Novel susceptibility loci for steroid-associated osteonecrosis of the femoral head in systemic lupus erythematosus.

Osteonecrosis of the femoral head (ONFH) involves necrosis of bone and bone marrow of the femoral head caused by ischemia with unknown etiology. Previous genetic studies on ONFH failed to produce consistent results, presumably because ONFH has various causes with different genetic backgrounds and the underlying diseases confounded the associations. Steroid-associated ONFH (S-ONFH) accounts for one-half of all ONFH, and systemic lupus erythematosus (SLE) is a representative disease underlying S-ONFH. We performed a genome-wide association study (GWAS) to identify genetic risk factors for S-ONFH in patients with SLE. We conducted a two-staged GWAS on 636 SLE patients with S-ONFH and 95 588 non-SLE controls. Among the novel loci identified, we determined S-ONFH-specific loci by comparing allele frequencies between SLE patients without S-ONFH and non-SLE controls. We also used Korean datasets comprising 148 S-ONFH cases and 37 015 controls to assess overall significance. We evaluated the functional annotations of significant variants by in silico analyses. The Japanese GWAS identified 4 significant loci together with 12 known SLE susceptibility loci. The four significant variants showed comparable effect sizes on S-ONFH compared with SLE controls and non-SLE controls. Three of the four loci, MIR4293/MIR1265 [odds ratio (OR) = 1.99, P-value = 1.1 × 10-9)], TRIM49/NAALAD2 (OR = 1.65, P-value = 4.8 × 10-8) and MYO16 (OR = 3.91, P-value = 4.9 × 10-10), showed significant associations in the meta-analysis with Korean datasets. Bioinformatics analyses identified MIR4293, NAALAD2 and MYO16 as candidate causal genes. MIR4293 regulates a PPARG-related adipogenesis pathway relevant to S-ONFH. We identified three novel susceptibility loci for S-ONFH in SLE.

Bimekizumab in patients with active psoriatic arthritis and previous inadequate response or intolerance to tumour necrosis factor-α inhibitors: a randomised, double-blind, placebo-controlled, phase 3 trial (BE COMPLETE).

BACKGROUND: Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F and IL-17A. This study compared the efficacy and safety of bimekizumab with placebo over 16 weeks in patients with active psoriatic arthritis and previous inadequate response or intolerance to tumour necrosis factor-α (TNFα) inhibitors. METHODS: BE COMPLETE was a phase 3, multicentre, randomised, double-blind, placebo-controlled trial conducted across 92 sites (including hospitals, clinics, and research centres) in 11 countries (Australia, Canada, Czech Republic, Germany, Hungary, Italy, Japan, Poland, Russia, the UK, and the USA). Eligible patients were aged 18 years or older with adult-onset psoriatic arthritis (meeting the Classification Criteria for Psoriatic Arthritis for at least 6 months before screening) with a history of inadequate response or intolerance to treatment with one or two TNFα inhibitors for either psoriatic arthritis or psoriasis. We stratified patients with active psoriatic arthritis by region and previous TNFα inhibitor use. Patients were randomly assigned (2:1) to receive subcutaneous bimekizumab 160 mg every 4 weeks or placebo by an interactive-voice and web-response system on the basis of a predetermined randomisation schedule. The primary endpoint was the proportion of patients with 50% or greater improvement in American College of Rheumatology criteria (ACR50) at week 16 (non-responder imputation). Efficacy analyses were done in the randomised population. The safety analysis set comprised patients who received one or more doses of study treatment. This trial was registered at ClinicalTrials.gov, NCT03896581, and is completed. FINDINGS: Between March 28, 2019, and Feb 14, 2022, 556 patients were screened and 400 patients were randomly assigned to bimekizumab 160 mg every 4 weeks (n=267) or placebo (n=133). The primary and all hierarchical secondary endpoints were met at week 16. 116 (43%) of 267 patients receiving bimekizumab reached ACR50, compared with nine (7%) of 133 patients receiving placebo (adjusted odds ratio [OR] 11·1 [95% CI 5·4-23·0], p<0·0001). 121 (69%) of 176 patients with psoriasis affecting at least 3% body surface area at baseline who received bimekizumab reached 90% or greater improvement in the Psoriasis Area and Severity Index (PASI90), compared with six (7%) of 88 patients who received placebo (adjusted OR 30·2 [12·4-73·9], p<0·0001). Treatment-emergent adverse events up to week 16 were reported in 108 (40%) of 267 patients receiving bimekizumab and 44 (33%) of 132 patients receiving placebo. There were no new safety signals and no deaths. INTERPRETATION: Bimekizumab treatment led to superior improvements in joint and skin efficacy outcomes at week 16 compared with placebo in patients with psoriatic arthritis and inadequate response or intolerance to TNFα inhibitors. The safety profile of bimekizumab was consistent with previous phase 3 studies in patients with plaque psoriasis, and studies of IL-17A inhibitors. FUNDING: UCB Pharma.

