpartum was methotrexate in 18 (7.3%) deliveries. OCS were the most commonly prescribed medications throughout the observation period. Tumour necrosis factor alpha inhibitors were prescribed at similar rates as OCS before pregnancy and in the first trimester, but declined during the second and third trimesters, and returned postpartum. The number of deliveries that required intensive treatment postpartum was lower than in previous studies. Our results suggest that the latest guidelines for pregnant women with RA help control disease activity.

Rheumatoid arthritis (RA) is a systemic inflammatory disorder and the most common form of inflammatory arthritis.It has a substantial societal impact in terms of cost, disability, and lost productivity.RA signs and symptoms in early disease are driven by inflammation and include joint pain, joint stiffness, and joint swelling.Untreated, the disease can affect many organs throughout the body, but the joints are usually most severely affected.Although there is impressive knowledge on the pathology of RA, the cause of RA remains unknown.Presently, the hypothesis that the combination of a susceptible genetic profile in combination with external factors triggers the onset of the inflammatory disease is widely accepted.The prevalence of RA is estimated around 1%.The course of the disease is variable if untreated.Approximately 15% to 20% of patients have a relatively good prognosis.In other patients, a more progressive disease course is present.In some patients a rapid course of increasing joint damage is seen (1,2) .Several auto-antibodies have been found in RA, especially rheumatoid factor (RF) and anticitrullinated peptide antibodies (ACPA).Although RF is the 'classic' auto-antibody in RA, it can be found also in healthy people and other types of immune mediated diseases.The sensitivity and specificity of RF for RA are up to 70% and 85%, respectively.ACPA is slightly more specific for RA (sensitivity up to about 70% and specificity up to 95%) and thought to play a role in the pathogenesis of the disease (3) .Therapeutic strategies in RA have been changed in the last decades.In the 1970s, it was common to start with Aspirin or non-steroidal anti-inflammatory drugs (NSAIDs).In those days, available disease-modifying anti-rheumatic drugs (DMARDs) were only initiated once radiographic damage had been demonstrated (4) .Especially outside Europe, patients were frequently treated with corticosteroids only.Over the last decades of the last century, conventional DMARDs became available, such as anti-malaria (hydroxychloroquine), sulphasalazine, oral gold, intramuscular gold, azathioprine and methotrexate (MTX).In general, the dose effect relation and the dose toxicity relation were disappointing, resulting in their application being restricted to late in course of the disease.At the turn of the century, treatment strategies changed.DMARD therapy was started earlier in the disease course and sometimes in combination therapy. Some Dutch clinical trials such as the COBRA, DREAM Remission Induction Study andBeSt-study showed that initiation of combination therapy including corticosteroids in an early phase of RA leads to less joint destruction and better outcomes (5)(6)(7) .10 CHAPTER 1 A major breakthrough for the treatment of RA was the development and introduction of inhibitors of Tumor Necrosis Factor (TNFi) early this century (8) .If csDMARDs are unable to control RA disease activity, addition of a TNFi or other biological (b)DMARD should be considered (9) .Also, it has been demonstrated that early effective treatment in RA is associated with prevention, or at least limitation, of joint damage and long term disability.Suggesting a possible therapeutic "window of opportunity," by starting effective DMARD therapy immediately after making the diagnosis (10,11) .A fundamental improvement in RA treatment strategies was the adoption of the remission induction, or treat-to-target of remission, principle.The underlying principle of treat-totarget (T2T) strategies is that in a specific outcome domain, a measurement instrument and measurement target is defined.Well-known examples of T2T are diabetes mellitus and hypertension treatment.Subsequent use of T2T principles in RA confirmed that treating RA to a target of remission, allows patients to reach better outcomes (12)(13)(14)(15) .According to the 2016 update of the EULAR recommendations, monitoring should be frequent in early and active disease and if the target is not met at 3-6 months after the start of treatment, therapy should be adjusted (9) .There have been many studies demonstrating the efficacy of adding TNFi to csDMARDs to achieve disease remission (16)(17)(18) .Whenthe prescription of a TNFi for RA patients results in remission or low disease activity (LDA), however, prescribers and patients generally stay with TNFi indefinitely.This may result in overtreatment, unnecessary side effects, and related costs in some patients (19) .TNFi are known to increase the risk of infections and are related to the occurrence of some types of cancer (20)(21)(22)(23)(24)(25) .Since TNFi's come at a considerable price, reducing or stopping TNFi when the disease course allows to do so, might reduce side effects and costs.However, it is unclear whether patients in remission or stable low disease activity need to continue TNFi indefinitely or can safely and effectively stop this treatment.

