Safety of the JAK and TNF inhibitors in rheumatoid arthritis: real world data from the Hong Kong Biologics Registry.

OBJECTIVES: To compare the incidence of major adverse cardiovascular events (MACEs), cancer and infective complications in RA patients using Janus kinase (JAKis) and TNF (TNFis) inhibitors. METHOD: A retrospective analysis of data from the Hong Kong Biologics Registry 2008-2021 was performed. RA patients who had ever used JAKis or TNFis were included. The incidence of MACEs, cancer and infections were compared between the two groups, with adjustment for confounding factors. RESULTS: A total of 2471 courses of JAKis (n = 551) and TNFis (n = 1920) were used in 1732 RA patients (83.7% women, age 53.8 [12.5] years; follow-up 6431 patient-years). JAKi users had significantly older age, more atherosclerotic risk factors and higher frequency of past malignancies. A total of 15 and 40 MACEs developed in the JAKi and TNFi users, respectively (incidence 1.34 vs 0.75 per 100 patient-years; P = 0.22). There was no significant difference in the incidence of cancers between the two groups (0.81 [JAKi] vs 0.85 [TNFi] per 100 patient-years; P = 0.25). The adjusted hazard ratios of MACE and cancer in the JAKi users were 1.36 (95% CI: 0.62, 2.96) (P = 0.44) and 0.87 (95% CI: 0.39, 1.95) (P = 0.74), respectively. Rates of infections were significantly higher in the JAKi than TNFi users (16.3 vs 9.9 per 100 patient-years; P = 0.02), particularly herpes zoster (3.49 vs 0.94 per 100 patient-years; P < 0.001). CONCLUSIONS: In a real-life setting, there is no increase in MACEs or cancers in users of JAKis compared with TNFis. However, the incidence of non-serious infections, including herpes zoster, was increased in users of JAKis.

Five-year cardiovascular event risk in early rheumatoid arthritis patients who received treat-to-target management: a case-control study.

OBJECTIVES: This study explored whether the excess cardiovascular (CV) disease (CVD) risk in RA could be ameliorated by suppression of inflammation using a treat-to-target (T2T) approach. We compared the CV event (CVE) incidence among ERA patients managed by a T2T strategy with a CV risk factor-matched non-RA population and a historical RA cohort (HRA). METHODS: This was an observational study using the city-wide hospital data and the ERA registry. ERA patients received T2T management while HRA patients received routine care. Each ERA/HRA patient was matched to three non-RA controls according to age, gender and CV risk factors. Patients on antiplatelet/anticoagulant agents, with pre-existing CVD, chronic kidney disease or other autoimmune diseases were excluded. All subjects were followed for up to 5 years. The primary end point was the first occurrence of a CVE. RESULTS: The incidence of CVE in the ERA cohort (n = 261) and ERA controls were similar with a hazard ratio of 0.53 (95% CI 0.15, 1.79). In contrast, the incidence of CVE in the HRA cohort (n = 268) was significantly higher than that of the HRA controls with a hazard ratio of 1.9 (95% CI 1.16, 3.13). The incidence of CVE in the ERA cohort was significantly lower than that of the HRA cohort and the difference became insignificant after adjusting for inflammation, the use of methotrexate and traditional CV risk factors. CONCLUSION: ERA patients managed by a T2T strategy did not develop excess CVE compared with CV risk factor-matched controls over 5 years.

