Immunogenicity, reactogenicity, and safety of two-dose adjuvanted herpes zoster subunit vaccine in patients with systemic lupus erythematosus in South Korea: a single-centre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: The adjuvanted herpes zoster subunit vaccine has shown good efficacy and safety in the general population. However, its effectiveness has not been comprehensively assessed in patients with systemic lupus erythematosus (SLE). This study aimed to evaluate the immunogenicity and safety of the adjuvanted herpes zoster subunit vaccine in patients with SLE. METHODS: This single-centre, randomised, double-blind, placebo-controlled, trial was done at the rheumatology outpatient clinic at Seoul National University Hospital, South Korea. Patients (aged ≥19 years) with clinically stable SLE and previous exposure (≥4 weeks) to immunosuppressive drugs were randomly assigned (4:1) via a central interactive web response system to receive herpes zoster subunit vaccine or placebo (0·5 mL intramuscular injection) at weeks 0 and 8. Investigators and participants were masked to intervention and group assignment. Anti-glycoprotein E antibody titres and glycoprotein E-specific cell-mediated vaccine responses were evaluated at baseline and at week 8 after the first dose, and at week 4, week 26, and week 52 after the second dose using enzyme-linked immunosorbent assay and flow cytometry, respectively. Reactogenicity, SLE disease activity, including Systemic Lupus Erythematosus Disease Activity Index 2000 and British Isles Lupus Assessment Group-flare rate, were examined. The primary outcome was the proportion of patients with a positive humoral vaccine response 4 weeks after the second dose. The primary and safety analyses were done in a modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT06001606. FINDINGS: Between June 14, and July 19, 2023, 65 patients with SLE were enrolled, of whom 52 were randomly assigned to the herpes zoster subunit vaccine and 13 to placebo. 49 patients in the vaccine group and 11 patients in the placebo group were included in the modified intention-to-treat population. 56 (93%) of 60 patients were women and four (7%) were men. Mean age was 48·7 years (SD 11·4). The proportion of participants with a humoral vaccine response at 4 weeks after the second dose was significantly higher in the vaccine group (48 [98%] of 49 participants) than the placebo group (none [0%] of 11 patients; p<0·0001). More patients in the vaccine group than placebo group reported injection site reactions (42 patients vs two patients), fever (ten vs none), and fatigue (26 vs two). There were no differences in Systemic Lupus Erythematosus Disease Activity Index 2000 and British Isles Lupus Assessment Group-flare rates between the groups. There were no treatment-related deaths. INTERPRETATION: The herpes zoster subunit vaccine induces humoral and cellular immunity against herpes zoster with a good safety profile in patients with SLE. A larger study is warranted to assess the efficacy of vaccines to prevent herpes zoster in patients with SLE. FUNDING: Ministry of Science and ICT, The Government of the Republic of Korea.

Risk of urolithiasis associated with allopurinol versus benzbromarone among patients with gout: a population-based cohort study.

OBJECTIVES: To compare the risk of urolithiasis in gout patients initiating allopurinol, a xanthine oxidase inhibitor, vs benzbromarone, a uricosuric. METHODS: Using the 2011-2020 Korea National Health Insurance Service database, we conducted a cohort study on gout patients initiating allopurinol vs benzbromarone as the 1st-line urate-lowering treatment (ULT). The primary outcome was a new onset urinary stone. The secondary outcome was a stone requiring intervention. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox proportional hazard models with a 5:1 ratio propensity-score matching on > 80 variables. Subgroup analyses were done by age, sex, thiazide use, and cardiovascular (CV) risk. RESULTS: 61 300 allopurinol initiators PS-matched on 12 260 benzbromarone initiators were included (mean age 59 years, 79% male). During a mean follow-up of 322 days, 619 urolithiasis cases occurred with an incidence rate of 0.87 per 100 person-years in allopurinol and 1.39 in benzbromarone initiators, showing a HR of 0.64 (95% CI, 0.51-0.80). ∼44% of urinary stones required intervention with a HR of 0.61 (95% CI 0.43-0.88). The lower risk associated with allopurinol compared with benzbromarone persisted across subgroups but was greater in the high than non-high CV risk subgroup (p for interaction = 0.02). CONCLUSION: This population-based cohort study found that allopurinol compared with benzbromarone was associated with a substantially lower risk of urolithiasis particularly in the presence of the high CV risk. This finding provides important safety information for clinicians' decision-making on ULTs of different mechanisms of action.