Exploration of PRO-CTCAE Data Used for Exposure-Response Relationships in an Oncology Clinical Trial

The aim of this cross-sectional study was to investigate clinical periodontal findings as well as prevalence of selected potentially periodontal pathogenic bacteria in patients with rheumatoid arthritis (RA) treated with different immunosuppressive rheumatic medications. One hundred sixty-eight patients with RA undergoing different immunosuppressive medications were included and divided into subgroups according to their medication, which was taken in the past 6 months, in detail, 1) non-steroidal anti-inflammatory drugs (NSAID) and glucocorticoids combined, and the following different disease modifying anti-rheumatic drugs (DMARDs): 2) methotrexate (MTX), 3) leflunomide, 4) MTX and TNF-α antagonists combined, 5) interleukin-6 (IL-6) antagonist, 6) MTX and rituximab combined, and 7) combination therapies of>2 of these DMARDs. Periodontal examination consisted of papilla bleeding index (PBI), periodontal status with periodontal probing depth (PD), bleeding on probing (BOP), and clinical attachment loss (AL). Periodontitis was classified as none/mild, moderate, or severe. Samples obtained from gingival crevicular fluid were analyzed for presence of 11 periodontal pathogenic bacteria. Patients with MTX+TNF-α antagonists therapy showed higher PBI and BOP values compared with leflunomide (P<0.01) and higher BOP than MTX+rituximab (P=0.02). Porphyromonas gingivalis (P<0.01), Treponema denticola (P<0.01), Fusobacterium nodatum (P=0.02) and Capnocytophaga species (P=0.05) was associated with medication subgroup, whereby post hoc testing confirmed singular differences for several medication subgroups. RA medication is associated with periodontal inflammation, without differences in periodontal disease severity. Thereby, combination of MTX+TNF-α shows an increased potential to periodontal inflammation. Additionally, several differences in prevalence of selected bacteria were detected.

2121 Athletes use a variety of drugs especially for the prevention and treatment of sports related injuries and disorders. A few studies have investigated use of medication in highly-trained athletes. PURPOSE: To investigate use of medication in a national cohort of elite athletes. METHODS: A cross-sectional survey was carried out in 2002. The study group consisted of all the athletes (N = 494) financially supported by National Olympic Committee. Of the athletes 446 (90.3%; mean of age 23.0 SD 4.5 years) filled in a structured questionnaire concerning characteristics of sport activities, sports related injuries, physician diagnosed disorders, use of medication. As a control group was used the data gathered by the National Health Institute in 2001 (N = 1504). RESULTS: Any prescribed medication was used by 75.5% of the athletes and 43.0% of the controls the recent year (p<0.0001). After adjusting for age and sex, ORs (95% CI) for any prescribed medication were 8.8 (5.4–14.5) for speed and power athletes, 8.3 (4.9–14.1) for endurance, 3.1 (1.8–5.1) for motor skills demanding, and 4.6 (3.1–6.9) for team sports athletes as compared with controls. Most frequently used medications are shown in Table 1.Table 1: Use of different medications during the recent year.After adjusting for age and sex, OR (95% CI) for use of NSAIDs was 5.3 (4.2–6.7), use of antibiotics 27.1 (18.0–40.9), and use of anti-asthmatic medications 2.5 (1.7–3.8) in the athletes as compared with controls. CONCLUSION: Athletes use non-steroidal anti-inflammatory drugs, antibiotics, and anti-asthmatic medication significantly more often than representative sample of controls. Of the athlete groups, speed and power and endurance athletes were most frequent drug users. Extremely high use of antibiotics in the athletes compared with controls indicates probably use without firm clinical indications. It should be noted that all these drugs have possible side effects. Immediate and long-term side effects of medicine overuse should be taken into account. Financially supported by Finnish Ministry of Education and Olympic Committee.

Cancer therapeutics frequently lead to symptomatic adverse events (AE) that can affect treatment tolerability. The NCI has developed the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) to assess symptomatic AEs by direct patient self-report. Although longitudinal assessment of patient-reported symptomatic AEs holds promise to better inform treatment tolerability, using patient-reported outcome (PRO) measures to assess symptomatic AEs has raised several regulatory and good clinical practice issues among those who conduct cancer clinical trials. These include concerns regarding trial monitoring, clinical review of PRO results by investigators and delegated clinical staff, whether PRO data on symptomatic AEs require investigational new drug (IND) safety reporting, and how the trial conduct and resultant PRO data will be assessed during clinical investigator site inspections. This article addresses current thinking regarding these issues in cancer clinical trials from the FDA, the NCI, and the Office for Human Research Protections. PRO measures, such as PRO-CTCAE, that assess symptomatic AEs in cancer trials are considered similar to other PRO assessments of symptoms, function, and health-related quality of life and can generate complementary data that may inform tolerability. Clarity on operational concerns related to incorporating PRO measures to inform tolerability is critical to continue the advancement of rigorous PRO assessment in cancer clinical trials. Clin Cancer Res; 24(8); 1780-4. ©2017 AACRSee related commentary by Nipp and Temel, p. 1777.