Bimekizumab in patients with psoriatic arthritis, naive to biologic treatment: a randomised, double-blind, placebo-controlled, phase 3 trial (BE OPTIMAL).

BACKGROUND: Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17A and IL-17F. We assessed the efficacy and safety of bimekizumab in patients with active psoriatic arthritis who were naive to biologic disease-modifying antirheumatic drugs (DMARDs). METHODS: BE OPTIMAL was a 52-week, phase 3, multicentre, randomised, double-blind, placebo-controlled, active reference (adalimumab) trial done at 135 sites (hospitals, clinics, doctors' offices, and research centres) in 14 countries. Eligible patients were 18 years or older with a documented diagnosis of adult-onset psoriatic arthritis that met the Classification Criteria for Psoriatic Arthritis for at least 6 months before screening. Participants were randomly assigned with an interactive-voice and web-response system on the basis of a predetermined randomisation schedule (3:2:1, stratified by region and bone erosion number at baseline) to bimekizumab 160 mg every 4 weeks, placebo every 2 weeks, or the reference group (adalimumab 40 mg every 2 weeks), all administered subcutaneously. At week 16, patients randomly assigned to placebo switched to bimekizumab 160 mg every 4 weeks. The primary endpoint was the proportion of patients reaching 50% or greater improvement in American College of Rheumatology criteria (ACR50) at week 16 (non-responder imputation). Efficacy analyses included all patients who were randomly assigned (intention-to-treat population); the safety analysis set comprised patients who received one or more doses of treatment. Data are presented to week 24 (preplanned analysis). This trial is registered at ClinicalTrials.gov, NCT03895203. FINDINGS: Between April 3, 2019, and Oct 25, 2021, 1163 patients were screened and 852 were randomly assigned to bimekizumab (n=431), placebo (n=281), and reference (adalimumab; n=140) groups. At week 16, significantly more patients receiving bimekizumab (189 [44%] of 431) reached ACR50 response versus placebo (28 [10%] of 281; odds ratio 7·1 [95% CI 4·6-10·9], p<0·0001; adalimumab 64 [46%] of 140). All secondary hierarchical endpoints were met. Treatment-emergent adverse events up to week 16 were reported in 258 [60%] of 431 patients receiving bimekizumab, 139 [49%] of 281 patients receiving placebo, and 83 [59%] of 140 patients receiving adalimumab. No deaths occurred. INTERPRETATION: Bimekizumab treatment had superior improvements in joint, skin, and radiographic efficacy outcomes at week 16 compared with placebo in patients with psoriatic arthritis who were naive to biologic DMARDs. The safety profile of bimekizumab, including the occurrence of fungal infections, was consistent with previous phase 3 studies in patients with plaque psoriasis, and with IL-17A inhibitors. FUNDING: UCB Pharma.

Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 3 trial (SLE-BRAVE-II).

BACKGROUND: Baricitinib is an oral selective inhibitor of Janus kinase 1 and 2 approved for the treatment of rheumatoid arthritis, atopic dermatitis, and alopecia areata. In a 24-week phase 2 study in patients with systemic lupus erythematosus (SLE), baricitinib 4 mg significantly improved SLE disease activity compared with placebo. In this Article, we report the evaluation of efficacy and safety of baricitinib in patients with SLE in a 52-week phase 3 study. METHODS: In this phase 3 double-blind, randomised, placebo-controlled study, SLE-BRAVE-II, patients (aged ≥18 years) with active SLE receiving stable background therapy were randomly assigned 1:1:1 to baricitinib 4 mg, baricitinib 2 mg, or placebo once daily for 52 weeks. The primary endpoint was the proportion of patients with an SLE Responder Index (SRI)-4 response at week 52 in the baricitinib 4 mg treatment group compared with placebo. Glucocorticoid tapering was encouraged but not required per protocol. The primary endpoint was assessed by logistic regression analysis with baseline disease activity, baseline corticosteroid dose, region, and treatment group in the model. Efficacy analyses were done on an intention-to-treat population, comprising all participants who were randomly assigned and received at least one dose of investigational product and who did not discontinue from the study for the reason of lost to follow-up at the first post-baseline visit. Safety analyses were done on all randomly assigned participants who received at least one dose of investigational product and who did not discontinue. This study is registered with ClinicalTrials.gov, NCT03616964, and is complete. FINDINGS: A total of 775 patients were randomly assigned and received at least one dose of baricitinib 4 mg (n=258), baricitinib 2 mg (n=261), or placebo (n=256). There was no difference in the primary efficacy outcome of the proportion of SRI-4 responders at week 52 between participants who received baricitinib 4mg (121 [47%]; odds ratio 1·07 [95% CI 0·75 to 1·53]; difference with placebo 1·5 [95% CI -7·1 to 10·2]), 2 mg (120 [46%]; 1·05 [0·73 to 1·50]; 0·8 [-7·9 to 9·4]) and placebo (116 [46%]). None of the major secondary endpoints, including glucocorticoid tapering and time to first severe flare, were met. Serious adverse events were observed in 29 (11%) participants in the baricitinib 4 mg group, 35 (13%) in the baricitinib 2 mg group, and 22 (9%) in the placebo group. The safety profile of baricitinib in patients with SLE was consistent with the known baricitinib safety profile. INTERPRETATION: Although phase 2 data suggested baricitinib as a potential treatment for patients with SLE, which was supported in SLE-BRAVE-I, this result was not replicated in SLE-BRAVE-II. No new safety signals were observed. FUNDING: Eli Lilly and Company.

