Rheumatology and Therapy最新文献

Introduction: Interim analysis of the long-term safety and effectiveness of canakinumab, at a patient level, in the mevalonate kinase deficiency/hyperimmunoglobulin-D syndrome (MKD/HIDS) cohort of the RELIANCE registry.

Methods: From June 2018, the RELIANCE registry enrolled paediatric (aged ≥ 2 years) and adult patients (aged ≥ 18 years) with MKD/HIDS who were receiving canakinumab as part of their routine medical care. Safety, physician- and patient-reported measures of disease activity and dosing patterns were evaluated at baseline and every 6 months until end-of-study visit.

Results: At the analysis cut-off date of December 2022, eight patients with MKD/HIDS were enrolled. Five (62.5%) were children (< 18 years) and five (62.5%) were female. The median patient age was 8.0 (range 2.0-39.0) years, and all patients were pre-treated with canakinumab prior to enrolment (median duration of canakinumab treatment: 3.8 years). Canakinumab was well tolerated, with seven (87.5%) patients reporting 48 adverse events (incidence rate/100 patient years: 218.1). No serious adverse drug reactions were reported. Patients continued to receive vaccinations during long-term treatment with canakinumab. Disease activity, evaluated by physician-reported (physician's global assessment, disease remission, C-reactive protein, serum amyloid A, erythrocyte sedimentation rate) and patient-reported (autoinflammatory disease activity index diary, disease activity, fatigue, impact on social life) measures, was generally well controlled throughout the study. Over 50.0% of patients maintained disease remission from baseline to month 24, and medians of all inflammatory markers remained within normal limits throughout the study. Most patients received higher than the recommended starting dose of canakinumab throughout the study.

Conclusion: Data from this interim analysis of a unique registry of patients with a rare disease support the long-term safety and effectiveness of the IL-1-blocking agent canakinumab for the treatment of MKD/HIDS.

Introduction: 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).

Methods: 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.

Results: 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.

Conclusions: 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.

Objective: Gout is a progressive form of arthritis that causes significant pain and disability. Patients with treatment-refractory (or uncontrolled) gout experience a higher prevalence and severity of comorbidities than those whose gout is controlled. Pegloticase is a recombinant PEGylated uricase indicated for the treatment of gout in patients refractory to conventional therapy. We evaluated the treatment journey of patients with chronic uncontrolled gout before initiation of pegloticase therapy.

Methods: Using IQVIA's PharMetrics^® Plus database, we conducted a retrospective observational analysis of adults with ≥ 1 pegloticase claim between April 1, 2011, and August 31, 2020. Demographics were assessed at baseline. Clinical outcomes, health care resource utilization (HCRU), and associated costs were compared over two 12-month periods (months 13-24 and 1-12) prior to the first pegloticase claim (index date).

Results: The study included 408 patients. Prevalence of all gout-associated conditions increased between months 1-12 and 13-24 (P < 0.05 for all). The percentage of patients with tophi increased from 15.4% to 61.5%, the percentage with ≥ 1 flare increased from 49% to 84%, and mean number of flares per patient increased from 1.0 to 2.1 (P < 0.0001 for all). The frequency of all categories of HCRU except emergency department visits also increased (P < 0.0001 for all), as did gout-related healthcare utilization (P£0.005).

Conclusions: Patients with uncontrolled gout experienced an increase in the clinical burden of disease and HCRU in the 2 years before the initiation of pegloticase. Earlier patient identification and initiation of potentially effective therapy may help alleviate these burdens.

Introduction: Inflammatory bowel disease (IBD) related arthritis is the most prevalent extraintestinal manifestation (EIM) of IBD, ranging between 10 and 39%. Magnetic resonance enterography (MRE) is used to assess small bowel disease involvement in Crohn's disease (CD) and can detect signs of sacroiliitis in up to 23.5% of patients. The predicting role of sacroiliitis detected on MRE is still unknown. The aim of this study is to evaluate the predictive role of sacroiliitis at MRE and other clinical features for IBD-related arthritis development in a cohort of adult patients with CD.

Methods: Between December 2012 and May 2020, consecutive patients with CD who performed MRE were enrolled in the study. Patients with a previous diagnosis of IBD-related arthritis were excluded. A baseline demographics and clinical characteristics of the patients were retrospectively collected. The identification of new-onset IBD-related arthritis events during the follow-up was based on rheumatological clinical diagnosis and fulfillment of the ASAS classification criteria.

Results: Ninety-five patients, mean age 43.9 years (standard deviation [SD] ± 16.6), 52.6% female were enrolled in the study with a median follow-up of 83 months (Q25:75 25:143). Six out 95 (6.3%) developed IBD-related arthritis with a mean time of 11 months (SD ± 16.8). Sacroiliitis detected on MRE was not associated with an increased risk of IBD-related arthritis (odds ratio [OR] = 2.12 [95% confidence interval (CI) 0.36, 12.53, p = 0.408]). In contrast, the presence of arthralgia and EIMs were found to be a predictor for IBD-related arthritis development (OR = 84.0 [95% CI 8.18, 862.39, p < 0.0001] and OR = 7.37 [95% CI 1.25, 43.32, p = 0.027], respectively).

Conclusions: This study highlights that sacroiliitis, as assessed by MRE, was not associated with the development of IBD-related arthritis, whereas extraintestinal manifestations and arthralgia were significantly associated with later IBD-related arthritis development in patients with CD.

