csDMARD Therapy Research Articles

PREDICTORS OF RHEUMATOID ARTHRITIS FLARE AFTER GLUCOCORTICOIDS WITHDRAWAL WHILE RECEIVING CONVENTIONAL SYNTHETIC DISEASE-MODIFYING ANTIRHEUMATIC DRUGS

Summary: Predictors of rheumatoid arthritis (RA) flare after glucocorticoid (GC) withdrawal while receiving conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). The aim of this study is to investigate predictors of RA flare following GC withdrawal despite the continuation of csDMARDs in the Ukrainian cohort of patients with different disease durations. Materials and methods: One hundred twenty-six patients with early (56.3%) and advanced (43.7%) RA who newly started GC as bridging therapy with concomitant csDMARDs were included in the study. Most were female – 107 (84.9%), seropositive (RF: 60.3%; ACCP: 60.9%), with a mean age of 51.0±11.4 and disease duration of 42.1±57.6 months. Results: During the 3-year study, 89 patients managed to quit GC without further disease aggravation over a period of 3 to 30 months. Exacerbation of RA was observed in 29.4% of patients. Patients with RA flare had 1.7 times longer duration of GC exposure (ꭓ 2 =4.17, p < 0.05), a shorter duration of remission (ꭓ 2 =10.9, р < 0,01), higher disease activity after 12 months of therapy (р < 0,01), a cumulative GC dose (p < 0.001) and a higher proportion of dissatisfied control of RA (ꭓ2=45,5, р < 0,001) compared to the alternative group. In multivariate and ROC analysis, a higher cumulative GC dose (OR 17.4[2.62-116.4]; regression criterion >1.37), RA activity after 12 months (OR 4.06 [1.36-12.0]; regression criterion > 4.37) and dissatisfied control of RA activity were independently associated with the risk of RA flare after GC discontinuation. Conclusions: The flare following GC withdrawal is observed in one-third of patients with RA undergoing csDMARD therapy. Indicators of dynamic monitoring, rather than baseline data, affect the risk of RA exacerbation. Independent predictors of increased RA activity after GC withdrawal are a higher cumulative GC dose, dissatisfied control of RA activity and a higher DAS28 (ESR) after 12 months of treatment.

Increased risk of malignancy in HLA-B27-positive patients with ankylosing spondylitis requiring biologics for sustained inflammation: A long-term, single-center retrospective study.

To assess the link between the administration of biologic disease-modifying antirheumatic drugs (bDMARDs) and the risk of malignancy in human leukocyte antigen B27 (HLA-B27)-positive patients with ankylosing spondylitis (AS) experiencing sustained inflammation. Between 2006 and 2021, 1445 HLA-B27-positive patients with AS were retrospectively evaluated. Among them, 112 patients required bDMARD therapy. The study compared conventional therapy with bDMARDs and investigated the risk factors for developing malignancies. During 8253 patient-years of follow-up, 38 (2.6%) patients developed various malignancies, including lung, liver, breast, and colon cancer. The risk of malignancy was significantly higher in the bDMARD-treated group compared to PS-matched groups receiving conventional synthetic DMARDs (csDMARD) and non-steroidal anti-inflammatory drugs. The cumulative risk of malignancies increased significantly after 6 years of follow-up. All patients who developed malignancy after bDMARD therapy received tumor necrosis factor-α inhibitors. Requiring bDMARD therapy, requiring bDMARDs in combination with csDMARD therapy, and being diagnosed with AS after 30 years of age were independent risk factors for developing malignancy. HLA-B27-positive AS patients with sustained inflammation requiring biologic therapy, particularly if diagnosed after age 30, may have an increased risk of malignancy. Regular cancer screenings are advisable for these patients while undergoing biologic treatment.

Association of denosumab with serum cytokines, chemokines, and bone-related factors in patients with rheumatoid arthritis: A post hoc analysis of a multicentre, open-label, randomised, parallel-group study.

To clarify changes in serum cytokines, chemokines, and bone-related factors during denosumab treatment in rheumatoid arthritis (RA) patients. This was a post hoc analysis of a multicentre, open-label, randomised, parallel-group study. Patients were randomly assigned to continue treatment with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) plus receive treatment with denosumab (csDMARDs plus denosumab group) or to continue treatment with csDMARD therapy alone for 12 months. Serum biomarker levels were measured at baseline and at 6 and 12 months. Baseline and 6-month data from the csDMARDs plus denosumab (n = 22) and csDMARD therapy alone (n = 22) groups were analysed. Statistically significant changes from baseline were seen: Dickkopf-related protein 1 decreased at 6 and 12 months (both groups); osteopontin decreased at 6 months in the csDMARDs plus denosumab group; osteopontin and soluble CD40 ligand increased at 6 and 12 months in the csDMARD therapy alone group; osteocalcin decreased at 6 and 12 months, epidermal growth factor decreased at 12 months, and macrophage-derived chemokine decreased at 6 months in the csDMARDs plus denosumab group; and interferon gamma-induced protein-10 increased at 12 months in the csDMARD therapy alone group. Denosumab may inhibit bone destruction by suppressing bone-related factors/chemokines.