Long-Term Outcome of Tofacitinib Treatment for Systemic Autoimmune Disease-Associated Refractory Scleritis.

PURPOSE: To report the long-term outcome of three refractory anterior scleritis cases successfully treated with tofacitinib, a Janus-associated kinase inhibitor. METHODS: Three patients with systemic autoimmune disease-associated anterior scleritis (two with rheumatoid arthritis and one with systemic lupus erythematosus), resistant to conventional immunomodulatory therapy, were subsequently treated with tofacitinib (10 mg/day). RESULTS: Tofacitinib resulted in complete resolution of scleritis in all patients. During the 39-78 months of follow-up, no recurrence of scleritis occurred, and no adverse effects associated with tofacitinib were noted. At the last follow-up, all patients were free of scleritis with two patients receiving tofacitinib monotherapy and one without. CONCLUSION: Tofacitinib can be a safe and effective treatment for noninfectious refractory scleritis, warranting further investigation in large clinical trials.

Successful treatment of hemophagocytic lymphohistiocytosis in a patient with systemic lupus erythematosus with ruxolitinib: a case report.

Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening hematological disorder characterized by uncontrolled activation of CD8+ T and natural killer cells, leading to a cytokine storm and severe organ dysfunction. Although secondary HLH related to autoimmune diseases usually demonstrates a good treatment response to immunosuppressive therapy for underlying conditions, there is no consensus regarding the treatment in case of unresponsiveness to the treatment. Herein, we present a case of HLH that was unresponsive to high-dose glucocorticoid and cyclosporine treatment in a patient with newly diagnosed systemic lupus erythematosus. The patient's clinical features and laboratory abnormalities rapidly improved with ruxolitinib, an oral Janus kinase 1 and 2 (JAK1/2) inhibitor. This result suggests that blocking JAK-STAT pathway may be a potential treatment option in patients with refractory HLH secondary to autoimmune diseases.

Approval status of essential therapeutic drugs for systemic sclerosis versus that of drugs for rheumatoid arthritis.

Objective: Systemic sclerosis, a rare disease characterized by chronic multisystem fibrosis, requires lifelong management, necessitating enough insurance coverage for the patient. Official drug approval is the first step to ensuring that the drug is covered by insurance. In this study, we investigated the approval status of essential therapeutic drugs for systemic sclerosis across eight countries and compared it with that of drugs for rheumatoid arthritis. Methods: The essential therapeutic drug lists for systemic sclerosis and rheumatoid arthritis were taken from the guidelines of the American College of Rheumatology and the European Alliance of Associations for Rheumatology. Official drug approval status for the selected drugs was confirmed by searching representative Internet databases from eight countries: the United States, the United Kingdom, Germany, France, Italy, Switzerland, Japan, and the Republic of Korea. Results: A total of 21 and 16 drugs were selected for systemic sclerosis and rheumatoid arthritis, respectively. The drug approval rates of the 21 drugs for systemic sclerosis varied among countries. Most drugs used to treat pulmonary arterial hypertension, which were developed recently and are expensive, are approved by most countries; however, most older drugs-which are still essential for management of Raynaud's phenomenon, digital ulcers, interstitial lung disease, and skin fibrosis-are not approved by most countries. By contrast, almost all of the 16 drugs used to treat rheumatoid arthritis, whether old or new, are approved by most countries. Conclusion: Approval rates for drugs used to treat systemic sclerosis, a rare disease, are much lower than those for drugs used to treat rheumatoid arthritis. Thus, approval rates of essential therapeutic drugs for systemic sclerosis need to improve, which will benefit patients by increasing the number of drugs covered by insurance.

Impact of socioeconomic status on biologics utilization in rheumatoid arthritis: revealing inequalities and healthcare efficiency.