Short-term effectiveness and safety of rituximab versus cyclophosphamide for life-threatening ANCA-associated vasculitis: a propensity score analysis of the real-world nationwide database.

OBJECTIVES: Life-threatening antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) with rapidly progressive glomerulonephritis (RPGN) and/or alveolar haemorrhage (AH) has a poor prognosis. Rituximab (RTX) is as effective as cyclophosphamide (CY) in remission induction therapy; however, the effectiveness and safety of RTX have not been established in life-threatening AAV. This study aimed to investigate the short-term effectiveness and safety of RTX in life-threatening AAV with RPGN and/or AH. METHODS: Between April 2018 and March 2020, cases treated with systemic glucocorticoids and RTX or intravenous CY (IVCY) was extracted from a Japanese nationwide inpatient database. Effectiveness was evaluated by in-hospital mortality and severe renal dysfunction requiring haemodialysis (HD) at discharge. Safety was evaluated by the in-hospital incidence of infections. The propensity score (PS) for RTX was estimated. Multivariable Cox and logistic regression with adjustment for PS were conducted to estimate the association of RTX with outcomes. RESULTS: From 16 001 612 hospitalised records, 687 life-threatening AAV cases were extracted. No significant difference in in-hospital mortality (adjusted HR 1.06; 95% CI 0.62 to 1.80) was found between the groups. Although the RTX group had a lower risk of fungal infections (adjusted OR (aOR) 0.45; 95% CI 0.23 to 0.84) and pneumocystis pneumonia (aOR 0.58; 95% CI 0.32 to 1.00), they might have an increased risk of severe renal dysfunction requiring HD at discharge (aOR 2.58; 95% CI 1.02 to 6.91). CONCLUSIONS: In life-threatening AAV, RTX has similar short-term effectiveness on mortality to IVCY. Although RTX might have a lower risk of fungal infections and pneumocystis pneumonia, the short-term renal prognosis might be inferior to IVCY.

Extracting immunological and clinical heterogeneity across autoimmune rheumatic diseases by cohort-wide immunophenotyping.

OBJECTIVE: Extracting immunological and clinical heterogeneity across autoimmune rheumatic diseases (AIRDs) is essential towards personalised medicine. METHODS: We conducted large-scale and cohort-wide immunophenotyping of 46 peripheral immune cells using Human Immunology Protocol of comprehensive 8-colour flow cytometric analysis. Dataset consisted of >1000 Japanese patients of 11 AIRDs with deep clinical information registered at the FLOW study, including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). In-depth clinical and immunological characterisation was conducted for the identified RA patient clusters, including associations of inborn human genetics represented by Polygenic Risk Score (PRS). RESULTS: Multimodal clustering of immunophenotypes deciphered underlying disease-cell type network in immune cell, disease and patient cluster resolutions. This provided immune cell type specificity shared or distinct across AIRDs, such as close immunological network between mixed connective tissue disease and SLE. Individual patient-level clustering dissected patients with AIRD into several clusters with different immunological features. Of these, RA-like or SLE-like clusters were exclusively dominant, showing immunological differentiation between RA and SLE across AIRDs. In-depth clinical analysis of RA revealed that such patient clusters differentially defined clinical heterogeneity in disease activity and treatment responses, such as treatment resistance in patients with RA with SLE-like immunophenotypes. PRS based on RA case-control and within-case stratified genome-wide association studies were associated with clinical and immunological characteristics. This pointed immune cell type implicated in disease biology such as dendritic cells for RA-interstitial lung disease. CONCLUSION: Cohort-wide and cross-disease immunophenotyping elucidate clinically heterogeneous patient subtypes existing within single disease in immune cell type-specific manner.

Peripheral blood immunophenotypic diversity in patients with rheumatoid arthritis and its impact on therapeutic responsiveness.