Efficacy and Safety of Upadacitinib in Rheumatoid Arthritis: Real-Life Experience from a Prospective Longitudinal Multicentric Study.

We provide the first prospective longitudinal multicenter experience on Upadacitinib efficacy and safety profile in Rheumatoid Arthritis (RA) in a real-life context, focusing on clinimetric and ultrasonographic (US) data. RA patients referred to three Italian tertiary Centers who started Upadacitinib were enrolled as per ACR/EULAR classification criteria and prospectively reviewed. The primary aim of this study was to assess changes in clinimetric and ultrasonographic scores through time (at baseline, after 1 month, 3 months, and 6 months from the beginning of the therapy). Secondary aims were to: (i) estimate the impact of biologic lines of treatment and concomitant therapies on response to therapy; (ii) explore changes in laboratory parameters; and (iii) find potential predictive factors associated with response to therapy. Seventy-one patients (49 Females and 22 Males) were included. Clinimetric scores, including the Disease Activity Score (DAS28-CRP) and Simplified Clinical Disease Activity Index (SDAI), and US findings (synovial hypertrophy and power Doppler) significantly improved (p = 0.029, p = 0.001, p = 0.001, p = 0.001, respectively). Regression analysis revealed a significant association between the concomitant csDMARDs therapy at baseline and the lack of improvement in synovial hypertrophy [OR -4.824, p = 0.010] as well as with DAS28-CRP [OR -0.690, p = 0.045], whereas the presence of increased ESR or CRP at baseline was able to predict a significant improvement in SDAI [OR 8.481, p = 0.003]. No adverse events, such as deep venous thrombosis, pulmonary embolism, or herpes zoster virus infection, were reported during this study observation. Our real-life experience confirms the efficacy of Upadacitinib in terms of clinical and ultrasonographic improvement, as well as displaying a good safety profile.

The protocol of a clinical effectiveness trial comparing standard step-up care, early combination DMARD therapy and early use of TNF inhibitors for the treatment of moderate to severe psoriatic arthritis: the 3-arm parallel group SPEED randomized controlled trial.

The aim of the Severe Psoriatic arthritis - Early intervEntion to control Disease trial is to compare outcomes in psoriatic arthritis (PsA) patients with poor prognostic factors treated with standard step-up conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), combination csDMARDs or a course of early biologics. This multicentre UK trial was embedded within the MONITOR-PsA cohort, which uses a trial within cohort design. Patients with newly diagnosed PsA and at least one poor prognostic factor (polyarthritis, C-reactive protein >5 mg/dL, health assessment questionnaire >1, radiographic erosions) were randomized equally and open-label to either standard care with 'step-up' csDMARD therapy, initial therapy with combination csDMARDs (methotrexate with either sulfasalazine or leflunomide) or to early biologics induction therapy (adalimumab plus methotrexate). The primary outcome is the PsA disease activity score at week 24. Ethical approval for the study was granted by the South Central Research Ethics Committee (ref 18/SC/0107). Treatment recommendations for PsA suggest more intensive therapy for those with poor prognostic factors but there are no studies that have previously used prognostic factors to guide therapy. Applying initial intensive therapy has shown improved outcomes in other inflammatory arthritides but has never been tried in PsA. Combination csDMARDs have shown some superiority over single therapies but there are limited data and concerns about side effects. Early use of biologics has also been shown to be superior to methotrexate but these drugs are costly and not usually funded first line. However, if a short course of biologics can rapidly suppress inflammation allowing treatment to be withdrawn and response maintained on methotrexate, this may be a cost-effective model for early use. ClinicalTrials.gov (NCT03739853) and EudraCT (2017-004542-24).

