Discrete Event Dynamic Systems: Theory and Applications

Postmenopausal osteoporosis (PMO) increases the risk of fragility fractures (FF), leading to disability, higher mortality, and elevated healthcare costs. Despite available treatments, osteoporosis (OP) remains undertreated, especially in women over 50 years at high risk for FF. Real-world data on OP care in Spain are limited. This study aims to assess the OP treatment gap, healthcare resource utilisation (HCRU), and costs among Spanish women following a first FF or PMO diagnosis. This retrospective study used data from the BIG-PAC® administrative database on women aged ≥ 50 years with a first FF (cohort 1) or newly diagnosed PMO (cohort 2) between 2014 and 2018. Patients were followed for 2 years after the index event. The primary outcome was the proportion of women not prescribed OP medication within 6 months after the index event (treatment gap). Secondary outcomes included fracture incidence, mortality, HCRU, and costs. The study included 22,142 women: 3190 in cohort 1 and 18,952 in cohort 2. The OP treatment gap was higher in cohort 1 vs cohort 2 (41.5% vs 23.6%). In cohort 1, 59.2% were diagnosed with PMO after the first FF, with 88% experiencing subsequent fracture(s). OP treatment persistence decreased over time in both cohorts. Fracture rates were lower in women prescribed OP treatment vs those who were not (8.35 vs 13.8 per 1000 patient-years) and in those who showed 24-month-persistence and 12-month adherence to treatment vs those who did not (8.98 and 7.66 vs 10.79 and 10.76). The 2-year mean cost per patient was higher in cohort 1 (€10,601) than in cohort 2 (€1659), with the highest costs incurred for hip (€15,833) and vertebral (€10,593) fractures. This study highlights a significant treatment gap in Spanish women aged ≥ 50 with a first FF or newly diagnosed PMO. Costs are particularly high for those with a first FF, especially for hip or vertebral fractures. Improving treatment adherence could reduce fracture risk, healthcare costs, and resource utilisation.

It is important to understand the differences in patient–physician perceptions and factors affecting satisfaction with treatment in patients with systemic sclerosis (SSc). This web-based survey (conducted in Japan in March 2023) targeted patients aged ≥ 18 years with SSc and physicians in hospitals with ≥ 20 beds and seeing ≥ 3 patients with SSc monthly. Physicians and patients answered similar questions. Responders were 301 patients (63.8% female; 47.5% limited cutaneous SSc; 44.9% diffuse cutaneous SSc) and 129 physicians (51.2% rheumatologists; 20.9% dermatologists). The most common problematic symptoms reported by patients having each symptom were Raynaud’s phenomenon (RP) (59.5%), skin tightening (47.4%), and malaise (45.5%). Physicians also perceived RP as the common problematic symptoms (46.5%). Conversely, there was a large gap in the perception of malaise as problematic (5.4%). There was a ≥ 20% difference in the percentage of respondents who felt that treatments improved symptoms of reflux esophagitis (48.8% in patients vs. 76.7% in physicians), dysphagia (25.0% vs. 52.7%), constipation (35.1% vs. 62.8%), diarrhea (36.1% vs. 62.8%), and pain (47.6% vs. 69.0%). Patient characteristics associated with high satisfaction with treatment included treatment responsiveness, age ≥ 50 years, being anti-topoisomerase I antibody positive, having dermatological or digestive symptoms as problematic symptoms, and not feeling they should have seen their physician earlier. Patients and physicians had different perceptions of symptoms and treatment response. Patients’ perception of improvement affected their satisfaction with treatment. Reviewing treatment goals and content between patients and physicians is necessary to improve treatment satisfaction. UMIN000050368.