This study aimed to develop an identification algorithm for validating the International Classification of Diseases-Tenth diagnostic codes for rheumatoid arthritis (RA) in the Korean National Health Insurance (NHI) claims database. An individual copayment beneficiaries program for rare and intractable diseases, including seropositive RA (M05), began in South Korea in July 2009. Patients registered in this system pay only 10 % of their total medical costs, but registration requires an official report from a doctor documenting that the patient fulfills the 1987 ACR criteria. We regarded patients registered in this system as gold standard RA and examined the validity of several algorithms to define RA diagnosis using diagnostic codes and prescription data. We constructed nine algorithms using two highly specific prescriptions (positive predictive value >90 % and specificity >90 %) and one prescription with high sensitivity (>80 %) and accuracy (>75 %). A total of 59,823 RA patients were included in this validation study. Among them, 50,082 (83.7 %) were registered in the individual copayment beneficiaries program and considered true RA. We tested nine algorithms that incorporated two specific regimens [biologics and leflunomide alone, methotrexate plus leflunomide, or more than 3 disease-modifying anti-rheumatic drugs (DMARDs)] and one sensitive drug (any non-steroidal anti-inflammatory drug (NSAID), any DMARD, or any NSAID plus any DMARD). The algorithm that included biologics, more than 3 DMARDs, and any DMARD yielded the highest accuracy (91.4 %). Patients with RA diagnostic codes with prescription of biologics or any DMARD can be considered as accurate cases of RA in Korean NHI claims database.

155 Background: The Pt-Reported Outcomes Version of the Common Terminology Criteria for AE (PRO-CTCAE) was developed for pts to report on the frequency, severity, and interference of SymAE. A study was conducted to identify a hepatocellular carcinoma (HCC)-relevant subset of the PRO-CTCAE's 124 items to enhance evaluation of SymAE in HCC trials and long-term effects in survivorship. Methods: Qualitative and quantitative data were collected from medical oncologists specializing in HCC and pts diagnosed with HCC stratified by Child-Pugh class and treatment. Oncologists were asked about HCC diagnosis, treatment, and SymAE and provided ratings (ranging from 0 = unimportant to 10 = very important) of the following: 1) importance to pts of 34 prevalent SymAE from past HCC trials (all phases); 2) importance to pts of each PRO-CTCAE item; and 3) their own perceived importance of each PRO-CTCAE item with regard to tolerability. Pts were asked about their diagnosis, treatment, and experience of SymAE after which they completed the PRO-CTCAE and were debriefed on the importance of each item. Results: Four medical oncologists from Spain, Taiwan, Korea, and Hong Kong with ≥ 20 years of experience completed interviews. SymAE from prior trials rated highly important to pts (mean rating across oncologists ≥ 7) included hand-foot syndrome, diarrhea, fatigue, decreased appetite, rash, vomiting, and weight loss. PRO-CTCAE items rated highly important to pts included diarrhea, vomiting, shivering or shaking chills, hand-foot syndrome, rash, fatigue, difficulty swallowing, and loss of control of bowel movements. Items rated highly for tolerability included diarrhea, shivering or shaking chills, and hand-foot syndrome. Pt interviews (planned up to 24) are ongoing. Conclusions: Oncologists identified 10 clinically relevant items from sponsor SymAE data and the PRO-CTCAE for use in HCC trials. Findings from pt interviews will compare provider and pt perspectives about SymAE and strengthen the set of selected items. Combining clinician and pt ratings with clinical trial data may be a promising method for identifying cancer-specific PRO-CTCAE item sets for use throughout the cancer care continuum.

Background:Cardiovascular (CV) disease risk is increased in rheumatoid arthritis (RA) and is the leading cause of mortality. Improved CV risk stratification tools in RA could enhance use of preventative care and improve outcomes.Methods:We previously studied biomarkers of CV disease – adiponectin, hsCRP, Lp(a), osteoprotegerin (OPG), high-sensitivity cardiac troponin T (hsTnT), serum amyloid A (SAA), YKL-40, soluble TNF receptor1 (sTNFR1) -- that were associated with CV risk. In the current study, these biomarkers were tested in an unrelated external cohort of RA patients followed at a single academic medical center without a history of CV events. CV events were identified through Medicare and Medicaid administrative data or through medical record review of self-reported events.Biomarkers were assessed at cohort entry among a nested cohort of cases and controls, matched 1:1 on sex and age. Analyses were conducted using conditional logistic regression. We examined whether the candidate biomarkers added to clinical CV risk factors improved model prediction, using the area under the curve (AUC) as well as the net reclassification index (NRI).Results:From a cohort of 1,345 eligible patients with RA, we identified 123 patients with confirmed CV events. Cases and matched controls were typical of RA: median age 63 years, 77% women, RA disease duration 11 years, 72% seropositive, 85% used a biologic or conventional disease modifying anti-rheumatic drug, 58% non-steroidal anti-inflammatory drugs, and 30% oral glucocorticoids. From the candidate biomarkers, LASSO regression selected hsTnT and sTNFR1 as associated with CV events. The AUC for models that included only clinical risk factors was 0.758 (95% CI 0.689–0.829); after adding hsTnT and sTNFR1, the AUC increased to 0.802 (95% CI 0.718–0.998). The NRI of the model with biomarkers was 16.3%, with improvement only observed in patients who did not have CV events during follow-up.Conclusions:Adding selected biomarkers to clinical risk factors enhances the discrimination of models predicting CV events among patients with RA. These risk models require prospective testing to see if they have value in clinical practice decision-making regarding preventative care.