Effects of RANKL inhibition on promoting healing of bone erosion in rheumatoid arthritis using HR-pQCT: a 2-year, randomised, double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate the effects of denosumab on erosion healing at 2-4 metacarpophalangeal (MCP) head as determined by high-resolution peripheral quantitative CT (HR-pQCT) in patients with rheumatoid arthritis (RA) with stable disease. METHODS: This was a randomised, placebo-controlled, double-blind study. Patients with RA with disease activity score 28 joints (DAS28) ≤5.1 were randomised (1:1) to subcutaneous denosumab 60 mg or placebo once every 6 months for 24 months. The primary outcome was erosion healing at MCP 2-4 on HR-pQCT at 12 months. The effects of denosumab on erosion and joint space parameters on HR-pQCT and radiographs, disease activity and health assessment questionnaire-disability index (HAQ-DI) were also examined. RESULTS: At 24 months, HR-pQCT images were analysed in 98 patients. One-third of the patients achieved sustained low disease activity throughout the study. At 12 months, changes in erosion parameters on HR-pQCT were similar between the two groups. At 24 months, new erosions (19% vs 9%, p=0.009) and erosion progression (18% vs 8%, p=0.019) were more common in the placebo group than the denosumab group. Erosion healing was seen in a significantly higher proportion of patients in the denosumab group (20% vs 6%, p=0.045) at 24 months. No significant changes in joint space parameters on HR-pQCT, van der Heijde-Sharp erosion score, DAS28 and HAQ-DI were observed in the two groups at 12 and 24 months. CONCLUSION: Although no differences in erosion parameters were observed at 12 months, denosumab was more efficacious than placebo in erosion repair on HR-pQCT after 24 months. TRIAL REGISTRATION NUMBER: NCT03239080.

Role of Interleukin 6 Inhibitors in the Management of Rheumatoid Arthritis.

ABSTRACT: Rheumatoid arthritis (RA) is a multisystem disease that affects the joints and various organs, resulting in compromised quality of life and increased mortality. A wide spectrum of treatment options is available for RA. Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) are the first-line of treatment for RA, whereas tumor necrosis factor α inhibitors are commonly used as a second-line biological disease-modifying antirheumatic drug following inadequate response to csDMARDs. However, remission remains difficult to achieve. No single agent is effective for all patients. It is important to consider patients' comorbidities, perspectives, and preferences when selecting treatment.Interleukin 6 (IL-6) plays a prominent role in the pathophysiology of RA and is an important therapeutic target for RA. Tocilizumab and sarilumab are approved IL-6 inhibitors, which have demonstrated good efficacy and tolerability as combination therapy or monotherapy in RA patients with inadequate response to csDMARDs or tumor necrosis factor α inhibitors. Apart from alleviating joint symptoms, inducing remission, and reducing structural damage, tocilizumab and sarilumab exhibit additional advantages in alleviating extra-articular symptoms, such as fatigue and morning stiffness, and have positive effect on anemia and glucose metabolism. Additionally, evidence showed that certain patient subgroups, such as those with comorbidities including anemia and diabetes mellitus, those with early RA, those with high baseline IL-6 levels, those at high risk of tuberculosis infection, or those intolerant to methotrexate monotherapy, may benefit from IL-6 inhibition. Given these advantages, tocilizumab and sarilumab can be considered earlier as a rational choice for treating RA in suitable patients. Future clinical investigations will help refine the use of these agents.

DAPSA, carotid plaque and cardiovascular events in psoriatic arthritis: a longitudinal study.

OBJECTIVE: To examine whether Disease Activity in Psoriatic Arthritis (DAPSA) reflecting the inflammatory component of psoriatic arthritis (PsA) can predict cardiovascular (CV) events independent of traditional CV risk factors and subclinical carotid atherosclerosis. METHODS: A cohort analysis was performed in patients with PsA who had been followed since 2006. The outcome of interest was first CV event. Four different CV disease (CVD) risk scores and DAPSA were computed at baseline. The presence of carotid plaque (CP) and carotid intima-media thickness (CIMT) was also determined in a subgroup of patients using high-resolution ultrasound. The association between DAPSA, CVD risk scores, CP, CIMT and the occurrence of CV events was assessed using Cox proportional hazard models. RESULTS: 189 patients with PsA (mean age: 48.9 years; male: 104 (55.0%)) were recruited. After a median follow-up of 9.9 years, 27 (14.3%) patients developed a CV event. Higher DAPSA was significantly associated with an increased risk of developing CV events (HR: 1.04, 95% CI (1.01 to 1.08), p=0.009). The association remained significant after adjusting for all CV risk scores in the multivariable models. In the subgroup analysis, 154 patients underwent carotid ultrasound assessment and 23 (14.9%) of them experienced a CV event. CP was associated with increased risk of developing CV events after adjusting for three CV risk scores and DAPSA, with HR ranging from 2.35 to 3.42. CONCLUSION: Higher DAPSA and the presence of CP could independently predict CVD events in addition to traditional CV risk scores in patients with PsA.

Rationale and design of the screening of pulmonary hypertension in systemic lupus erythematosus (SOPHIE) study.