Abstract 5 — Prediction of Flare Following Glucocorticoids Withdrawal in Rheumatoid Arthritis Patients with Continuation of csDMARDs: A Real-Life Study

Background In patients with rheumatoid arthritis (RA), glucocorticoids (GC) should be firstly discontinued before considering tapering conventional synthetic disease-modifying anti-rheumatic drugs (csDMARD) or other biological agents. We aim to determine risk factors for flare after GC withdrawal in RA patients undergoing csDMARDs. Method RA patients who discontinued GC with continuation of csDMARD were selected from a longitudinal real-world cohort. Established RA was defined as disease duration over 12 months. Dissatisfied RA control was defined as the proportion of simplified disease activity index (SDAI)-based remission time to total time from GC initiation to discontinuation less than 50%. Logistic regression was used to analyze the independent risk factors for flare after GC discontinuation and results were expressed as odds ratio (OR). Results There were 115 eligible RA patients discounted GC with continuation of csDMARDs (methotrexate: 80%; hydroxychloroquine: 61%; csDMARDs combination: 79%). Of these, 24 patients experienced flare after GC discontinuation. Compared with relapse-free patients, flare patients were more likely to have established RA (75% vs. 49%, p=0.025), higher median cumulative prednisolone dosages (3.3g vs. 2.2g, p=0.004), and higher proportion of dissatisfied RA control during GC usage (66% vs. 33%, p=0.038). In multivariate analysis, significantly increased flare risk was predicted by established RA (OR 2.93 [1.02-8.43]), cumulative prednisolone dose > 2.5g (OR 3.69 [1.34-10.19]) and dissatisfied RA control (OR 3.00 [1.09-8.30]). Flare risk was increased with increases in number of risk factors, with highest OR of 11.56 in patients with three risk factors (p for trend=0.002). Conclusions Flare following GC withdrawal is not common in RA patients with undergoing csDMARDs therapy. Established RA, higher cumulative GC dose and dissatisfied RA control before GC discontinuation are important factors associated with flare after GC withdrawal.

Effectiveness and safety of 99Tc-methylene diphosphonate as a disease-modifying anti-rheumatic drug (DMARD) in combination with conventional synthetic (cs) DMARDs in the treatment of rheumatoid arthritis: A systematic review and meta-analysis of 34 randomized controlled trials

BackgroundTechnetium [99Tc] methylene diphosphonate injection (99Tc-MDP) is widely used for the treatment of rheumatoid arthritis (RA), but there is still insufficient evidence for its application. Through the utilization of meta-analysis and systematic reviews, this study aimed to evaluate the effectiveness and safety of 99 TC-MDP in combination with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) for RA. MethodsThis study was registered on PROSPERO in advance (CRD42021220780). A systematic search was conducted in PubMed, Embase, the Cochrane Library, and multiple international public databases from their inception to April 2023 to identify clinical randomized controlled trials exploring the use of 99Tc-MDP combined with csDMARDs in the treatment of RA. Each outcome was subjected to meta-analysis, and the quality of evidence was assessed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The American College of Rheumatology's 50 %/70 % response criteria scores (ACR50/70) scores were utilized as the primary effectiveness outcomes, and risks were measured by assessing the rates of AEs. Moreover, secondary efficacy outcomes were evaluated, including the Disease Activity Score 28 (DAS28) and bone mineral density (BMD) as joint function indicators and the erythrocyte sedimentation rate (ESR) and interleukin-17 (IL-17) as inflammatory indicators. ResultsIn this meta-analysis, a total of 34 studies (2296 patients) were included out of 1149 retrieved studies. The summarized results showed that the treatment group treated with the combination of 99Tc-MDP and csDMARDs had significantly higher ACR50 (RR = 1.32, 95 % CI: 1.13–1.55, P = 0.0004) and ACR70 (RR = 1.40, 95 % CI: 1.07–1.82, P = 0.01) scores than the control group receiving csDMARDs alone. In addition, the overall incidence of AEs was lower with the combination of 99Tc-MDP and csDMARDs than with csDMARDs alone (RR = 0.75, 95 % CI: 0.60–0.93, P = 0.009), but the possibility of phlebitis was higher in the treatment group (RR = 4.15, 95 % CI: 1.04–16.50, P = 0.04). In addition, the combination of 99Tc-MDP and csDMARDs had advantages over csDMARDs alone in improving DAS28 (WMD = 1.56, 95 % CI: 0.86–2.25, P < 0.0001), BMD (SMD = 1.12, 95 % CI 0.46–1.78, P = 0.0008), ESR (SMD = 0.71, 95 % CI 0.45–0.97, P < 0.00001), and IL-17 (WMD = 5.82, 95 % CI 3.86–7.77, P < 0.00001). However, the above results might have been influenced by the 99Tc-MDP dosage, csDMARD category, and treatment duration. Combining methotrexate and leflunomide, administering continuous treatment for 24 weeks, or using 3 sets of 99Tc-MDP doses (16.5 mg) may be the optimal 99Tc-MDP treatment plan for RA. ConclusionCompared with csDMARD therapy alone, the combination therapy with 99Tc-MDP is more effective for RA patients and is associated with a lower overall incidence of adverse events, although the possibility of phlebitis was higher. However, due to the inherent limitations of the included RCTs, high-quality clinical trials are still needed to further assess the effectiveness and safety of this combination therapy.

