Clinical features of patients with rheumatic and musculoskeletal diseases during the coronavirus disease 2019 pandemic and the association of its relapse with infection: Across-sectional study.

AIM: The aim of this study was to investigate the clinical features of patients with rheumatic and musculoskeletal diseases (RMDs) infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the relationship between RMDs relapse and SARS-CoV-2 infection. METHODS: We carried out a cross-sectional observational study among 585 patients with RMDs and 619 individuals without RMDs. Data on demographics, the clinical features of coronavirus disease 2019 (COVID-19), antirheumatic therapy, and RMD relapse were collected. Differences between RMDs and control groups, infected and uninfected groups, relapse and non-relapse RMDs groups were examined. The influence of COVID-19 infection on medications and relapse of RMDs was also assessed. RESULTS: Among 1204 participants finally recruited for analysis, 1030 (85.5%) were infected with COVID-19. Seven hundred and ninety-five (77.2%) of infected individuals were female, and the median age was 40 years (IQR 33, 50). Patients in the RMD group had a relatively lower risk of COVID-19 symptoms whereas were significantly more likely to require hospitalization (6.7% vs. 2.2%). In the RMDs group, younger patients who were under the age of 65 were more likely to report more symptoms. More patients with RMD relapse (27, 34.6%) adjusted their medications during the period of COVID-19 infection than those without relapse (59, 13.2%). CONCLUSION: Patients with RMDs were at lower risk of symptoms of COVID-19. Rheumatic and musculoskeletal disease patients experience a higher risk of relapse especially when they adjust medications during COVID-19 infection. The long-term prognosis of infected RMDs patients need further investigation.

Sonic Hedgehog Promotes Proliferation and Migration of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis via Rho/ROCK Signaling.

Objective: To explore the underlying mechanism of the sonic hedgehog (Shh) signaling pathway in promoting cell proliferation and migration in fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA). Method: FLS were collected from 8 patients with RA and 3 patients with osteoarthritis (OA). The expression of smoothened (Smo, the Shh pathway activator) was quantified by real-time PCR and western blot. FLS were incubated with cyclopamine (a Smo antagonist), purmorphamine (a Smo agonist), Y27632 (a Rho/ROCK signaling inhibitor), or a combination of purmorphamine and Y27632, respectively. Cell proliferation was examined using cell counting kit-8 and cell cycle assays while cell migration was measured with Transwell and wound healing assays. Results: The expression of Smo was higher in FLS from RA patients than from OA patients (p < 0.05). RA-FLS treated with purmorphamine showed significantly activated proliferation (119.69 vs. 100.0) and migration (252.38 vs. 178.57) compared to untreated cells (both p < 0.001). RA-FLS incubated with cyclopamine or a combination of purmorphamine and Y27632 exhibited significant suppression of proliferation (81.55 vs. 100.0 and 85.84 vs. 100.0) and migration (100 vs. 178.57 and 109.52 vs. 185) ability (all p < 0.001). Conclusion: Our results demonstrated that Shh promoted cell growth and migration of FLS in RA patients through the Rho/ROCK signaling pathway.

Rare cause of diffuse alveolar haemorrhage and subconjunctival haemorrhage rescued by extracorporeal membrane oxygenation and rituximab.

A previously healthy man in his 20s presented with acute respiratory distress syndrome and subconjunctival haemorrhage. Imaging was indicative of pervasive pulmonary haemorrhage. There was no evidence of renal involvement. The patient rapidly deteriorated with aggravating respiratory failure regardless of invasive mechanical ventilation and required extracorporeal membrane oxygenation (ECMO). This maintained the patient adequate time to allow aggressive therapy. Skin biopsy indicated leucocytoclastic vasculitis. Given that the patient was C-antinuclear cytoplasmic autoantibody (ANCA) positive, pulse dose steroids and rituximab were initiated for the suspicion of ANCA-associated vasculitis (AAV) which resulted in improvement of airspace disease and subconjunctival haemorrhage. Only a few cases reported successful use of ECMO in severe diffuse alveolar haemorrhage (DAH) due to AAV, but no case was in DAH combined with subconjunctival haemorrhage. The need for systemic anticoagulation with pre-existing haemorrhage is still a challenging dilemma.

Aberrant upregulation of CaSR promotes pathological new bone formation in ankylosing spondylitis.