Ozoralizumab (OZR) is a novel tumor necrosis factor (TNF) inhibitor that was launched in Japan for treating patients with rheumatoid arthritis (RA) who have had an inadequate response to existing therapies. This post-hoc analysis aimed to compare the efficacy of OZR administered without methotrexate (MTX) with placebo or OZR administration in combination with MTX. We analyzed the OZR group (30 mg) in the NATSUZORA trial (non-MTX, open trial) (OZR group; n = 94) and the placebo group (MTX group; n = 75) and the 30-mg OZR group (OZR + MTX group; n = 152) in the OHZORA trial (combined MTX, double-blind trial), and the covariates were adjusted by propensity score matching. Subsequently, the American College of Rheumatology (ACR) 20/50/70 response rates from baseline to 24 or 52 weeks were compared. Furthermore, to compare longitudinal data on disease activity indicators, a mixed-effects model for repeated-measures analyses was used. Comparing the OZR and MTX groups, 52 patients were matched in each group. The OZR group showed improvements in the ACR20 (OZR group, 67.3% vs. MTX group, 34.6%, p = 0.001), ACR50 (51.9% vs. 17.3%, p < 0.001), and ACR70 (26.9% vs. 11.5%, p = 0.047) response rates compared to those in the MTX group. Comparing the OZR and OZR + MTX groups, 77 patients were matched in each group. No significant difference was observed in the ACR20 response rate (OZR group, 58.4% vs. OZR + MTX group, 70.1%, p = 0.130). However, the OZR + MTX group showed higher ACR50 (44.2% vs. 62.3%, p = 0.024) and ACR70 (29.9% vs. 45.5%, p = 0.046) response rates. OZR administration without MTX was associated with an improvement in the signs and symptoms of RA compared to placebo administration (continuation of MTX monotherapy). OZR and MTX administration showed better efficacy than OZR administration alone.

Prescribable digital health applications (DiGAs) present scalable solutions to improve patient self-management in rheumatology, however real-world evidence is scarce. Therefore, we aimed to assess the effectiveness, usage, and usability of DiGAs prescribed by rheumatologists, as well as patient satisfaction. The DiGAReal registry includes adult patients with rheumatic conditions who received a DiGA prescription. Data at baseline (T0) and the 3-month follow-up (T1) were collected through electronic questionnaires. Study outcomes included DiGA-specific outcome assessments as well as generic outcome assessments, including the Patient Global Impression of Change (PGIC), Patient Activation Measure (PAM®), and the German Telehealth Usability and Utility Short Questionnaire (TUUSQ). Changes between T0 and T1 were analyzed using descriptive statistics and paired tests. A total of 191 patients were included between June 2022 and April 2023. Of these, 127 completed the 3-month follow-up, and 114 reported using the prescribed DiGA, with 66% reporting weekly use and 15% completing the full DiGA program. The most commonly prescribed DiGAs targeted pain management (53%). Symptom improvement was reported by 51% of patients using a DiGA, with significant reductions in exhaustion levels (p = 0.03). Significant DiGA-specific improvements were observed for DiGAs addressing back pain (p = 0.05) and insomnia (p = 0.006). However, no overall significant changes were detected in patient activation, health literacy, pain, overall health, or disease activity. Back pain and weight management DiGAs were the most effective, frequently used, and best-rated DiGAs, with symptom improvements reported by 50% to 82% of patients. The findings suggest that DiGAs can improve symptom management in rheumatic patients, especially for conditions like back pain and weight control. Further real-world evidence is needed and may support value-based digital health efforts and reimbursement frameworks.