P11 A case of Mycobacterium marinum infection in a patient with rheumatoid arthritis recently initiated on adalimumab

P11 A case of <i>Mycobacterium marinum</i> infection in a patient with rheumatoid arthritis recently initiated on adalimumab

The universal presence of poor prognostic factors based on EULAR recommendations: A real-world study in 1164 Chinese RA patients

IntroductionPoor prognostic factors (PPFs) have been used in assisting therapeutic decision-making in rheumatoid arthritis (RA). There are no standard lists of PPFs for RA, and whether PPFs can guide RA treatment remains controversial. ObjectivesTo analyze the profile of PPF based on EULAR recommendations in RA patients and explore the necessity of considering these PPFs in adjusting therapy. MethodsPrognostic factors including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), rheumatoid factor (RF), anti-citrullinated protein antibody (ACPA), swollen joint count (SJC), early erosions, and response to first conventional synthetic disease-modifying anti-rheumatic drugs (csDMARD) therapy in 1164 RA patients were collected. The profile of PPFs was graphically displayed. The correlation between different PPFs was analyzed. ResultsElevated ESR/CRP was presented in 746 (64%) patients, and positive RF/ACPA in 1021 (88%) patients. Two hundred and sixty-eight (23%) patients had≥4 swollen joints. Three hundred (26%) patients had moderate or high disease activity (MDA/HDA) despite csDMARD therapy. Failure of≥2 csDMARDs was found in 30% (224/740) of patients. One hundred and fifty-three out of 459 (33%) patients had early bone erosions, usually coexisted with other PPFs. Ninety-seven percent of RA patients had≥1 PPF. Being MDA/HDA≥3 months was significantly correlated with elevated ESR/CRP or high SJC, however uncorrelated with RF/ACPA positivity or early erosions. ConclusionsPPFs are universally present in RA patients. The reasonability of guiding treatment strategies just based on the presence or absence of PPFs requires further investigation. The categories of PPFs can be simplified and the role of different PPFs combinations in guiding treatment needs to be explored.

Prediction of flare following glucocorticoids withdrawal in rheumatoid arthritis patients with continuation of csDMARDs: a real-life study.

To determine the risk factors for flare after glucocorticoids (GC) withdrawal in rheumatoid arthritis (RA) patients with undergoing conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). RA patients who discontinued GC with continuation of csDMARD were selected from a longitudinal real-world cohort. Established RA was defined as disease duration over 12months. Dissatisfied RA control was defined as the proportion of simplified disease activity index (SDAI)-based remission time to total time from GC initiation to discontinuation less than 50%. Logistic regression was used to analyze the independent risk factors for flare after GC discontinuation and results were expressed as odds ratio (OR). There were 115 eligible RA patients discounted GC with continuation of csDMARDs (methotrexate: 80%; hydroxychloroquine: 61%; csDMARDs combination: 79%). Of these, 24 patients experienced flare after GC discontinuation. Compared with relapse-free patients, flare patients were more likely to have established RA (75% vs 49%, p = 0.025), higher median cumulative prednisolone dosages (3.3 vs 2.2g, p = 0.004), and higher proportion of dissatisfied RA control during GC usage (66% vs 33%, p = 0.038). In multivariate analysis, significantly increased flare risk was predicted by established RA (OR 2.93 [1.02-8.43]), cumulative prednisolone dose > 2.5g (OR 3.69 [1.34-10.19]) and dissatisfied RA control (OR 3.00 [1.09-8.30]). Flare risk was increased with increases in number of risk factors with highest OR of 11.56 in patients with three risk factors (p for trend = 0.002). Flare following GC withdrawal is not common in RA patients with undergoing csDMARDs therapy. Established RA, higher cumulative GC dose and dissatisfied RA control before GC discontinuation are important factors associated with flare after GC withdrawal.

P154 Real-world audit of patients with idiopathic inflammatory myositis-related interstitial lung disease in a European population