BACKGROUND/AIMS: This cross-sectional study aimed to investigate biologics treatment disparities in rheumatoid arthritis (RA) patients based on socioeconomic status (SES). METHODS: Data from the KOrean Observational Study Network for Arthritis (KORONA) database were analyzed to assess various factors associated with SES, health behaviors, and biologics use. Logistic regression and structured equation modeling (SEM) were utilized for data analysis. RESULTS: Among 5,077 RA patients included, 393 (7.7%) patients were identified as biologics users. Within the entire cohort, 31.8% of the participants were in the low-income and low-education groups, and 39.3% of the participants were in the high-income and high-education groups. Despite the patients with low income or low education experienced higher disease activity at diagnosis, had more comorbidities, exhibited higher medication compliance, underwent more check-ups, and had more hospital admissions than their counterparts, the odds of patients with low-income receiving biologics were 34% lower (adjusted odds ratio = 0.76, 95% confidence interval: 0.60-0.96, p = 0.021) after adjustment for demographics and comorbidities. SEM and pathway analyses confirmed the negative impact of low SES on biologics use. CONCLUSION: The findings suggest that SES plays a significant role in biologics use among RA patients, indicating potential healthcare inefficiencies for low SES patients. Moreover, adverse healthcare habits negatively affect biologics use in RA patients. The study highlights the importance of considering socioeconomic factors while discussing biologics use and promoting equitable access to biologics for optimal RA management.

All-cause and cause-specific mortality in patients with Behçet disease versus the general population.

BACKGROUND: The comparative risk of cause-specific mortality in patients with Behçet disease (BD) vs. the general population is not known. OBJECTIVES: To compare the risk of all-cause and cause-specific mortality in patients with BD vs. the general population. METHODS: Using data from the Korea National Health Insurance Service database for the period 2002-20, we conducted a cohort study comparing patients with BD with the general population, matched according to age and sex (1 : 4 ratio). We used Cox proportional hazard models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cause-specific mortality. Subgroup analyses by age and sex were done. RESULTS: We included 24 669 patients with BD and 98 676 age- and sex-matched controls [mean (SD) age 40.5 (12.9) years; 34% male]. During a mean follow-up of 11.9 years, the incidence rate (IR) of death per 100 person-years was 0.36 in patients with BD and 0.29 in controls [hazard ratio (HR) 1.28, 95% confidence interval (CI) 1.20-1.38]. The risk of mortality was highest in the first year after BD diagnosis (HR 2.66, 95% CI 2.09-3.40). Patients with BD died more often in this period as a result of malignancy (HR 1.96, 95% CI 1.30-2.98); cardiovascular (HR 2.68, 95% CI 1.45-4.97), gastrointestinal (HR 3.50, 95% CI 1.35-9.07) and respiratory disease (HR 5.00, 95% CI 1.34-18.62); and infection (HR 3.33, 95% CI 1.02-10.92). Mortality as a result of neurological (HR 1.58, 95% CI 1.06-2.35) or genitourinary disease (HR 2.20, 95% CI 1.43-3.37) was also more common in patients with BD during the overall follow-up. Subgroup analyses showed consistent results. The risk of cardiovascular mortality vs. the general population was higher in younger patients (P = 0.006) and the risk of gastrointestinal mortality was increased in women vs. men (P = 0.04). CONCLUSIONS: This population-based cohort study revealed that the first year after diagnosis is the highest risk period for excess mortality in people with BD. The mortality burden in BD derives from a wide spectrum of organ involvement and should serve as a warning to clinicians about the systemic nature of the disease.

Behçet disease (BD) is a multisystem vasculitis (inflammation of the blood vessels) of unknown origin that commonly results in oral and genital ulcers, uveitis (eye inflammation) and skin lesions. BD is most prevalent in people from the Mediterranean to East Asia, affecting 0.4% of people in this area. Most lesions go away with time, but more severe forms that involve the cardiovascular and neurological systems can lead to death. It is estimated that people with BD have 1.4 times the risk of dying than the general population. Using large insurance databases in Korea, we investigated the risk of death in people with BD versus age- and sex-matched controls (i.e. people without the disease) from the general population. We found that patients with BD had a 28% greater risk of death than controls over 11.9 years of follow-up, with the highest risk being in first year after diagnosis. Top causes of death in people with BD included cancer, and cardiovascular, gastrointestinal, neurological, genitourinary, respiratory and infectious disease. Further analyses of the data showed that the risk of death in BD is affected by age and sex. In particular, younger patients were more susceptible to death as a result of cardiovascular disease and women were more susceptible to dying of gastrointestinal disease. Our study suggests that there could be an increased risk of death within the first year of being diagnosed with BD and highlights how BD is a systemic disease (i.e. the involvement of any internal organ system could lead to an increase in mortality). Finally, there were unique patterns of cause-specific deaths across subgroups of people with BD.