Introduction: We aim to assess the association of patient-reported pain and remission or low disease activity (LDA) at 3 months (M) in patients receiving baricitinib or other treatments in RA-BE-REAL.

Methods: RA-BE-REAL reports on patients with rheumatoid arthritis (RA) who were prescribed, for the first time, baricitinib (cohort A) or a tumour necrosis factor inhibitor (TNFi) (cohort B-TNFi) or any other mode of action (OMA) (cohort B-OMA). Pain was measured using the visual analogue scale (VAS) (0-100 mm) and clinically meaningful pain improvement thresholds of ≥ 30%, ≥ 50% and ≥ 70% from baseline to 3, 6, 12 and 24 M.

Results: At 3 M, the mean change from baseline (CFB) pain VAS of patients in remission/LDA was - 32.6 mm (cohort A), - 27.3 mm (cohort B-TNFi) and - 28.0 mm (cohort B-OMA). Almost half the patients who were in remission/LDA receiving baricitinib achieved ≥ 70% pain relief. At 3 M, the proportion of patients in remission/LDA with pain VAS ≤ 20 mm was 62.1% (cohort A), 55.0% (cohort B-TNFi) and 55.6% (cohort B-OMA), while for those not in remission/LDA, it was 8.5% and 8.7% (cohort A and B-TNFi, respectively) and 5.3% (B-OMA). More patients on baricitinib achieved pain improvement in all analyzed thresholds than patients in cohort B-TNFi and B-OMA at 3 M. At 24 M, - 26.2 mm (cohort A), - 20.8 mm (cohort B-TNFi) and - 16.0 mm (cohort B-OMA) mean CFBs in pain measurement were observed. For baricitinib and the other treatments, residual pain decreased with achievement of remission/LDA and was sustained up to 24 M.

Conclusions: Patients in remission/LDA receiving baricitinib are more likely to achieve pain control than patients receiving TNFi/OMA.

Introduction: While modern treatments can prevent progressive bone destruction in patients with rheumatoid arthritis (RA) achieving clinical remission, it is unclear whether residual clinical activity may cause or be associated with progressive joint damage. This post hoc analysis evaluated the association between clinical disease activity and structural progression in patients with RA treated with filgotinib (FIL) in FINCH 1 (NCT02889796).

Methods: Patients with RA and inadequate response to methotrexate (MTX) use were randomized 3:3:2:3 to FIL 200 mg (FIL200) or FIL 100 mg (FIL100) once daily, adalimumab 40 mg biweekly, or placebo, all with background MTX. We evaluated the change from baseline (CFB) in modified total Sharp score (mTSS), erosion score, and joint space narrowing score among patients achieving Clinical Disease Activity Index (CDAI) remission (CDAI ≤ 2.8), low disease activity (LDA; 2.8 < CDAI ≤ 10), medium disease activity (MDA; 10 < CDAI ≤ 22), and high disease activity (HDA; CDAI > 22) at 24 weeks.

Results: At week 24, the least squares (LS) mean CFB in mTSS was similarly low across treatments among patients who achieved CDAI remission (range 0.00-0.11) or LDA (n = 285 and 575, respectively). In patients with MDA and HDA (n = 471 and 157, respectively), smaller LS mean CFB in mTSS was seen in the FIL200 group vs. the placebo group (P < 0.05 for both).

Conclusions: RA clinical remission and LDA achievement were associated with suppressed progression of joint destruction over 24 weeks in all treatment groups. Only FIL200 significantly inhibited joint damage compared with placebo in patients with MDA or HDA, indicating an uncoupling of clinical disease activity and structural progression in patients receiving FIL200.

Trial registration: NCT02889796.

The transition from a comorbidity-based to a multimorbidity-focused to ultimately a network medicine approach in people with rheumatic diseases might mark a significant shift in how we understand and manage these complex conditions. Multimorbidity expands on the concept of comorbidity by encompassing the presence of multiple diseases, which results in further individual and societal impacts. This approach, while valuable, often leads to fragmented care focused on individual diseases rather than the patient as a whole.Network medicine, on the other hand, offers a more integrated perspective. It is an emerging concept that leverages the understanding of biologic networks and their interactions within the human body to gain insights into disease mechanisms. In the context of rheumatic diseases, network medicine involves examining how different diseases interconnect and influence each other through shared pathways, genetic factors, and molecular mechanisms.This paradigm shift allows for a more holistic understanding in how we manage rheumatic diseases. For instance, rheumatic diseases such as rheumatoid arthritis and systemic lupus erythematosus are not just a collection of symptoms affecting various organs but are also interconnected through underlying systemic inflammatory processes, immune system dysregulation, and genetic predispositions.

Current literature regarding cancer risk in rheumatic and musculoskeletal diseases (RMDs) is particularly poor and controversial, even though the incidence of malignancy in some patients with RMDs is considered to be increased compared with the general population. Malignancy may be a major comorbidity in subjects with spondyloarthritis (SpA) as the result of multifactorial mechanisms, from disease pathogenesis to the iatrogenic effect of immunomodulating drugs. Several recommendations for screening and management of cancer risk have been developed in recent years with the aim of improving the different outcomes in these patients. The goal of this narrative review is to provide an overview of the currently available evidence on the risk of malignancy connected with RMDs and examine the association of SpA with cancer and the potential impact of its treatment with biologic and targeted synthetic disease-modifying anti-rheumatic drugs on development of malignancy.

Introduction: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Clinical trial registration number: NCT02951026.

Introduction: 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.

Methods: 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.

Results: 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.

Conclusion: 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.