Abstract Background/Aims The British Society for Rheumatology (BSR) has released guidelines for managing idiopathic inflammatory myositis (IIM). Our centre operates specialist clinics for scleroderma and lupus, but to date, IIM patients are seen in a general CTD clinic. As part of work to establish a dedicated myositis clinic, we collated data on 71 patients under active follow-up with myositis spectrum disease deemed appropriate for follow-up within a specialist clinic. We aimed to review patients diagnosed with IIM-ILD and review serological immune profile, screening practices for pulmonary involvement, findings on CT/pulmonary function tests (PFTs) and pharmacological management. Methods We performed a detailed retrospective review of the notes of suitable patients, identified using diagnostic codes attached to clinic letters. Results 71 patients were identified: 14 with anti-synthetase syndrome (ARS), 21 with dermatomyositis (DM), 13 with polymyositis (PM), 3 with immune-mediated necrotising myopathy (IMNM) and 17 with overlap syndrome. 65% (46/70) of adult IIM patients were screened for pulmonary involvement. Screening practices of patients based on antibody profile and myositis subtype are further described in the table. 31% of patients (22/70) had IIM-ILD, of which 12 had ARS, 4 had PM, 1 had DM and 5 had overlap disease (2 PM/scleroderma, 1 DM/ARS, 1 DM/scleroderma and 1 scleroderma/ARS). 21/22 underwent PFTs; 53% of patients had active ILD over an average of 51.8 months. On imaging, 76.2% (16/22) had changes consistent with ILD. Ground glass change and reticulation were demonstrated in 50% of scans. In comparison, honeycombing and traction bronchiectasis was found in 22% and 44% of scans, respectively. A non-specific interstitial pneumonia (NSIP) pattern was described in 44% of scans, organising pneumonia (OP) pattern in 22%, and 17% had a mixed OP and NSIP pattern. 20/22 patients were prescribed high-dose steroids, csDMARD therapy or aggressive immunosuppression (cyclophosphamide or rituximab). Conclusion Our review demonstrates that 65% of patients with adult IIM were screened for ILD. NSIP and OP were the most common radiological appearances. Half of our cohort required aggressive immunosuppression, cyclophosphamide being the most commonly prescribed agent and mycophenolate being preferred for maintenance therapy. No patients were prescribed tacrolimus or ciclosporin. Despite treatment, 52% of patients had evidence of progressive disease on serial PFTs. Disclosure A. Loganathan: Grants/research support; Arthritis Australia. S. Sturney: None. N. Foley: None. T. Hartley: None. S. Tansley: None.

Real-world treatment persistence in patients with rheumatoid arthritis initiating DMARDs in Germany-ahealth insurance claims data analysis.

To investigate treatment patterns in patients with rheumatoid arthritis (RA) in Germany who had previously received conventional synthetic (cs) or biologic(b) disease-modifying antirheumatic drugs (DMARDs). Patients with RA who initiated treatment with acsDMARD, bDMARD, or Janus kinase (JAK) inhibitor between 2017 and 2018 and who had previously received csDMARD or bDMARD therapy were retrospectively selected from the Institute for Applied Health Research Berlin GmbH (InGef). Time on treatment and discontinuation risk were assessed using the Kaplan-Meier method. Cox regression identified variables associated with an increased discontinuation risk. Atotal of 990 patients had received prior csDMARD therapy; 375 had received prior bDMARD therapy. Tumor necrosis factor (TNF)-α inhibitors and JAK inhibitors were the most commonly prescribed DMARD class in those previously treated with acsDMARD or bDMARD, respectively. In both cohorts, more patients received DMARD monotherapy than combination therapy. In the prior csDMARD cohort, median time on treatment was 276, 252, and 148 days with JAK inhibitors, TNF‑α inhibitors, and csDMARDs, respectively, and those treated with JAK or TNF‑α inhibitors were less likely to discontinue treatment than those on csDMARDs (log-rank test p-value < 0.01 for both comparisons); no significant differences were found within the prior bDMARD cohort. This is among the first detailed analyses of RA treatment patterns in areal-world setting in Germany since the introduction of JAK inhibitors. TNF‑α inhibitors were the most commonly prescribed DMARD after failure of an initial csDMARD, while JAK inhibitors were the most common among patients previously treated with abDMARD. In both groups, monotherapy with bDMARD or targeted synthetic DMARD was common. In the prior csDMARD cohort, treatment duration was significantly longer with JAK or TNF‑α inhibitors than with csDMARDs.

Serum Levels of IFABP2 and Differences in Lactobacillus and Porphyromonas gingivalis Abundance on Gut Microbiota Are Associated with Poor Therapeutic Response in Rheumatoid Arthritis: A Pilot Study.