Current guideline-recommended screening for pulmonary hypertension in patients with systemic sclerosis has not been evaluated in systemic lupus erythematosus (SLE), which is disproportionately prevalent in Asians. This multicentre, cross-sectional screening study aims to study the prevalence of pulmonary hypertension among SLE patients using these guidelines, and identify independent predictors and develop a prediction model for pulmonary hypertension in SLE patients. SLE patients from participating centres will undergo an echocardiography- and biomarker-based pulmonary hypertension screening procedure as in the DETECT study. Standard right heart catheterisation will be provided to patients with intermediate or high echocardiographic probability of pulmonary hypertension. Those with low echocardiographic probability will rescreen within 1 year. The primary measure will be the diagnosis and types of pulmonary hypertension and prevalence of pulmonary hypertension in SLE patients. The secondary measures will be the predictors and prediction models for pulmonary hypertension in SLE patients. The estimated sample size is approximately 895 participants. The results of the SOPHIE study will be an important contribution to the literature of SLE-related pulmonary hypertension and may be immediately translatable to real clinical practice. Ultimately, this study will provide the necessary evidence for establishing universal guidelines for screening of pulmonary hypertension in SLE patients.

Hyperuricemia in Asian psoriatic arthritis patients.

AIM: It is generally accepted that hyperuricemia is commonly associated with psoriatic arthritis (PsA). However, variations in ethnicity, diet and habitat may contribute to differences in prevalence and risk factors for hyperuricemia in PsA patients. Moreover, Asian specific data is deficient. The primary objective of the present study was to determine the prevalence of hyperuricemia among PsA patients. The secondary objective was to explore its associated risk factors. METHODS: This was a multi-center, cross-sectional observational study of 160 PsA patients from local Rheumatology clinics. Serum uric acid (SUA) level and other clinical parameters were measured and hyperuricemia was defined as SUA level greater or equal to 360 umol/L in females and 420 umol/L in males. RESULTS: Forty-nine of 160 patients (30.6%) had hyperuricemia, of which 32 were men, 17 were women. Among those with hyperuricemia, mean SUA level was 500.7 ± 95.9 umol/L and 427.8 ± 83.1 umol/L in males and females, respectively. Univariate analysis found: (i) overweight status; (ii) obesity; (iii) Psoriasis Area and Severity Index; (iv) body surface area; (v) severe skin involvement, as being potentially associated with hyperuricemia. Regression model identified overweight status increased the likelihood of hyperuricemia in PsA, with an odds ratio of 4.4 (95% CI: 2.0-9.5). Furthermore, there was moderately positive correlation (r = 0.37) between body mass index (BMI) and SUA level. No associations were found between arthritis conditions and duration, lipid profile, creatinine clearance; and hyperuricemia. CONCLUSION: A significant proportion of PsA patients had asymptomatic hyperuricemia. It was closely related with BMI, which represented metabolic dysregulation; but not with severity of skin disease, joint involvement or renal function.

Tacrolimus versus mycophenolate mofetil for induction therapy of lupus nephritis: a randomised controlled trial and long-term follow-up.

OBJECTIVE: To compare the efficacy of tacrolimus (TAC) and mycophenolate mofetil (MMF) for the initial therapy of lupus nephritis (LN). STUDY DESIGN: This is an open randomised controlled parallel group study. METHODS: Adult patients with biopsy-confirmed active LN (class III/IV/V) were randomised to receive prednisolone (0.6 mg/kg/day for 6 weeks and tapered) in combination with either TAC (0.06-0.1 mg/kg/day) or MMF (2-3 g/day) for 6 months. Good responders were shifted to azathioprine for maintenance. The primary outcome was the rate of complete renal response (CR) at 6 months and the secondary outcomes included partial renal response, renal flares and decline of renal function over time. RESULTS: 150 patients (92% women; aged 35.5±12.8 years; 81% class III/IV) were randomised (76 MMF, 74 TAC). At month 6, the rate of CR was 59% in the MMF and 62% in the TAC group (treatment difference: 3.0% (-12%, 18%); p=0.71). Major infective episodes occurred in 9.2% patients treated with MMF and in 5.4% patients treated with TAC (p=0.53). Maintenance therapy with azathioprine was given to 79% patients. After 60.8±26 months, proteinuric and nephritic renal flares developed in 24% and 18% of patients in the MMF group and 35% (p=0.12) and 27% (p=0.21) in the TAC group, respectively. The cumulative incidence of a composite outcome of decline of creatinine clearance by ≥30%, development of chronic kidney disease stage 4/5 or death was 21% in the MMF and 22% in the TAC group of patients (p=0.35). CONCLUSIONS: TAC is non-inferior to MMF, when combined with prednisolone, for induction therapy of active LN. With azathioprine maintenance for 5 years, a non-significant trend of higher incidence of renal flares and renal function decline is observed with the TAC regimen. TRIAL REGISTRATION NUMBER: Hospital Authority Research Ethics Committee Clinical Trial Registry (HARECCTR0500018; Hong Kong) and US ClinicalTrials.gov (NCT00371319).