What rheumatologists need to know about mRNA vaccines: current status and future of mRNA vaccines in autoimmune inflammatory rheumatic diseases.

Messenger RNA (mRNA) vaccines as a novel vaccine platform offer new tools to effectively combat both emerging and existing pathogens which were previously not possible. The 'plug and play' feature of mRNA vaccines enables swift design and production of vaccines targeting complex antigens and rapid incorporation of new vaccine constituents as needed. This feature makes them likely to be adopted for widespread clinical use in the future.Currently approved mRNA vaccines include only those against SARS-CoV-2 virus. These vaccines demonstrate robust immunogenicity and offer substantial protection against severe disease. Numerous mRNA vaccines against viral pathogens are in the early to late phase of development. Several mRNA vaccines for influenza are tested in clinical trials, with some already in phase 3 studies. Other vaccines in the early and late phases of development include those targeting Cytomegalovirus, varicella zoster virus, respiratory syncytial virus and Epstein-Barr virus. Many of these vaccines will likely be indicated for immunosuppressed populations including those with autoimmune inflammatory rheumatic diseases (AIIRD). This review focuses on the mechanism, safety and efficacy of mRNA in general and summarises the status of mRNA vaccines in development for common infectious diseases of particular interest for patients with AIIRD.

Modeling of antibody responses to COVID-19 vaccination in patients with rheumatoid arthritis.

To construct a model of the antibody response to COVID-19 vaccination in patients with rheumatoid arthritis (RA), and to identify clinical factors affecting the antibody response. A total of 779 serum samples were obtained from 550 COVID-19-naïve RA patients who were vaccinated against COVID-19. Antibody titers for the receptor binding domain (anti-RBD) and nucleocapsid (anti-N) were measured. The time from vaccination, and the log-transformed anti-RBD titer, were modeled using a fractional polynomial method. Clinical factors affecting antibody responses were analyzed by a regression model using generalized estimating equation. The anti-RBD titer peaked at about 2 weeks post-vaccination and decreased exponentially to 36.5% of the peak value after 2 months. Compared with the first vaccination, the 3rd or 4th vaccinations shifted the peaks of anti-RBD antibody response curves significantly upward (by 28-fold [4-195] and 32-fold [4-234], respectively). However, there was no significant shift in the peak from the 3rd vaccination to the 4th vaccination (p = 0.64). Multivariable analysis showed that sulfasalazine increased the vaccine response (by 1.49-fold [1.13-1.97]), but abatacept or JAK inhibitor decreased the vaccine response (by 0.13-fold [0.04-0.43] and 0.44-fold [0.26-0.74], respectively). Age was associated with lower ln [anti-RBD] values (coefficient: - 0.03 [- 0.04 to - 0.02]). In conclusion, the anti-RBD response of RA patients peaked at 2 weeks after COVID-19 vaccination, and then decreased exponentially, with the maximum peak increase observed after the 3rd vaccination. The antibody response was affected by age and the medications used to treat RA.

COVID-19 infection and efficacy of vaccination in patients with rheumatic diseases during Omicron outbreak in South Korea: a prospective cohort study.