Intestinal dysbiosis is related to the physiopathology and clinical manifestation of rheumatoid arthritis (RA) and the response to pharmacologic treatment. The objectives of this study were (1) to analyze the effect of conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) on the abundance of gut microbiota's bacteria; (2) to evaluate the relationship between the differences in microbial abundance with the serum levels of intestinal fatty-acid binding protein 2 (IFABP2), cytokines, and the response phenotype to csDMARDs therapy in RA. A cross-sectional study was conducted on 23 women diagnosed with RA. The abundance of bacteria in gut microbiota was determined with qPCR. The ELISA technique determined serum levels of IFABP2, TNF-α, IL-10, and IL-17A. We found that the accumulated dose of methotrexate or prednisone is negatively associated with the abundance of Lactobacillus but positively associated with the abundance of Bacteroides fragilis. The Lactobacillus/Porphyromonas gingivalis ratio was associated with the Disease Activity Score-28 for RA with Erythrocyte Sedimentation Rate (DAS28-ESR) (r = 0.778, p = 0.030) and with the levels of IL-17A (r = 0.785, p = 0.027) in the group treated with csDMARD. Moreover, a relation between the serum levels of IFABP2 and TNF-α (r = 0.593, p = 0.035) was observed in the group treated with csDMARD. The serum levels of IFABP2 were higher in patients with secondary non-response to csDMARDs therapy. In conclusion, our results suggest that the ratios of gut microbiota's bacteria and intestinal permeability seems to establish the preamble for therapeutic secondary non-response in RA.

Using Treg, Tr1, and Breg Expression Levels to Predict Clinical Responses to csDMARD Treatment in Drug-naive Patients With Rheumatoid Arthritis.

Regulatory T cells (Treg) play a crucial role in maintaining immune tolerance and preventing autoimmune diseases. Recent data also indicate that type 1 regulatory T (Tr1) and regulatory B (Breg) cells play an inhibitory (i.e., protective) role in autoimmune diseases. Conventional synthetic disease-modifying antirheumatic drugs (csDMARD) are a first-line therapy for rheumatoid arthritis (RA), and our aim was to predict clinical responses of this treatment using immunophenotyping. We first detected the presence of immune cells in fresh blood from 16 healthy controls (HC) and 26 patients with RA (14 drug-naive and 12 csDMARD-experienced). Then, we recorded immunophenotypic changes in 14 drug-naive RA (naive RA) patients prior to csDMARD treatment (i.e., day 0) and after receiving treatment for 6 months. The observed changes were also compared with other clinical indicators, including the presence of anti-citrullinated peptide antibodies (anti-CCP), rheumatoid factor (RF) levels, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) levels. Naive RA patients had significantly lower Tregs than HC and csDMARD-experienced patients (both p<0.0001) and the number of Tregs correlated with the diagnosis of RA and therapeutic efficacy of csDMARD treatment. Furthermore, lower baseline levels of Treg, memory Treg, Tr1, and higher PD-1+ Marginal B, Breg cells were significantly associated with decreased development of the 28-joint Disease Activity Score (DAS28) (all p<0.05), revealing better medical response. Multiple regression and principal component analysis identified Treg, Tr1, and Breg as potential predictors of csDMARD responses (Area under curve: 0.9; Accuracy: 92.86%). Furthermore, elevated Treg, Tr1, and Breg cells were associated with decreased DAS28, ESR, and CRP (all p<0.05); changes in Treg and Breg cell expression were also more pronounced among double negative anti-CCP and RF in RA patients with better outcomes (p<0.05). Immunophenotyping can be an adjunct clinical tool to identify patients who are poor candidates for csDMARD therapy. Alternative therapeutic interventions in the early stages of disease should be formulated for these patients.

Inhibition of bone erosion, determined by high-resolution peripheral quantitative computed tomography (HR-pQCT), in rheumatoid arthritis patients receiving a conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) plus denosumab vs csDMARD therapy alone: an open-label, randomized, parallel-group study

BackgroundThis exploratory study compared the inhibition of bone erosion progression in rheumatoid arthritis (RA) patients treated with a conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) plus denosumab versus csDMARD therapy alone and investigated the effects of denosumab on bone micro-architecture and other bone-related parameters using high-resolution peripheral quantitative computed tomography (HR-pQCT).MethodsIn this open-label, randomized, parallel-group study, patients with RA undergoing treatment with a csDMARD were randomly assigned (1:1) to continue csDMARD therapy alone or to continue csDMARDs with denosumab (60-mg subcutaneous injection once every 6 months) for 12 months. The primary endpoint was the change from baseline in the depth of bone erosion, measured by HR-pQCT, in the second and third metacarpal heads at 6 months after starting treatment. Exploratory endpoints were also evaluated, and adverse events (AEs) were monitored for safety.ResultsIn total, 46 patients were enrolled, and 43 were included in the full analysis set (csDMARDs plus denosumab, N = 21; csDMARD therapy alone, N = 22). Most patients were female (88.4%), and the mean age was 65.3 years. The adjusted mean (95% confidence interval) change from baseline in the depth of bone erosion, measured by HR-pQCT, in the 2–3 metacarpal heads at 6 months was − 0.57 mm (− 1.52, 0.39 mm) in the csDMARDs plus denosumab group vs − 0.22 mm (− 0.97, 0.53 mm) in the csDMARD therapy alone group (between-group difference: − 0.35 mm [− 1.00, 0.31]; P = 0.2716). Similar results were shown for the adjusted mean between-group difference in the width and volume of bone erosion of the 2–3 metacarpal heads. Significant improvements in bone micro-architecture parameters were shown. The incidence of AEs and serious AEs was similar between the csDMARDs plus denosumab and the csDMARD therapy alone groups (AEs: 52.2% vs 56.5%; serious AEs: 4.3% vs 8.7%).ConclusionsAlthough the addition of denosumab to csDMARDs did not find statistically significant improvements in bone erosion after 6 months of treatment, numerical improvements in these parameters suggest that the addition of denosumab to csDMARDs may be effective in inhibiting the progression of bone erosion and improving bone micro-architecture.Trial registrationUniversity Hospital Medical Information Network Clinical Trials Registry, UMIN000030575. Japan Registry for Clinical Trials, jRCTs071180018