Celiac disease (CD) affects the small intestine, leading to a progressive disappearance of intestinal villi, and can be found in association with several other autoimmune and inflammatory conditions. The main objective of this study was to determine the prevalence and the clinical significance of anti-transglutaminase and anti-endomysium antibodies in patients diagnosed with early rheumatoid arthritis (RA) and spondyloarthritis (SpA). We measured anti-transglutaminase and anti-endomysium antibodies in biobanked serum samples at inclusion in two French prospective multicenter cohorts of patients with suspected early rheumatoid arthritis (ESPOIR, n = 713) and spondyloarthritis (DESIR, n = 709). Results were compared with the clinical, laboratory, and radiographic findings obtained in patients during a 10-year follow-up period. In the DESIR cohort, anti-transglutaminase antibodies were evidenced at low levels (less than three times the upper limit of normal) in 2/709 (0.42%) patients and anti-endomysium antibodies in 0/709 (0%). In the ESPOIR cohort, anti-transglutaminase antibodies were evidenced in 6/713 (0.84%) patients and anti-endomysium antibodies in 1/713 (0.14%). Only the latter patient was confirmed to have celiac disease. Interestingly, this patient was ultimately diagnosed with Sjögren’s disease, an autoimmune condition known to be associated with an increased risk of celiac disease. The very low identified prevalence of anti-transglutaminase and anti-endomysium antibodies suggests a negligible risk of celiac disease in patients with early-stage RA or SpA, which are among the most common inflammatory rheumatic conditions. Consequently, routine screening for celiac disease via these antibodies in patients presenting with early inflammatory rheumatic conditions should not be performed except in case of clinical suspicion of celiac disease.

Axial spondyloarthritis (axSpA) is a chronic inflammatory condition associated with considerable pain and impaired health-related quality of life (HRQoL) for affected patients. Despite the documented increase in healthcare resource utilization (HRU) related to axSpA, few studies have explored the impact of diagnostic delays on these outcomes. This study sought to determine the association between diagnostic delay of axial spondyloarthritis (axSpA) and costs in the 3 years after diagnosis. This is a retrospective, observational study based on routine follow-up data from adult patients with confirmed axSpA diagnosis in three tertiary Spanish hospitals. Sociodemographic and clinical variables were collected at diagnosis. Direct and indirect healthcare costs were estimated from healthcare resource use (HRU) and productivity losses. The correlation between diagnostic delay and total healthcare costs was analyzed. Eighty-two patients (62.2% men; mean age: 39.3 years at diagnosis) were included, mostly with radiographic axSpA (r-axSpA) (67.1%). The mean (standard deviation, SD) diagnostic delay was 10.1 (9.3) years, with a median (interquartile range, IQR) of 5.4 (2.3, 17.2) years. The mean total healthcare cost per patient accumulated over 3 years was €25,812.6 (direct: €16,384.7; indirect: €9427.9). Patients with longer diagnostic delay (> 5.4 years) had 57% higher total healthcare cost (€31,717.7 vs. €20,188.7, p = 0.029) and higher disease activity at diagnosis (BASDAI score 4.7 vs. 3.4, p = 0.007) and after 3 years (3.9 vs. 2.9, p = 0.042) compared to those with shorter delay (≤ 5.4 years). The diagnostic delay in axSpA remains high and is associated with an increase in healthcare costs post-diagnosis. Actions to reduce diagnostic delay should be prioritized by healthcare systems to potentially improve outcomes and reduce long-term costs.

This study evaluated the prevalence and incidence of systemic lupus erythematosus (SLE) in Germany and explored real-world data on sequence of therapy (SOT; sequence of drugs as prescribed in clinical practice). This retrospective, observational, longitudinal cohort study using German claims data from the WIG2 GmbH Scientific Institute for Health Economics and Health System Research database (January 2011–December 2019), extrapolated to the statutory health insurance (SHI)-insured population, evaluated prevalence and incidence in an epidemiological analysis group and SLE treatment patterns in an incident cohort (subgroup ≥ 18 years of age with incident disease and ≥ 24-month follow-up post index date). Analyses were descriptive. Based on the epidemiological analysis (N = 3017), annual SLE prevalence per 100,000 gradually increased from 40.47 in 2012 to 59.87 in 2019 in the SHI population. In contrast, annual SLE incidence was relatively stable, ranging from 8.83 in 2012 to 8.86 in 2019. In the incident cohort (n = 941), based on SOT analysis (n = 681), treatment gaps of > 60 days were common: 67.1%, 51.2% and 54.9% in SOT1, SOT2 and SOT3, respectively. Corticosteroids were the most frequent monotherapy in SOT1 (31.0% vs 0% in SOT2/SOT3); 30.0–70.0% of patients received a corticosteroid combination therapy across SOTs. Over 50% of patients in each SOT received an antimalarial therapy (combination or monotherapies). The use of biologic disease-modifying drugs was low, ranging from 0.4% in SOT1 to 9.7% in SOT3. Our data demonstrate an increased prevalence of SLE with stable incidence in Germany, suggesting improved survival of affected patients. Nevertheless, suboptimal treatment patterns, including limited use of biologics, reflect a high unmet need for optimised and personalised therapies in patients with SLE.