OBJECTIVE: Considering the diverse aetiologies and immunodysregulatory statuses observed in each patient with rheumatoid arthritis (RA), stratification based on peripheral blood immunophenotyping holds the potential to enhance therapeutic responses to molecular targeted therapies, biological/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs). METHODS: Immunophenotype analysis was conducted on a cohort of over 500 b/tsDMARDs-naïve patients using flow cytometry. Patients with RA were stratified based on their immunophenotypes, and the treatment response to each targeted therapy was evaluated. Validation was performed using an additional cohort of 183 b/tsDMARDs-naïve patients with RA. RESULTS: Patients with RA were stratified into five clusters, two of which exhibited distinct RA phenotypes compared with controls, characterised by significant increases in CD4+ effector memory T cells re-expressing CD45RA. Notably, the effectiveness of different b/tsDMARDs varied across clusters. The group using promising b/tsDMARDs was labelled as 'expected' whereas the 'non-expected' group comprised those using others. The expected group outperformed the non-expected group with higher 26-week remission rates (39.9% vs 24.6%, p=0.0004) and low disease activity achievement (80.8% vs 60.2%, p<0.0001). Trajectory analysis showed the non-expected group's 26-week disease activity was influenced by Clinical Disease Activity Index at baseline unlike the expected group. Additionally, different molecular targeted therapies influenced the proportions of each immune cell subset variably. To validate, immunophenotyping was performed on a validation cohort. When 183 cases were grouped based on their b/tsDMARDs usage into expected/non-expected groups, the expected group had a higher remission rate (p=0.0021), further confirming the observed trend. CONCLUSION: Our findings offer valuable insights into the diversity of RA and potential therapeutic strategies grounded in the molecular underpinnings.

Integrated safety analysis of filgotinib in patients with moderate-to-severe rheumatoid arthritis over a treatment duration of up to 8.3 years.

OBJECTIVES: To update the long-term safety profile of filgotinib, a Janus kinase-1 preferential inhibitor, in patients with moderate-to-severe rheumatoid arthritis. METHODS: Data from seven trials were integrated (NCT01888874, NCT01894516, NCT02889796, NCT02873936, NCT02886728, NCT02065700 and NCT03025308). Patients received once-daily filgotinib 100 mg or 200 mg. Exposure-adjusted incidence rates (EAIRs)/100 patient-years of exposure (PYE) were calculated for treatment-emergent adverse events (TEAEs). Post hoc analyses assessed patients aged <65 and ≥65 years. RESULTS: Patients (N=3691) received filgotinib for a median (maximum) of 3.8 (8.3) years (12 541 PYE). Rates of TEAEs of interest: serious infections, malignancies, major adverse cardiovascular events (MACE) and venous thromboembolism were stable over time and comparable between doses. In the overall population, numerically lower EAIR (95% CI)/100 PYE of herpes zoster was observed for filgotinib 100 mg versus 200 mg (1.1 (0.8 to 1.5) vs 1.5 (1.2 to 1.8)). Incidence of serious infections, herpes zoster, MACE, malignancies and all-cause mortality was higher in patients aged ≥65 versus <65 years. In patients aged ≥65 years, EAIRs (95% CI)/100 PYE for non-melanoma skin cancer (NMSC) (0.4 (0.1 to 1.1) vs 1.4 (0.8 to 2.2)), malignancies excluding NMSC (1.0 (0.5 to 1.9) vs 2.0 (1.3 to 2.9)) and all-cause mortality (1.3 (0.7 to 2.2) vs 1.6 (1.0 to 2.5)) were numerically lower for filgotinib 100 mg versus 200 mg. CONCLUSIONS: In the overall population, TEAEs of interest were stable over time and similar between filgotinib 100 mg and 200 mg dose groups, except for herpes zoster. A dose-dependent relationship between malignancies and all-cause mortality was suggested in patients ≥65 years old.

EULAR recommendations for the management of psoriatic arthritis with pharmacological therapies: 2023 update.