Different humoral but similar cellular responses of patients with autoimmune inflammatory rheumatic diseases under disease-modifying antirheumatic drugs after COVID-19 vaccination

ObjectivesThe effect of different modes of immunosuppressive therapy in autoimmune inflammatory rheumatic diseases (AIRDs) remains unclear. We investigated the impact of immunosuppressive therapies on humoral and cellular responses after two-dose...

Upadacitinib for the Treatment of Rheumatoid Arthritis: An Extensive Review.

To review the characteristics, efficacy, safety, pharmacoeconomics, and place in therapy of upadacitinib, a Janus kinase (JAK) inhibitor, in the treatment of rheumatoid arthritis (RA). PubMed (January 2003-May 2022) was searched using upadacitinib and ABT-494. Human studies published in peer-reviewed publications in English were the primary sources for efficacy and safety data. In randomized, double-blind, controlled clinical studies, upadacitinib demonstrated statistically significant improvement in RA symptoms as monotherapy and in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) when compared with csDMARD monotherapy or to adalimumab or abatacept in combination with csDMARD therapy in patients with RA. American College of Rheumatology 20% response rates were 68% to 79% for upadacitinib monotherapy and 64% to 84% for upadacitinib plus csDMARD therapy, compared with 28% to 59% for csDMARD-only therapy and 63% to 74% for biologic DMARD (bDMARD) plus csDMARD therapy. Long-term extension studies demonstrated similar findings. Upadacitinib had similar rates of serious infections, herpes zoster, major cardiovascular events, and venous thromboembolic events as other JAK inhibitors. Upadacitinib was similar in cost to tofacitinib and twice as high as baricitinib based on current estimated costs to patients, but actual costs may vary. Upadacitinib is an alternative therapy to other JAK inhibitors and bDMARDs in patients with moderate to severe RA who have had an inadequate response to a tumor necrosis factor inhibitor alone or in combination with a csDMARD. Upadacitinib is an effective JAK inhibitor for use in RA.

Harmonization of Public Coverage Policies for Biologic Drugs in the Treatment of Rheumatoid Arthritis

&#x0D; For rheumatoid arthritis (RA), treatment guidelines and clinical evidence support the combination (either dual or triple) of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) before accessing a biologic DMARD (bDMARD). Federal, provincial, and territorial (FPT) drug plans currently have different coverage criteria for bDMARD eligibility in RA. To align their criteria, these plans should consider the inclusion of at least 1 line of combination csDMARDs before a bDMARD:&#x0D; &#x0D; For dual csDMARDs: Saskatchewan, Veterans Affairs Canada, and Canadian Armed Forces would need to change their current coverage criteria to include at least 1 line of dual csDMARDs before access to a bDMARD.&#x0D; For triple csDMARDs: Alberta, Saskatchewan, Manitoba, Veterans Affairs Canada, and Canadian Armed Forces would need to alter their current coverage criteria because each of these FPT drug plans only consider csDMARD monotherapy or dual csDMARDs in their current coverage criteria.&#x0D; &#x0D; &#x0D; Most FPT drug plans require a failure of at least 2 lines to 3 lines of csDMARD therapy before a bDMARD, except British Columbia, Ontario, Newfoundland and Labrador, Veterans Affairs Canada, and Canadian Armed Forces, which offer an option to access bDMARDs after 1 line of combination csDMARDs. British Columbia, Ontario, the Atlantic provinces, Yukon, Correctional Service of Canada, and Non-Insured Health Benefits include triple csDMARDs in their coverage criteria. Alberta, Manitoba, Veterans Affairs Canada, and Canadian Armed Forces include dual, but not triple, csDMARDs in their criteria; however, Veterans Affairs Canada and Canadian Armed Forces do not require a trial of dual csDMARDs if 2 lines of csDMARD monotherapy have been attempted. Saskatchewan is the only jurisdiction that only requires csDMARD monotherapy. Canadian private insurers have also reached a consensus to implement a trial requirement of dual csDMARDs before a bDMARD across their formularies.&#x0D; Evidence-based guidelines, including the 2012 Canadian Rheumatology Association guidelines, recommend csDMARD monotherapy (methotrexate [MTX] is preferred unless contraindicated) as first-line treatment for RA, although a guideline published in 2018 by the Brazilian Society of Rheumatology stated that combination therapy with 2 or more csDMARDs may also be used as a first-line treatment. These guidelines generally recommend combination csDMARDs after csDMARD monotherapy is deemed ineffective.&#x0D; A network meta-analysis found that triple csDMARDs is more efficacious than dual csDMARDs, etanercept monotherapy, and 4 mg/kg tocilizumab monotherapy and comparable to other bDMARDs (alone or in combination with MTX), targeted synthetic DMARDs in combination with MTX, and biosimilars in combination with MTX. Additionally, economic evidence demonstrated that triple csDMARDs is more cost-effective than etanercept plus MTX combination therapy.&#x0D; Time to first bDMARD was, on average, longer in Alberta, British Columbia, and Ontario than in Saskatchewan, Manitoba, and the Atlantic provinces by approximately 4 months, which may be partially explained by differences in coverage criteria for the number of prior lines of csDMARD therapy required. Increasing the time to initiating a bDMARD could lead to budget savings without impacting clinical outcomes.&#x0D;