This study sought to describe treatment patterns, persistence, and effectiveness of upadacitinib (UPA) alone and compared to other Janus kinase inhibitors (JAKis) or tumor necrosis factor inhibitors (TNFis) in patients with rheumatoid arthritis (RA). This retrospective, non-interventional study used the OPAL dataset, derived from electronic medical records. Patients initiated UPA (N = 2624), other JAKis (baricitinib and tofacitinib [N = 925]), or TNFis (adalimumab, etanercept, certolizumab, golimumab, infliximab [N = 3540]) between May 2020 and March 2023. Median persistence (Kaplan–Meier) and effectiveness (Disease Activity Score 28-joint C-reactive protein, three variables [DAS28CRP{3}]) were evaluated for UPA-treated patients and in three propensity score-matched cohorts: UPA monotherapy versus combination therapy, UPA versus other JAKis, and UPA versus TNFis. In patients prescribed UPA, 41.3% were ≥ 65 years old, 33.8% were prescribed as first-line advanced therapy, and 27.2% were prescribed monotherapy. Persistence on UPA was 26.6 months (95% confidence intervals: 24.4, 29.9) and longest in earlier lines of therapy. The DAS28CRP(3) remission rate was 73% at 3 months, with improvements observed across lines of therapy. UPA monotherapy and combination therapy had similar persistence (27.8 [23.5, 33.4] versus 30.4 months [22.1, 35.3], p = 0.84) and effectiveness. UPA showed longer persistence than other JAKis (28.8 [25.6, 32.4] versus 17.2 months [14.9, 19.8], p < 0.001) and TNFis (26.6 [24.9, 30.8] versus 13.3 months [11.5, 14.5], p < 0.001). DAS28CRP(3) remission rates were greater at 3 months for UPA than other JAKis (75.0% versus 61.5%) and TNFis (72.7% versus 59.5%). In unmatched subgroups, compared to cycling between TNFis, switching to UPA from other JAKis or TNFis resulted in longer persistence (JAKi-to-UPA: 25.3 [16.1, not reached]; TNFi-to-UPA: 27.8 [23.2, 35.4]; TNFi-to-TNFi: 9.6 [8.4, 10.7]) and greater DAS28CRP(3) remission rates over 9 months. Overall, the breadth and depth of data from this large real-world dataset continue to support a favorable clinical profile of UPA for the treatment of RA and may inform treatment choices in everyday clinical practice. This study of patients treated in clinical practice looked at how a targeted medication, a Janus kinase inhibitor (JAKi) called upadacitinib, was used to treat rheumatoid arthritis, a disease that causes joint pain and damage. The researchers wanted to see how long patients continued treatment with upadacitinib, how effective it was at reducing symptoms, and how these outcomes compared to other JAKis (baricitinib and tofacitinib) and tumor necrosis factor inhibitors, a different type of advanced medication. Patients continued upadacitinib treatment for a median time of over 2 years. Those patients who had never previously used JAKis or tumor necrosis factor inhibitors continued upadacitinib treatment longer than those patients with previous experience. Patients treated with upadacitinib alone or in combination with less advanced medications like methotrexate continued treatment for a similar length of time. Compared to other JAKis and tumor necrosis factor inhibitors, patients prescribed upadacitinib stayed on their treatment the longest. Upadacitinib helped to lessen the symptoms of rheumatoid arthritis, whether patients took it alone or in combination with medications like methotrexate. After 3 months, more patients treated with upadacitinib experienced reduced symptoms than patients treated with other JAKis or tumor necrosis factor inhibitors. Additionally, patients who switched to upadacitinib after using other JAKis or tumor necrosis factor inhibitors reduced their symptoms and continued treatment for longer than those switching between tumor necrosis factor inhibitors. Overall, patients treated with upadacitinib continued treatment for longer and saw greater improvements in the symptoms of rheumatoid arthritis than patients prescribed other advanced medications.