OBJECTIVE: New modes of action and more data on the efficacy and safety of existing drugs in psoriatic arthritis (PsA) required an update of the EULAR 2019 recommendations for the pharmacological treatment of PsA. METHODS: Following EULAR standardised operating procedures, the process included a systematic literature review and a consensus meeting of 36 international experts in April 2023. Levels of evidence and grades of recommendations were determined. RESULTS: The updated recommendations comprise 7 overarching principles and 11 recommendations, and provide a treatment strategy for pharmacological therapies. Non-steroidal anti-inflammatory drugs should be used in monotherapy only for mild PsA and in the short term; oral glucocorticoids are not recommended. In patients with peripheral arthritis, rapid initiation of conventional synthetic disease-modifying antirheumatic drugs is recommended and methotrexate preferred. If the treatment target is not achieved with this strategy, a biological disease-modifying antirheumatic drug (bDMARD) should be initiated, without preference among modes of action. Relevant skin psoriasis should orient towards bDMARDs targeting interleukin (IL)-23p40, IL-23p19, IL-17A and IL-17A/F inhibitors. In case of predominant axial or entheseal disease, an algorithm is also proposed. Use of Janus kinase inhibitors is proposed primarily after bDMARD failure, taking relevant risk factors into account, or in case bDMARDs are not an appropriate choice. Inflammatory bowel disease and uveitis, if present, should influence drug choices, with monoclonal tumour necrosis factor inhibitors proposed. Drug switches and tapering in sustained remission are also addressed. CONCLUSION: These updated recommendations integrate all currently available drugs in a practical and progressive approach, which will be helpful in the pharmacological management of PsA.

Risk of flare and damage accrual after tapering glucocorticoids in modified serologically active clinically quiescent patients with systemic lupus erythematosus: a multinational observational cohort study.

OBJECTIVES: To assess the risk of flare and damage accrual after tapering glucocorticoids (GCs) in modified serologically active clinically quiescent (mSACQ) patients with systemic lupus erythematosus (SLE). METHODS: Data from a 12-country longitudinal SLE cohort, collected prospectively between 2013 and 2020, were analysed. SLE patients with mSACQ defined as the state with serological activity (increased anti-dsDNA and/or hypocomplementemia) but without clinical activity, treated with ≤7.5 mg/day of prednisolone-equivalent GCs and not-considering duration, were studied. The risk of subsequent flare or damage accrual per 1 mg decrease of prednisolone was assessed using Cox proportional hazard models while adjusting for confounders. Observation periods were 2 years and censored if each event occurred. RESULTS: Data from 1850 mSACQ patients were analysed: 742, 271 and 180 patients experienced overall flare, severe flare and damage accrual, respectively. Tapering GCs by 1 mg/day of prednisolone was not associated with increased risk of overall or severe flare: adjusted HRs 1.02 (95% CI, 0.99 to 1.05) and 0.98 (95% CI, 0.96 to 1.004), respectively. Antimalarial use was associated with decreased flare risk. Tapering GCs was associated with decreased risk of damage accrual (adjusted HR 0.96, 95% CI, 0.93 to 0.99) in the patients whose initial prednisolone dosages were >5 mg/day. CONCLUSIONS: In mSACQ patients, tapering GCs was not associated with increased flare risk. Antimalarial use was associated with decreased flare risk. Tapering GCs protected mSACQ patients treated with >5 mg/day of prednisolone against damage accrual. These findings suggest that cautious GC tapering is feasible and can reduce GC use in mSACQ patients.

EULAR recommendations for the management of systemic lupus erythematosus: 2023 update.

OBJECTIVES: To update the EULAR recommendations for the management of systemic lupus erythematosus (SLE) based on emerging new evidence. METHODS: An international Task Force formed the questions for the systematic literature reviews (January 2018-December 2022), followed by formulation and finalisation of the statements after a series of meetings. A predefined voting process was applied to each overarching principle and recommendation. Levels of evidence and strengths of recommendation were assigned, and participants finally provided their level of agreement with each item. RESULTS: The Task Force agreed on 5 overarching principles and 13 recommendations, concerning the use of hydroxychloroquine (HCQ), glucocorticoids (GC), immunosuppressive drugs (ISDs) (including methotrexate, mycophenolate, azathioprine, cyclophosphamide (CYC)), calcineurin inhibitors (CNIs, cyclosporine, tacrolimus, voclosporin) and biologics (belimumab, anifrolumab, rituximab). Advice is also provided on treatment strategies and targets of therapy, assessment of response, combination and sequential therapies, and tapering of therapy. HCQ is recommended for all patients with lupus at a target dose 5 mg/kg real body weight/day, considering the individual's risk for flares and retinal toxicity. GC are used as 'bridging therapy' during periods of disease activity; for maintenance treatment, they should be minimised to equal or less than 5 mg/day (prednisone equivalent) and, when possible, withdrawn. Prompt initiation of ISDs (methotrexate, azathioprine, mycophenolate) and/or biological agents (anifrolumab, belimumab) should be considered to control the disease and facilitate GC tapering/discontinuation. CYC and rituximab should be considered in organ-threatening and refractory disease, respectively. For active lupus nephritis, GC, mycophenolate or low-dose intravenous CYC are recommended as anchor drugs, and add-on therapy with belimumab or CNIs (voclosporin or tacrolimus) should be considered. Updated specific recommendations are also provided for cutaneous, neuropsychiatric and haematological disease, SLE-associated antiphospholipid syndrome, kidney protection, as well as preventative measures for infections, osteoporosis, cardiovascular disease. CONCLUSION: The updated recommendations provide consensus guidance on the management of SLE, combining evidence and expert opinion.

