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.

The association of disease activity with depression and sleep quality in patients with rheumatoid arthritis in Hong Kong.

Patients with rheumatoid arthritis (RA) often experience depression and poor sleep. Depression and poor sleep may, in turn, worsen RA disease activity. This cross-sectional study aimed to investigate the relationship between RA disease activity as measured using the Disease Activity Score-28 (DAS28-ESR), depression measured using the Beck's Depression Inventory-II (BDI-II), and sleep quality measured using the Pittsburgh Sleep Quality Index (PSQI). Anxiety was measured using the Hospital Anxiety and Depression Scale-Anxiety subscale (HADS-A). A total of 164 consecutive patients with RA were recruited from the Rheumatology Specialist Clinic of a regional hospital in Hong Kong. They were asked to complete questionnaires that included demographic information, the Health Assessment Questionnaire (HAQ), BDI-II, HADS-A, and PSQI. The DAS28-ESR was assessed by the attending rheumatologists. Clinical information was retrieved from the electronic medical records. The mean DAS28-ESR score was 3.35 ± 1.24 (SD). The mean BDI-II was 10.97 ± 9.15 (SD). The mean HADS-A score was 5.57 ± 3.77 (SD). The mean PSQI score was 7.55 ± 4.16 (SD). The BDI-II score was statistically correlated with the DAS28-ESR and PSQI scores. Multiple regression analysis revealed that the association of BDI-II with DAS28-ESR and PSQI was confounded by the HAQ. The association of DAS28-ESR with BDI-II but not with PSQI is in accordance with the results of previous studies. The association between the HAQ and BDI-II has also been demonstrated in previous studies. Clinicians should be aware of mood and sleep problems in patients with RA and adopt a multidisciplinary approach to their management. Future studies should provide information on causality in a more representative sample of patients with RA.

Sicca Symptoms, Oral Health Conditions, Salivary Flow and Oral Candida in Sjögren's Syndrome Patients.

This study aimed to investigate the relationships among sicca symptoms, oral health conditions, salivary profiles and oral Candida in Sjögren's syndrome (SS) patients. Eighty-five SS patients (mean age = 50.5) and 40 healthy non-SS individuals (mean age = 51.4) were recruited. They self-completed the Sicca Symptoms Inventory (SSI). Decayed, missing and filled surface (DMFS) scores, salivary flow rates, pH and oral Candida colonization were determined. Mean SSI summary scores of SS patients and non-SS individuals were 11.1 and 5.4 respectively (p < 0.001). The most prevalent sicca symptoms in SS patients were eye irritation (93%), dry throat or nose (88%) and need of fluid for mouth wetting (88%). SS patients had significantly lower whole salivary flow rates than the non-SS individuals. Candida strains were isolated from over 60% of SS patients but not in non-SS patients. C. albicans was the predominant species. SSI summary score was negatively correlated to salivary flow rates while SSI summary and domain scores were positively correlated to the number of filled surfaces (FS) and DMFS scores and oral Candida counts. In conclusion, SS patients had more severe sicca symptoms than non-SS individuals. SSI scores were negatively correlated to the salivary flow rates but positively correlated to caries experience and oral Candida colonization.

Clinical presentation, treatment and outcome of Takayasu's arteritis in southern Chinese: a multicenter retrospective study.