IL-33 and soluble ST2 levels as novel predictors for remission and progression of carotid plaque in early rheumatoid arthritis: A prospective study.

OBJECTIVES: To study the association between the baseline IL-33 and soluble ST2 (sST2) levels with disease remission and progression of carotid atherosclerosis in early rheumatoid arthritis (ERA) patients. METHODS: A total of 98 ERA patients were enrolled. Disease activity and the presence of carotid plaque were evaluated at baseline and 12 months later. Plasma IL-33 and sST2 levels were determined using enzyme-linked immunosorbent assay kits. RESULTS: Baseline IL-33 and sST2 levels were associated with inflammatory markers and cardiovascular (CV) risk factors. Overall, 44(45%), 18(18%), and 21(21%) patients achieved remission based on 28-joint disease activity score (DAS28), Boolean, and simplified disease activity score (SDAI) criteria at 12 months, respectively. Patients with detectable IL-33 at baseline were less likely to achieve DAS28 (P = 0.010) and SDAI remission (P = 0.021), while a lower baseline sST2 level was able to predict DAS28, Boolean, and SDAI remission (P = 0.005, 0.001, and <0.001, respectively). Using multivariate analysis, a lower baseline sST2 level independently predict Boolean (OR = 0.789; P = 0.005) and SDAI remission (0.812; P = 0.008). Regarding carotid atherosclerosis, 9/98(9.2%) patients had plaque progression at 12 months. Baseline IL-33 was detectable in 8/9(89%) and 42/83(51%) of patients with and without plaque progression respectively (P = 0.029). Baseline detectable IL-33 was an independent predictor for plaque progression after adjusting for traditional CV risk factors (P = 0.017). CONCLUSIONS: Lower baseline sST2 levels independently predict disease remission and baseline detectable IL-33 independently predicts carotid plaque progression in ERA patients. This study suggests that inflammation induced by the IL-33/ST2 axis may play a significant role in the development of cardiovascular disease in RA.

Serum soluble receptor for advanced glycation end products levels and aortic augmentation index in early rheumatoid arthritis--a prospective study.

OBJECTIVE: We assessed whether a serum soluble receptor for advanced glycation end product (sRAGE) levels were associated with a progression of carotid atherosclerosis and arterial stiffness indexes in a cohort of early rheumatoid arthritis (RA) patients. METHODS: RA patients with symptoms onset <2 years were recruited. Vascular assessments and serum sRAGE levels were measured at baseline and 1 year later. Arterial stiffness was determined by pulse wave velocity and aortic augmentation index (AIx). Carotid intima-media thickness was measured using high-resolution ultrasound. RESULTS: Ninety-four patients completed the 1-year study. Fifty-three (56.4%) achieved disease remission [28-joint disease activity score (DAS28 < 2.6)] at 12 months. Improvement in arterial stiffness was observed as reflected by the significant reductions in AIx and pulse wave velocity. At 12 months, the sRAGE levels increased significantly compared with baseline (939.8 ± 517.7 pg/ml to 1272.1 ± 567.3 pg/ml, P < 0.001). Changes in sRAGE levels were significantly higher in men compared to women (768 ± 510 pg/ml versus 271 ± 490 pg/ml, P < 0.05) and was negatively associated with the change in AIx (r = -0.259, P = 0.023). Changes in sRAGE level were not associated with other demographic, clinical, cardiovascular risk factors or treatment. Using multivariate analysis, the change in sRAGE levels and baseline high-density lipoprotein were independent predictors associated with the change in AIx. CONCLUSIONS: Arterial stiffness improved significantly in patients with early RA after effective control of inflammation. Increase in sRAGE level was associated with a decrease in AIx, suggesting that sRAGE may play an important role in the ligand-soluble receptor for advanced glycation end product interaction propagated inflammation and vascular stiffness in these patients.