Anti-survival motor neuron complex antibodies as a novel biomarker for pulmonary arterial hypertension and interstitial lung disease in mixed connective tissue disease.

OBJECTIVE: The presence of anti-U1 RNP antibodies (Abs) is critical for diagnosing MCTD. The aim of this study is to evaluate the clinical relevance of anti-survival motor neuron (SMN) complex Abs, which often coexist with anti-U1 RNP Abs. METHODS: A total of 158 newly diagnosed consecutive cases of SLE, SSc or MCTD with anti-U1 RNP Abs were enrolled in this multicentre observational study between April 2014 and August 2022. Serum anti-SMN complex Abs were screened by immunoprecipitation of 35S-methionine-labelled cell extracts, and associations between anti-SMN complex Abs positivity and clinical characteristics were analysed. RESULTS: Anti-SMN complex Abs were detected in 36% of MCTD patients, which was significantly higher than that in SLE (8%) or SSc (12%). Among MCTD patients classified based on the combination of the clinical features of SLE, SSc and idiopathic inflammatory myopathies, anti-SMN complex Abs showed the highest prevalence in a subset with clinical features of all three components. Anti-SMN complex Abs-positive MCTD had a higher prevalence of pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD), which are related to poor prognosis, than negative patients. Moreover, all three cases of death within 1 year of the treatment were positive for anti-SMN complex Abs. CONCLUSIONS: Anti-SMN complex Abs is the first biomarker of a typical subset of MCTD which bears organ damages such as PAH and ILD.

Differential properties of Janus kinase inhibitors in the treatment of immune-mediated inflammatory diseases.

Janus kinases (JAKs) are a family of cytosolic tyrosine kinases that regulate cytokine signal transduction, including cytokines involved in a range of inflammatory diseases, such as RA, psoriasis, atopic dermatitis and IBD. Several small-molecule JAK inhibitors (JAKis) are now approved for the treatment of various immune-mediated inflammatory diseases. There are, however, key differences between these agents that could potentially translate into unique clinical profiles. Each JAKi has a unique chemical structure, resulting in a distinctive mode of binding within the catalytic cleft of the target JAK, and giving rise to distinct pharmacological characteristics. In addition, the available agents have differing selectivity for JAK isoforms, as well as off-target effects against non-JAKs. Other differences include effects on haematological parameters, DNA damage repair, reproductive toxicity and metabolism/elimination. Here we review the pharmacological profiles of the JAKis abrocitinib, baricitinib, filgotinib, peficitinib, tofacitinib and upadacitinib.

Comparison of anti-IL-6 receptor and JAK inhibitors in patients with rheumatoid arthritis from the real-world practice FIRST study.

OBJECTIVES: A molecular-targeted drug that is suitable as the second choice for patients with rheumatoid arthritis (RA) who show an inadequate response to the first biological disease-modifying antirheumatic drug (bDMARD) is unknown. This study aimed to analyze the efficacy and safety of interleukin-6 receptor (IL-6Ri) and Janus kinase inhibitors (JAKis), often selected as molecular-targeted drugs for second or subsequent treatments. METHODS: The efficacy and safety of JAKis and IL-6Ri were compared using propensity score-based inverse probability of treatment weighting (PS-IPTW) using propensity scores after 26 weeks of therapy in patients with RA. RESULTS: The remission rate at week 26, determined by the clinical disease activity index (CDAI), and the incidence of infection were higher in the JAKis than in the IL-6Ri group. The CDAI trajectories were divided into four according to the growth mixture modeling. IL-6Ri demonstrated greater efficacy in RA patients with ineffective to single bDMARD therapy compared with those with multiple ineffective bDMARDs. In patients who failed to respond to one bDMARD, there was no significant difference in the CDAI remission rate at week 26 between the JAKis (29.1%) and IL-6Ri (21.8%) groups (p= 0.21). However, for patients who did not respond to at least two bDMARDs, the CDAI remission rate at week 26 was higher in the JAKis than in the IL-6Ri group. CONCLUSIONS: IL-6Ri offers a superior balance of efficacy and safety compared with JAKis for RA patients unresponsive to one bDMARD. However, JAKis may suit patients who do not respond to multiple bDMARDs.

Efficacy, safety, and optimal intervention of belimumab for proliferative lupus nephritis patients in real-world settings: LOOPS registry.