OBJECTIVES: This study aims to investigate COVID-19 epidemiological data in patients with autoimmune inflammatory rheumatic diseases (AIRDs) during Omicron wave and to identify clinical factors associated with infection, including COVID-19 vaccination. METHODS: This prospective longitudinal study was performed between January and October 2022 in South Korea. Patients were classified into AIRD and non-AIRD groups according to their underlying diseases. COVID-19 status, date of confirmed infection and vaccination status were captured from the patient survey and national database. The COVID-19 incidence during the study period was examined and compared between the two groups. The effect of clinical factors on the infection rate was analysed in the AIRD group. RESULTS: A total of 1814 patients (1535 and 279 in the AIRD and non-AIRD groups, respectively) were analysed. During the study period, 857 COVID-19 cases were reported in 834 patients (46.0%). The infection rates in the AIRD and non-AIRD groups were comparable. In the AIRD group, older age (≥70 years) and glucocorticoid use were significantly associated with a lower rate of COVID-19 infection. The third booster vaccination significantly lowered the incidence of COVID-19 (adjusted HR 0.85 (95% CI 0.73 to 0.99)), and the prophylactic effect was more evident in patients aged <70 years (0.81 (95% CI 0.69 to 0.95), p value for interaction 0.036). CONCLUSION: The risk of SARS-CoV-2 infection with the Omicron variant did not increase in patients with AIRDs. The third booster vaccination regimen decreased the infection rate in patients aged <70 years.

Association of Tumor Necrosis Factor Inhibitors with the Risk of Nontuberculous Mycobacterial Infection in Patients with Rheumatoid Arthritis: A Nationwide Cohort Study.

Tumor necrosis factor inhibitors (TNFi) are proposed as a risk factor for nontuberculous mycobacteria (NTM) infection. Limited research investigates NTM infection risk in rheumatoid arthritis (RA) patients treated with TNFi compared to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), considering other concurrent or prior non-TNFi antirheumatic drugs. We aimed to evaluate the NTM infection risk associated with TNFi using a real-world database. Patients with RA treated with TNFi or csDMARDs between 2005 and 2016 were identified utilizing the Korean National Health Insurance Service database. To minimize potential bias, we aligned the initiation year of csDMARDs for both TNFi and csDMARD users and tracked them from their respective treatment start dates. The association of TNFi with NTM infection risk was estimated in a one-to-one matched cohort using a multivariable conditional Cox regression analysis. In the matched cohort (n = 4556), the incidence rates of NTM infection were 2.47 and 3.66 per 1000 person-year in TNFi and csDMARD users. Compared to csDMARDs, TNFi did not increase the risk of NTM infection (adjusted hazard ratio (aHR) 0.517 (95% confidence interval, 0.205-1.301)). The TNFi use in RA patients was not associated with an increased risk of NTM infection compared to csDMARDs. Nevertheless, monitoring during TNFi treatment is crucial.

Physicians' Agreement on and Implementation of the 2019 European Alliance of Associations for Rheumatology Vaccination Guideline: An International Survey.

Objective: To evaluate the perspective of healthcare professionals towards the 2019 European Alliance of Associations for Rheumatology (EULAR) vaccination guideline in patients with autoimmune inflammatory rheumatic diseases (AIIRD). Methods: Healthcare professionals who care for patients with AIIRD were invited to participate in an online survey regarding their perspective on the 2019 update of the EULAR recommendations for vaccination in adult patients with AIIRD. Level of agreement and implementation of the 6 overarching principles and 9 recommendations were rated on a 5-point Likert scale (1~5). Results: Survey responses of 371 healthcare professionals from Asia (42.2%) and North America (41.6%), Europe (13.8%), and other countries were analyzed. Only 16.3% of participants rated their familiarity with the 2019 EULAR guideline as 5/5 ("very well"). There was a high agreement (≥4/5 rating) with the overarching principles, except for the principles applying to live-attenuated vaccines. There was a high level of agreement with the recommendations regarding influenza and pneumococcal vaccinations; implementation of these recommendations was also high. Participants also reported a high level of agreement with the remaining recommendations but did not routinely implement these recommendations. Conclusion: The 2019 update of EULAR recommendations for the vaccination of adult patients with AIIRD is generally thought to be important by healthcare professionals, although implementation of adequate vaccination is often lacking. Better education of healthcare providers may be important to optimize the vaccination coverage for patients with AIIRD.

Comparative risk of infections between JAK inhibitors versus TNF inhibitors among patients with rheumatoid arthritis: a cohort study.