To study the clinical presentation, treatment and outcome of southern Chinese patients with Takayasu's arteritis (TA). This is a retrospective chart review study of 78 patients managed in 14 public hospitals in Hong Kong between the years 2000 and 2010. Patients were identified from the hospital registry using the ICD-10 diagnostic code of the disease. The classification of TA was based on the American College of Rheumatology (ACR) or modified Ichikawa's criteria. Demographic data, clinical presentation, angiographic findings, pattern of vascular involvement (Numano's classification), treatment and outcome of these patients were presented. 78 patients were studied (82% women, age at presentation 34.2 ± 14 years). The estimated point prevalence of TA was 11/million population. The commonest initial manifestations were hypertension (62%) and vascular ischemic symptoms (38%). Systemic symptoms occurred in nine (12%) patients only. The proportion of patients fulfilling the angiographic subtypes of the Numano's classification was: types I (13%), IIa (4%), IIb (12%), III (12%), IV (20%) and V (39%), respectively. Thirty-two patients (41%) were treated with high-dose glucocorticoids (GCs) and 22 patients (28%) received additional non-GC immunosuppressive drugs. Vascular complications occurred in 26 (33%) patients and revascularization surgery was performed in 23(29%) patients. Three (4%) patients died of vascular complication at a median of 8 years after disease onset. TA is rare in southern Chinese patients of Hong Kong. Most patients present with ischemic symptoms during the stenotic phase of the disease. Although mortality is low, a significant proportion of patients developed vascular stenosis that required surgical interventions. More awareness of TA as a differential diagnosis of non-specific systemic symptoms with elevated inflammatory markers in younger patients is needed for earlier diagnosis.

One amino acid makes a difference-Characterization of a new TPMT allele and the influence of SAM on TPMT stability.

Thiopurine induced toxicity is associated with defects in the thiopurine methyltransferase (TPMT) gene. TPMT is a polymorphic enzyme, with most of the single nucleotide polymorphisms (SNPs) causing an amino acid change, altering the enzymatic activity of the TPMT protein. In this study, we characterize a novel patient allele c.719A > C, named TPMT*41, together with the more common variant *3C c.719A > G, resulting in an amino acid shift at tyrosine 240 to serine, p.Y240S and cysteine, p.Y240C respectively. We show that the patient heterozygote for c.719A > C has intermediate enzymatic activity in red blood cells. Furthermore, in vitro studies, using recombinant protein, show that TPMT p.Y240S is less stable than both TPMTwt and TPMT p.Y240C. The addition of SAM increases the stability and, in agreement with Isothermal Titration Calorimetry (ITC) data, higher molar excess of SAM is needed in order to stabilize TPMT p.Y240C and TPMT p.Y240S compared to TPMTwt. Molecular dynamics simulations show that the loss of interactions is most severe for Y240S, which agrees with the thermal stability of the mutations. In conclusion, our study shows that SAM increases the stability of TPMT and that changing only one amino acid can have a dramatic effect on TPMT stability and activity.

A Case of Initially Undiagnosed Chikungunya Arthritis Developing into Chronic Phase in a Nonendemic Area.

This case report described a 40-year-old lady presented with fever, headache, arthralgia, myalgia, and impaired liver function after returning from the Philippines. Chikungunya virus (CHIKV) and dengue serology were negative. Eight weeks after initial presentation, she experienced inflammatory polyarthritis mimic rheumatoid arthritis. This time CHIKV-IgM was detected, together with a >4-fold rise of CHIKV-polyvalent-antibody titre. The first CHIKV-IgM negative sample was reexamined and was CHIKV-PCR positive. CHIKV infection was confirmed and diagnosis of CHIKV-related arthritis was made. A quarter of CHIKV infected individuals develop post-CHIKV rheumatisms that affect quality of life and may need treatment with Disease Modifying Antirheumatic Drugs. This case highlights the importance of considering CHIKV infection in patients present with symmetrical polyarthritis particularly after travel to endemic regions. Testing of both CHIKV acute and convalescent-phase serum for CHIKV antibodies and PCR is recommended in suspicious case.

A randomized, double-blind, placebo-controlled clinical trial of fluoride varnish in preventing dental caries of Sjögren's syndrome patients.