Lorecivivint (LOR), a CDC-like kinase/dual-specificity tyrosine kinase (CLK/DYRK) inhibitor thought to modulate inflammatory and Wnt pathways, is being developed as a potential intra-articular knee osteoarthritis (OA) treatment. The objective of this trial was to evaluate long-term safety of LOR within an observational extension of two phase 2 trials. This 60-month, observational extension study (NCT02951026) of a 12-month phase 2a trial (NCT02536833) and 6-month phase 2b trial (NCT03122860) was administratively closed after 36 months as data inferences became limited. Participants received a single intra-articular LOR or placebo (PBO) injection at their parent-trial baseline. The primary outcome was the comparative incidence of serious adverse events (SAEs), with AEs and similar safety measures comprising secondary outcomes. A post hoc baseline-adjusted analysis of covariance (ANCOVA) compared changes from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain and Function subscores and medial joint space width (JSW) between LOR 0.07 mg and PBO groups in a subpopulation of participants with unilateral knee pain and widespread pain low enough to allow participants to differentiate their target knee pain. The safety analysis set for the extension study included 495 LOR-treated and 208 control participants, with 409 (82.6%) and 175 (84.1%) remaining at study close, respectively. There were 68 SAEs reported in 38 (5.4%) patients; none were considered treatment-related by investigators. The incidence of AEs was similar between groups. In the post hoc subgroup efficacy analyses, LOR 0.07 mg demonstrated greater mean improvements from baseline compared with PBO in WOMAC pain and function scores out to 12 months post-injection. No between-group differences in medial JSW were observed out to 18 months. LOR appeared generally safe and well tolerated. Efficacy analyses on the subset of completer patients demonstrated durable symptom improvements in WOMAC pain and function for at least 12 months compared to PBO after a single injection of LOR. NCT02951026. Knee osteoarthritis (OA) is the most common degenerative joint disease and significantly impairs patients’ function and quality of life. Lorecivivint (LOR) is a drug candidate undergoing clinical trials as an injectable treatment for knee OA. It inhibits molecules in joint cells (called CLKs and DYRKs) that regulate inflammatory (affecting pain) and Wnt (affecting cartilage and bone turnover) pathways; abnormalities of both contribute to OA. We report data from patients with knee OA who completed two randomized, placebo (PBO)-controlled trials and who chose to continue to be observed for up to 3 years. They did not receive any new LOR injections but continued to get regular exams and annual X-rays by their clinicians and to report any (new / ongoing) health problems. An analysis was performed matching patients with similar clinical features (especially regarding their knee pain) from both trials, to see if a 0.07 mg dose of LOR was safe and if it affected knee pain and function. LOR appeared to be well tolerated, with few side effects that were similar in number to those receiving the placebo. More patients in the LOR-treated group reported feeling less knee pain and improved function than those in the PBO group; however, because knee x-rays of patients in both LOR and PBO groups showed no worsening of their OA over this time period, the evidence remained inconclusive. The profound need for safe, disease-modifying OA treatments and the encouraging results from this study support the continued development of LOR as a treatment for knee osteoarthritis.