Infliximab is associated with improvement in arterial stiffness in patients with early rheumatoid arthritis -- a randomized trial.

OBJECTIVE: To determine the efficacy of methotrexate (MTX) with infliximab (IFX) compared with MTX alone in the prevention of atherosclerosis and arterial stiffness in patients with early rheumatoid arthritis (RA). METHODS: A randomized, open-label study in which early RA patients with active disease were treated with MTX alone (n = 20) and MTX plus IFX (n = 20) for 6 months. Patients were assessed every 3 months. Patients from the MTX-alone group who failed to achieve 28-joint Disease Activity Score remission (DAS28 ≤ 2.6) at 6 months were permitted to escape to open-label IFX. Intima-media thickness (IMT), pulse wave velocity (PWV), and augmentation index (AIx) were measured at baseline, 6 months, and 12 months. RESULTS: At 6 months, there was a significantly greater reduction in PWV in the MTX-alone group (0.18 ± 1.59 m/s) compared with the MTX plus IFX group (-0.78 ± 1.13 m/s; p = 0.044), accompanied by significantly greater reduction in patient's global assessment, number of swollen joints, C-reactive protein, and DAS28 in the MTX plus IFX group compared to the MTX-alone group. The changes in IMT and AIx were similar between the 2 groups. At 12 months, there was a trend favoring early combination treatment with regard to the reduction in PWV (p = 0.06). CONCLUSION: MTX plus IFX causes a more significant reduction in PWV than MTX alone in patients with early RA after 6-month treatment, and further improvement may be achieved in patients who continued on longterm tumor necrosis factor-α blockers, suggesting that early, effective suppression of inflammation may prevent progression of atherosclerosis by improving vascular function.

Treatment of pure membranous lupus nephropathy with prednisone and azathioprine: an open-label trial.

BACKGROUND: The aim of this study was to report the outcome of pure membranous lupus nephropathy treated with prednisone and azathioprine (AZA). METHODS: Consecutive patients with pure membranous lupus glomerulonephritis (World Health Organization [WHO] Va and Vb) from 4 regional hospitals were recruited for an open-label treatment trial consisting of prednisone and AZA. Remission status was evaluated at 12 months. Maintenance treatment with low-dose prednisone and AZA was continued indefinitely for those who achieved remission. Factors predictive of initial renal remission and subsequent relapse were studied by statistical analyses. RESULTS: Thirty-eight patients (31 women and 7 men) were studied. The mean age was 35.0 +/- 9.2 years, and the duration of systemic lupus erythematosus was 48.5 +/- 59 months. Seventeen (45%) patients had WHO class Va lupus nephritis, whereas 21 (55%) had class Vb disease. Two patients withdrew from the protocol because of idiosyncratic reactions to AZA. At 12 months, 24 (67%) patients achieved complete remission (CR), 8 (22%) achieved partial remission (PR), and 4 (11%) were treatment resistant. Patients who achieved CR or PR were maintained on low-dose prednisone and AZA. Over a mean follow-up period of 90.4 +/- 59 months, 6 (19%) patients had relapse of nephritis (proteinuric flare in 4 and nephritic flare in 2). The cumulative risk of renal relapse was 12% at 36 months and 16% at 60 months. No particular clinical variables were found to predict renal remission or relapses. Over a mean follow-up of 90 months, 13% of patients had decline of creatinine clearance by 20%, but none had doubling of serum creatinine. Renal outcome was not significantly worse in patients presenting with nephrotic syndrome. Treatment generally was well tolerated. CONCLUSION: A combination of prednisone and AZA is reasonably effective for the initial treatment of pure membranous lupus nephritis. Severe adverse effects are uncommon. The additional efficacy of AZA in comparison with prednisone alone has to be confirmed with randomized, controlled trials.