A Blood Protein Signature Stratifies Clinical Response to csDMARD Therapy in Pediatric Uveitis.

PurposeTo identify a serum biomarker signature that can help predict response to conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy in pediatric noninfectious uveitis.MethodsIn this case-control cohort study, we performed a 368-plex proteomic analysis of serum samples of 72 treatment-free patients with active uveitis (new onset or relapse) and 15 healthy controls. Among these, 37 patients were sampled at diagnosis before commencing csDMARD therapy. After 6 months, csDMARD response was evaluated and cases were categorized as “responder” or “nonresponder.” Patients were considered “nonresponders” if remission was not achieved under csDMARD therapy. Serum protein profiles were used to train random forest models to predict csDMARD failure and compared to a model based on eight clinical parameters at diagnosis (e.g., maximum cell grade).ResultsIn total, 19 of 37 (51%) cases were categorized as csDMARD nonresponders. We identified a 10-protein signature that could predict csDMARD failure with an overall accuracy of 84%, which was higher compared to a model based on eight clinical parameters (73% accuracy). Adjusting for age, sex, anatomic location of uveitis, and cell grade, cases stratified by the 10-protein signature at diagnosis showed a large difference in risk for csDMARD failure (hazard ratio, 12.8; 95% confidence interval, 2.5–64.6; P = 0.002).ConclusionsMachine learning models based on the serum proteome can stratify pediatric patients with uveitis at high risk for csDMARD failure.Translational RelevanceThe identified protein signature has implications for the development of clinical decision tools that integrate clinical parameters with biological data to better predict the best treatment option.

Can biomarkers predict successful tapering of conventional disease-modifying therapy in rheumatoid arthritis patients in stable remission?

Specific guidelines for managing RA patients in clinical remission for ≥6 months on cs-DMARDs are lacking. Tapering of treatment is encouraged, however, without validated biomarkers for success. We aimed to assess the rate of sustained remission after 12 months in patients who either (i) followed structured cs-DMARD tapering or (ii) continued therapy, focusing on the added value of biomarkers as predictors of outcome. RA patients fulfilling 3v-DAS28CRP<2.6 for ≥6 months on stable cs-DMARD therapy were included. Patients were offered structured tapering, with 117 accepting tapering and 83 continuing therapy. Clinical, ultrasound, immunological (T-cell subsets) and patient-reported outcome (PRO) data were collected. The primary endpoint was the proportion of patients in sustained remission without relapse after 12 months. Regression analyses were used to identify predictors of sustained remission. Of those who tapered, 64% remained in clinical remission after 12 months compared with 80% (p=0.018) of patients on stable treatment. In the tapering group, higher levels of CRP, TJC, % inflammation-related T-cell (IRC) and PROs were associated with flare (all p<0.05), with a trend for total PD (p=0.066). A model predicting sustained remission retained RAQoL, total PD and IRC (85% accuracy, AUROC=0.893, p<0.0001). In the non-tapering group, higher CRP, ESR, SJC and shorter disease duration (all p<0.05) were associated with flare, with no parameter able to predict sustained remission. In the tapering group, the combination of clinical, PRO, US and T-cell parameters demonstrated added value for predicting sustained remission compared with clinical parameters alone. These data may inform best tapering practice.