OBJECTIVES: This study investigated the efficacy, safety, and predictive factors of belimumab (BEL) in induction therapy for patients with proliferative lupus nephritis (LN) in real-world settings. METHODS: Patients with biopsy-proven ISN/RPS class III or IV LN, with or without coexisting class V LN, who underwent standard of care (SoC), glucocorticoid (GC), and either mycophenolate mofetil or cyclophosphamide treatments were included. Participants were treated with SoC (SoC group, n = 32) or BEL and SoC (BEL+SoC group, n = 30). The primary end point was complete renal response (CRR) at 52 weeks. RESULTS: Baseline patient characteristics were not significantly different between the two groups. The 52-week retention rate of BEL was 90.0%. The BEL+SoC group showed significantly higher CRR and primary efficacy renal response achievement at 52 weeks and significantly lower GC dosage, adverse events, and Systemic Lupus International Collaborating Clinics damage index scores. Multivariate analysis of CRR achievement at 52 weeks revealed that the lack of estimated glomerular filtration rate (eGFR) improvement at 4 weeks was associated with CRR failure in the SoC group. A shorter duration (cut-off of 42 days) between the start of induction therapy and addition of BEL was also related to the CRR in the BEL+SoC group. CONCLUSION: BEL, in addition to SoC, controls disease activity, reduces GC use, and suppresses organ damage in case of proliferative LN. Earlier BEL induction within 6 weeks may help achieve CRR in treatment-resistant cases without eGFR improvement at 4 weeks after induction therapy.

Predictors of the effectiveness to first-line CTLA4-Ig in patients with rheumatoid arthritis: the FIRST registry.

OBJECTIVES: This study aimed to elucidate which bio-naïve patients with rheumatoid arthritis (RA) are suitable for treatment with CTLA4-Ig. METHODS: This study enrolled 953 patients with RA who were administered their first biological disease-modifying antirheumatic drug (CTLA4-Ig, n = 328; tumour necrosis factor inhibitor [TNFi], n = 625) from July 2013 to August 2022. The primary outcome was the Clinical Disease Activity Index (CDAI) remission rate at week 24 in each group, adjusted using Propensity Score-based Inverse Probability of Treatment Weighting (PS-IPTW). RESULTS: After minimizing selection bias using PS-IPTW, the CDAI remission showed no significant difference between the CTLA4-Ig and TNFi groups (p= 0.464). Multivariable logistic regression analysis identified low baseline Health Assessment Questionnaire-Disability Index (HAQ-DI) scores as a contributing factor to the CDAI remission rate at week 24 in both groups, along with high baseline anti-citrullinated peptide antibody (ACPA) levels in the CTLA4-Ig group. However, among patients with high baseline HAQ-DI scores and low baseline ACPA levels (≦57.2), the CDAI remission rate was significantly higher in the TNFi group (29.8%) compared with the CTLA4-Ig group (5.9%, p< 0.0001). Among patients with high baseline HAQ-DI scores and ACPA levels (>57.2), the CDAI remission rate was significantly higher in the CTLA4-Ig group (35.6%) compared with the TNFi group (22.1%, p= 0.0057). CONCLUSION: Bio-naive RA patients with low HAQ-DI scores showed high treatment efficacy with no significant difference between CTLA4-Ig and TNFi. Among patients with high baseline HAQ-DI scores, TNFi and CTLA4-Ig were more likely to be effective in those with lower and higher baseline ACPA levels, respectively.

Impact of high rheumatoid factor levels on treatment outcomes with certolizumab pegol and adalimumab in patients with rheumatoid arthritis.

OBJECTIVES: To assess the impact of baseline RF level on drug concentrations and efficacy of certolizumab pegol [CZP; TNF inhibitor (TNFi) without a crystallizable fragment (Fc)] and adalimumab (ADA; Fc-containing TNFi) in patients with RA. METHODS: The phase 4 EXXELERATE study (NCT01500278) was a 104-week, randomized, single-blind (double-blind until week 12; investigator-blind thereafter), head-to-head study of CZP vs ADA in patients with RA. In this post hoc analysis, we report drug concentration and efficacy outcomes stratified by baseline RF quartile (≤Q3 or >Q3). RESULTS: Baseline data by RF quartiles were available for 453 CZP-randomized and 454 ADA-randomized patients (≤Q3: ≤204 IU/ml; >Q3: >204 IU/ml). From week 12, the area under the curve (AUC) of ADA concentration was lower in patients with RF >204 IU/ml vs patients with RF ≤204 IU/ml; the AUC of CZP concentration was similar in patients with RF ≤204 IU/ml and >204 IU/ml. For patients with RF ≤204 IU/ml, disease activity score (DAS28)-CRP was similar between CZP- and ADA-treated patients through week 104. For patients with RF >204 IU/ml, mean DAS28-CRP was lower in CZP- vs ADA-treated patients at week 104. The proportion of patients with RF >204 IU/ml achieving DAS28-CRP low disease activity at week 104 was greater in CZP- vs ADA-treated patients. CONCLUSION: CZP was associated with maintained drug concentration and efficacy in patients with RA and high RF and may therefore be a more suitable therapeutic option than TNFis with an Fc fragment in these patients. TRIAL REGISTRATION: Clinicaltrials.gov, http://clinicaltrials.gov, NCT01500278.