BACKGROUND: To compare infectious risk between JAK inhibitors (JAKis) versus TNF inhibitors (TNFis) among rheumatoid arthritis (RA) patients in Korea. METHODS: Using 2009-2019 Korea National Health Insurance Service database, we conducted a cohort study on RA patients initiating a JAKi or TNFi. The primary outcomes were herpes zoster (HZ), serious bacterial (SBI), and opportunistic infections (OI). Propensity-score fine-stratification (PSS) and weighting were applied to adjust for > 70 baseline covariates. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard models comparing JAKi versus TNFi users. RESULTS: We included 2963 JAKi initiators PSS-weighted on 5169 TNFi initiators. During a follow-up of 1.16 years, the most frequent type of infections was HZ with incidence rate (IR) per 100 person-years of 11.54 and 4.88 in JAKi and TNFi users, respectively. The IR of SBI was 1.39 and 1.32, respectively. The OI was rare with a majority being tuberculosis and showed an IR of 0.11 and 0.49 in JAKi and TNFi users, respectively. The PSS-weighted HR (95% CI) for individual types of infections was 2.37 (2.00-2.80) for HZ, 1.04 (0.71-1.52) for SBI, and 0.25 (0.09-0.73) for OI. CONCLUSIONS: This population-based cohort study on RA patients treated with JAKi or TNFi in Korea showed an exceptionally high IR of HZ in both treatment groups compared to that from Western countries, with an approximately doubled risk associated with JAKi versus TNFi use. The risk of SBI was comparable, but the risk of OI, particularly tuberculosis, was less among JAKi than TNFi initiators.

Gastrointestinal Tract Considerations Part I: How Should a Rheumatologist Best Manage Common Upper Gastrointestinal Tract Complaints in Systemic Sclerosis?

The upper gastrointestinal (GI) tract is frequently involved in systemic sclerosis (SSc) and may impact quality of life, physical function and survival. Although we are currently very proactive in terms of screening for heart and lung involvement, patients with SSc are not routinely screened for GI involvement. This review details the available investigations for common upper GI symptoms in SSc, including dysphagia, reflux and bloating and provides advice as to how to integrate these investigations into current clinical care.

Gastrointestinal Tract Considerations: Part II: How Should a Rheumatologist Best Manage Common Lower Gastrointestinal Tract Complaints in Systemic Sclerosis?

Lower gastrointestinal (GI) symptoms are a frequently encountered problem for clinicians managing patients with systemic sclerosis. The current management practices are focused on the treatment of symptoms with little information available on how to use GI investigations in daily practice. This review demonstrates how to integrate the objective assessment of common lower GI symptoms into clinical care with the aim of guiding clinical decision making. Understanding the type of abnormal GI function that is affecting a patient and determining which parts of the gut are impacted can help clinicians to target therapy more precisely.

Risk-Benefit Analysis of Primary Prophylaxis Against Pneumocystis Jirovecii Pneumonia in Patients With Rheumatic Diseases Receiving Rituximab.

OBJECTIVE: To identify a specific population of patients with rheumatic diseases receiving rituximab treatment for whom the benefit from primary prophylaxis against Pneumocystis jirovecii pneumonia (PJP) outweighs the risk of adverse events (AEs). METHODS: This study included 818 patients treated with rituximab for rheumatic diseases, among whom 419 received prophylactic trimethoprim/sulfamethoxazole (TMP/SMX) with rituximab, while the remainder did not. Differences in 1-year PJP incidence between the groups were estimated using Cox proportional hazards regression. Risk-benefit assessment was performed in subgroups stratified according to risk factors based on the number needed to treat (NNT) to prevent 1 case of PJP and the number needed to harm (NNH) due to severe AEs. Inverse probability of treatment weighting was applied to minimize the confounding by indication. RESULTS: During the 663.1 person-years, there were 11 PJP cases, with a mortality rate of 63.6%. Concomitant use of high-dose glucocorticoids (≥30 mg/day of prednisone or equivalent during 4 weeks after rituximab administration) was the most important risk factor. The PJP incidence (per 100 person-years) was 7.93 (95% confidence interval [95% CI] 2.91-17.25) in the subgroup receiving high-dose glucocorticoids compared with 0.40 (95% CI 0.01-2.25) in the subgroup without high-dose glucocorticoid use. Although prophylactic TMP/SMX significantly reduced the overall PJP incidence (HR 0.11 [95% CI 0.03-0.43]), the NNT to prevent 1 case of PJP (146) was higher than the NNH (86). In contrast, the NNT fell to 20 (95% CI 10.7-65.7) in patients receiving concomitant high-dose glucocorticoids. CONCLUSION: The benefit associated with primary PJP prophylaxis outweighs the risk of severe AEs in patients with rheumatic diseases receiving rituximab and concomitant high-dose glucocorticoid treatment.