This review examines evidence on the prevalence of non-adherence to medication in adults with rheumatoid arthritis, the reasons for non-adherence, and the effectiveness of interventions to improve adherence. Medications for rheumatoid arthritis (NSAIDs, corticosteroids, disease-modifiers, and biologic agents) are not curative, but can reduce symptoms and slow progression of the disease. Evidence consistently suggests that adherence to medications for rheumatoid arthritis is low in adults, and is often <50%. These drugs can be associated with serious adverse effects. Evidence suggests that non-adherence in rheumatoid arthritis cannot be explained by gender or age. Other patient characteristics, such as educational level and socioeconomic status, may create literacy and financial barriers to adherence. The strongest associations are reported between adherence and views about rheumatoid arthritis as a disease; beliefs that disease-modifying antirheumatic drugs do not work and have too many adverse effects; unrealistic or uninformed patient expectations of risk; lack of self-efficacy; lack of social support; cost of prescription medications, and poor patient-provider relationships. There have been few interventions designed specifically to improve medication adherence in patients with rheumatoid arthritis. Most interventions have been based on patient education and the teaching of self-management techniques. Educational interventions have had limited effectiveness in changing behavior because of the limited ability of changes in knowledge to produce lasting behavioral change. The effect of group therapy and cognitive-behavioral therapy on medicine adherence is not clear. Those interventions that are effective tend to emphasize developing a daily routine of self-management activities, coping strategies, self-efficacy, and problem-solving. Future work is required to develop evidence-based, pragmatic, patient-centered interventions to improve medication adherence in patients with rheumatoid arthritis. Practitioners require support and training in the communication of risk and incorporation of patients’ beliefs into the consultation process. Policy makers need to reduce barriers to access, such as the costs of drugs.

AB0242 Delay in dmard initiation in patients newly diagnosed with rheumatoid arthritis: an analysis of united states military health system beneficiaries

To examine concordance in symptomatic adverse event (AE) grading using the Common Terminology Criteria for Adverse Events (CTCAE 4.0) for clinicians and its patient-reported outcome (PRO) versions for children (Ped-PRO-CTCAE) and caregivers (Ped-PRO-CTCAE [Caregiver]). Children age 7-18 years with a first cancer diagnosis, their clinicians, and caregivers completed CTCAE-based measures before starting a treatment course (T1) and after the treatment (T2). Grades (0-3) were assigned by each reporter for 15 core AEs spanning physical and mental health. Mean grades were compared between reporters using two-sample t-tests; agreement was estimated using weighted kappa (κ) statistics. Multivariable mixed regression models were used to evaluate associations of clinical factors with AE reporting concordance. Significance was set at α = .05 (two-sided). There were 438 child-clinician-caregiver triads with complete data at either T1 or T2. For children, the mean age was 13 years (standard deviation = 3.4), 53.7% were male, 32.6% non-White, and 56.4% had leukemia/lymphoma. At T1, clinician mean AE grades were significantly lower (ie, better) than children for all AEs and remained significantly lower at T2 except for constipation, nausea, anorexia, neuropathy, and anxiety. Caregiver mean AE grades were similar to children at T1 and significantly higher (ie, worse) at T2 for nausea, vomiting, anorexia, pain, fatigue, anxiety, and depression. Agreement for child-clinician grading was poor-to-fair at T1 (κ range, 0.08-0.34) and T2 (0.11-0.35), and for child-caregiver, was fair-to-good at T1 (0.34-0.65) and T2 (0.24-0.60). No factors were consistently associated with reporter concordance across AEs. Compared with children, symptomatic AEs were consistently under-reported by clinicians with low agreement and over-reported by caregivers with low-moderate agreement. Direct reporting by children using Ped-PRO-CTCAE or similar measures should be routinely incorporated for toxicity assessment in clinical trials.

Systematic review and meta-analysis of cardiovascular risk in rheumatological disease: Symptomatic and non-symptomatic events in rheumatoid arthritis and systemic lupus erythematosus