SMART-SLE: serology monitoring and repeat testing in systemic lupus erythematosus-an analysis of anti-double-stranded DNA monitoring.

OBJECTIVE: Disease activity monitoring in SLE includes serial measurement of anti-double stranded-DNA (dsDNA) antibodies, but in patients who are persistently anti-dsDNA positive, the utility of repeated measurement is unclear. We investigated the usefulness of serial anti-dsDNA testing in predicting flare in SLE patients who are persistently anti-dsDNA positive. METHODS: Data were analysed from patients in a multinational longitudinal cohort with known anti-dsDNA results from 2013 to 2021. Patients were categorized based on their anti-dsDNA results as persistently negative, fluctuating or persistently positive. Cox regression models were used to examine longitudinal associations of anti-dsDNA results with flare. RESULTS: Data from 37 582 visits of 3484 patients were analysed. Of the patients 1029 (29.5%) had persistently positive anti-dsDNA and 1195 (34.3%) had fluctuating results. Anti-dsDNA expressed as a ratio to the normal cut-off was associated with the risk of subsequent flare, including in the persistently positive cohort (adjusted hazard ratio [HR] 1.56; 95% CI: 1.30, 1.87; P < 0.001) and fluctuating cohort (adjusted HR 1.46; 95% CI: 1.28, 1.66), both for a ratio >3. Both increases and decreases in anti-dsDNA more than 2-fold compared with the previous visit were associated with increased risk of flare in the fluctuating cohort (adjusted HR 1.33; 95% CI: 1.08, 1.65; P = 0.008) and the persistently positive cohort (adjusted HR 1.36; 95% CI: 1.08, 1.71; P = 0.009). CONCLUSION: Absolute value and change in anti-dsDNA titres predict flares, including in persistently anti-dsDNA positive patients. This indicates that repeat monitoring of dsDNA has value in routine testing.

Comparison of Attainment and Protective Effects of Lupus Low Disease Activity State in Patients With Newly Diagnosed Versus Established Systemic Lupus Erythematosus.

OBJECTIVE: To assess whether Lupus Low Disease Activity State (LLDAS) attainment is associated with favorable outcomes in patients with recent onset systemic lupus erythematosus (SLE). METHODS: Data from a 13-country longitudinal SLE cohort were collected prospectively between 2013 and 2020. An inception cohort was defined based on disease duration < 1 year at enrollment. Patient characteristics between inception and noninception cohorts were compared. Survival analyses were performed to examine the association between LLDAS attainment and damage accrual and flare. RESULTS: Of the total 4106 patients, 680 (16.6%) were recruited within 1 year of SLE diagnosis (inception cohort). Compared to the noninception cohort, inception cohort patients were significantly younger, had higher disease activity, and used more glucocorticoids, but had less organ damage at enrollment. Significantly fewer inception cohort patients were in LLDAS at enrollment than the noninception cohort (29.6% vs 52.3%, P < 0.001), but three-quarters of both groups achieved LLDAS at least once during follow-up. Limiting analysis only to patients not in LLDAS at enrollment, inception cohort patients were 60% more likely to attain LLDAS (hazard ratio 1.37, 95% CI 1.16-1.61, P < 0.001) than noninception cohort patients and attained LLDAS significantly faster. LLDAS attainment was significantly protective against flare in both the inception and noninception cohorts. A total of 88 (13.6%) inception cohort patients accrued organ damage during a median 2.2 years of follow-up. CONCLUSION: LLDAS attainment is protective from flare in recent onset SLE. Significant protection from damage accrual was not observed because of low rates of damage accrual in the first years after SLE diagnosis. (ClinicalTrials.gov: NCT03138941).

Vitamin D efficacy in type 1 and type 2 diabetes.

It is well known that vitamin D has a profound effect on calcium and bone metabolism, but its influence on other organs (extraskeletal effect) has been proposed. Consistently, vitamin D deficiency is associated with an increased incidence of various diseases, including type 1 and type 2 diabetes, as reported by many observational studies. However, there has been no consensus on whether vitamin D deficiency is a causative factor in the incidence of diabetes mellitus. There have been no randomized controlled trials (RCTs) aimed at preventing the onset of type 1 diabetes with vitamin D intake. In addition, the results of RCTs evaluating the preventive effect of vitamin D supplementation on type 2 diabetes development have been inconsistent. The recent observational studies, randomized controlled trials, and meta-analyses are confirming that vitamin D or active vitamin D administration is effective in preventing the incident of type 1 and type 2 diabetes.