Efficacy and Safety of Lenabasum, a Cannabinoid Type 2 Receptor Agonist, in a Phase 3 Randomized Trial in Diffuse Cutaneous Systemic Sclerosis.

OBJECTIVE: This phase 3 study was undertaken to investigate the efficacy and safety of lenabasum, a cannabinoid type 2 receptor agonist, in patients with diffuse cutaneous systemic sclerosis (dcSSc). METHODS: A multinational double-blind study was conducted in 365 dcSSc patients who were randomized and dosed 1:1:1 with lenabasum 20 mg, lenabasum 5 mg, or placebo, each twice daily and added to background treatments, including immunosuppressive therapies (IST). RESULTS: The primary end point, the American College of Rheumatology combined response index in dcSSc (CRISS) at week 52 for lenabasum 20 mg twice a day versus placebo, was not met, with CRISS score of 0.888 versus 0.887 (P = 0.4972, using mixed models repeated measures [MMRM]). The change in the modified Rodnan skin thickness score (MRSS) at week 52 for lenabasum 20 mg twice a day versus placebo was -6.7 versus -8.1 (P = 0.1183, using MMRM). Prespecified analyses showed higher CRISS scores, greater improvement in MRSS, and lower decline in forced vital capacity in patients on background mycophenolate and those who were taking IST for ≤1 year. No deaths or excess in serious or severe adverse events related to lenabasum were observed. CONCLUSION: A benefit of lenabasum in dcSSc was not demonstrated. Most patients were treated with background IST, and treatment with mycophenolate mofetil in particular was associated with better outcomes. These findings support the use of IST in the treatment of dcSSc and highlight the challenge of demonstrating a treatment effect when investigational treatment is added to standard of care IST. These findings have relevance to trial design in SSc, as well as to clinical care.

Risk of Bloodstream Infection in Patients with Systemic Lupus Erythematosus Exposed to Prolonged Medium-to-High-Dose Glucocorticoids.

OBJECTIVES: This study aimed to investigate the incidence rate and risk factors of bloodstream infection (BSI) in patients with systemic lupus erythematosus (SLE) exposed to medium to high doses of glucocorticoids. METHODS: This study included 1109 treatment episodes with prolonged (≥4 weeks) medium-to-high-dose glucocorticoids (≥15 mg/day prednisolone) in 612 patients with SLE for over 14 years. Clinical features regarding systemic lupus erythematosus disease activity index 2000 (SLEDAI-2K), immunosuppressant use, and laboratory results were obtained from the electronic medical database. The primary outcome of this study was the 1-year incidence of BSI. The effect of clinical factors on the outcome was investigated using a generalized estimating equation. RESULTS: During a total of 1078.64 person-years, 30 cases of BSI occurred, with an incidence rate of 2.78 (95% confidence interval (CI) 1.88-3.97) per 100 person-years. Mortality rate of the treatment episodes with BSI was 16.7%, which was significantly higher than that in the other episodes (incidence rate ratio (IRR) 19.59, 95% CI 7.33-52.44). When the incidence rate of BSI was stratified by baseline glucocorticoid dose and SLEDAI-2K score, a higher incidence rate of BSI occurred as disease activity or baseline glucocorticoid dose increased. In the multivariable analysis, SLEDAI-2K ≥20 (adjusted IRR (aIRR) 4.66, 95% CI 2.17-10.00), initial baseline prednisolone ≥ 60 mg/day (aIRR 2.42, 95% CI 1.11-5.32), and cumulative prednisolone dose ≥15 mg/day during the previous 6 months (aIRR 2.13, 95% CI 1.03-4.40) significantly increased the risk of BSI. CONCLUSION: In patients with SLE exposed to prolonged medium-to-high-dose glucocorticoids, the 1-year incidence rate of BSI was significantly higher than previously reported in the general patients with SLE. Severe disease activity, and high-dose glucocorticoid treatment previously or at baseline increased the risk of BSI.