BACKGROUND: Sjögren's syndrome (SS) patients are prone to caries development due to reduction of salivary flow. Topical fluoride is commonly prescribed for caries prevention. METHODS: In this 24-month randomized, double-blind, placebo-controlled clinical trial, SS patients were randomly assigned to receive either fluoride varnish or placebo gel quarterly. Development and arrest of caries at the coronal and root surfaces were recorded at 12-month and 24-month and compared to that of the baseline. Effect of fluoride varnish on oral Candida and lactobacilli colonization was explored by comparing baseline oral microbiological assessments to data obtained at 12-month and 24-month. RESULTS: Seventy-eight SS patients (mean age = 50 years, 2 men) completed this trial. At 24-month, the mean new coronal enamel caries were 1.6 surfaces in both groups, and new dentin caries were 1.4 and 2.7 surfaces in the fluoride and placebo group respectively (p > 0.05). Mean arrested caries were 0.6 and 0.7 surfaces for fluoride and placebo groups respectively and that of root caries were 0.3 and 0.1 surfaces (p > 0.05). The mean oral Candida count was reduced by 30 % in the fluoride group but increased 61 % in the placebo group while no change in oral lactobacilli counts in both groups at 24 months (p > 0.05). SS patients receiving fluoride varnish were significantly less likely to develop dentin caries (p < 0.05). In contrast, those with high baseline DMFS scores (p = 0.05), harbored mixed Candida species (p < 0.05), or unstimulated whole saliva at low pH (p < 0.01) were significantly more likely to develop dentin caries. CONCLUSIONS: Results of this randomized clinical trial did not provide clear evidence to support or refute that quarterly applications of fluoride varnish can prevent development of dental caries in people with Sjögren's syndrome. TRIAL REGISTRATION: This study was retrospectively registered at the ISRCTN registry ( ISRCTN85164658 ) on 9 Sept 2016 and was funded by the Research Grant Council of Hong Kong.

Sequential occurrence of anti-glomerular basement membrane disease 9 years after anti-neutrophil cytoplasmic antibody-associated vasculitis.

We report a case of 63-year-old Chinese man, having a history of anti-myeloperoxidase (MPO) antibody anti-neutrophil cytoplasmic antibody (ANCA)-associated pulmonary-renal syndrome 9 years ago, presented with second episode of rapidly progressive glomerulonephritis (RPGN) and alveolar haemorrhage compatible with anti-glomerular basement membrane (GBM) disease. In first presentation, his anti-GBM antibody was negative. This time, anti-MPO antibody was negative, but anti-GBM antibody was positive. The long interval of sequential development of anti-GBM disease after ANCA-associated vasculitis in this patient may provide clues to the potential immunological links between these two distinct conditions. Clinicians should be aware of such double-positive association.

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.

The clinical course of polymyalgia rheumatica in Chinese.

Polymyalgia rheumatica (PMR) is diagnosed based on clinical features that may overlap with other rheumatic conditions like rheumatoid arthritis (RA). Furthermore, a proportion of PMR patients may subsequently evolve into RA. The aim of this study was to examine the clinical characteristics of PMR patients in a Chinese cohort compared to a Caucasian series. Patients diagnosed to have PMR during 1997-2008 were reviewed for clinical features and compared to a reported Caucasian series. Rheumatoid factor (RF) and anticyclic citrullinated peptide (CCP) antibodies were determined by immunonephelometry and enzyme-linked immunosorbent assay, respectively. Forty-four patients of southern Chinese origin were diagnosed to have PMR according to specialist opinion. Seventy-five percent of patients (n = 33) were >65 years of age at diagnosis (mean +/- standard deviation, 75.8 +/- 9.6 years). The commonest feature at disease onset was elevated erythrocyte sedimentation rate >40 mm/h (100% vs. 95.7%; p = 0.17) and bilateral shoulder pain or stiffness (95.5% vs. 90.8%; p = 0.31), comparable in frequency to the Caucasian cohort. However, Chinese patients had significantly longer duration of symptoms before diagnosis (p < 0.001) but less bilateral upper arm tenderness (p < 0.001) and generalized stiffness (p = 0.01). Twelve (27.3%) patients evolved into RA after a median duration of 2 months from onset of PMR. RF and anti-CCP antibodies were positive in 66.7% and 60% of these patients compared to 9.4% and 6.2%, respectively, among those who did not evolve into RA during the period observed. Chinese patients with PMR have modestly different clinical profile compared to the Caucasian counterpart. RF and anti-CCP antibodies were more likely to be present in those who subsequently developed into RA.