Pathological new bone formation is a typical pathological feature in ankylosing spondylitis (AS), and the underlying molecular mechanism remains elusive. Previous studies have shown that the calcium-sensing receptor (CaSR) is critical for osteogenic differentiation while also being highly involved in many inflammatory diseases. However, whether it plays a role in pathological new bone formation of AS has not been reported. Here, we report the first piece of evidence that expression of CaSR is aberrantly upregulated in entheseal tissues collected from AS patients and animal models with different hypothetical types of pathogenesis. Systemic inhibition of CaSR reduced the incidence of pathological new bone formation and the severity of the ankylosing phenotype in animal models. Activation of PLCγ signalling by CaSR promoted bone formation both in vitro and in vivo. In addition, various inflammatory cytokines induced upregulation of CaSR through NF-κB/p65 and JAK/Stat3 pathways in osteoblasts. These novel findings suggest that inflammation-induced aberrant upregulation of CaSR and activation of CaSR-PLCγ signalling in osteoblasts act as mediators of inflammation, affecting pathological new bone formation in AS.

Backfill is a specific sign of axial spondyloarthritis seen on MRI.

OBJECTIVES: To summarize the characteristics of backfill in patients with axial spondyloarthritis (SpA) and patients with non-specific back pain (NSBP) and healthy controls, and to assess the value of backfill in diagnosing axial SpA. METHODS: Three readers blinded recorded backfill seen on T1SE MRI scans from 647 subjects: 297 patients with ankylosing spondylitis (AS), 126 patients with non-radiographic axial SpA (nr-axSpA), 147 patients with NSBP, and 77 healthy controls. The SPARCC SIJ Structural Score (SSS) method was used to assess backfill. The changes of backfill were evaluated by the follow-up MRI scans from 157 patients. We summarized the characteristics of backfill and calculated its sensitivity and specificity for diagnosing axial SpA. RESULTS: Backfill was recorded in 78.8% AS patients, 11.1% nr-axSpA patients, 1.8% patients with NSBP, and no healthy control. Backfill affected more frequently at ilium bone, lower half of sacroiliac joints in axial SpA (both P<0.05). The SSS score of backfill was much higher in axial SpA than in patients with NSBP (both P<0.01) and it did not correlate with demographics and BASDAI, BASFI, and CRP (all P>0.05). The score of backfill only positively correlated with symptom duration in AS (r=0.251, P<0.01) and in nr-axSpA (r=0.743, P<0.01) patients. Only 8.9% patients had the change of backfill in an average follow-up time of 1.09 years. Backfill had high specificity (0.98) and moderate sensitivity (0.59) for diagnosing axial SpA. CONCLUSIONS: We summarized the characteristics of backfill and found that backfill is a specific sign of axial SpA seen on T1SE MRI.

Serum from patients with ankylosing spondylitis can increase PPARD, fra-1, MMP7, OPG and RANKL expression in MG63 cells.

OBJECTIVES: To explore the effects of serum from patients with ankylosing spondylitis on the canonical Wnt/ß-catenin pathway and to assess whether the serum has an osteogenic effect in MG63 cells. METHODS: MG63 cells were cultured with serum from 45 ankylosing spondylitis patients, 30 healthy controls, or 45 rheumatoid arthritis patients. The relative PPARD, fra-1, MMP7, OPG and RANKL mRNA levels were measured using quantitative real-time polymerase chain reaction. Associations between gene expression and patient demographics and clinical assessments were then analyzed. RESULTS: MG63 cells treated with serum from ankylosing spondylitis patients had higher PPARD, fra-1, MMP7 and OPG gene expression than did cells treated with serum from controls or rheumatoid arthritis patients (all p<0.05). RANKL expression was higher in MG63 cells treated with serum from patients with ankylosing spondylitis or rheumatoid arthritis than in those treated with serum from controls (both p<0.05). The OPG/RANKL ratio was also higher in MG63 cells treated with serum from ankylosing spondylitis patients than in those treated with serum from controls (p<0.05). No associations were found between the expression of the five genes and the patient demographics and clinical assessments (all p>0.05). CONCLUSIONS: Serum from ankylosing spondylitis patients increases PPARD, fra-1, MMP7, OPG and RANKL expression and the OPG/RANKL ratio in MG63 cells; these effects may be due to the stimulatory effect of the serum on the Wnt pathway.

Serum from patients with ankylosing spondylitis can increase PPARD, fra-1, MMP7, OPG and RANKL expression in MG63 cells

OBJECTIVES: To explore the effects of serum from patients with ankylosing spondylitis on the canonical Wnt/β-catenin pathway and to assess whether the serum has an osteogenic effect in MG63 cells. METHODS: MG63 cells were cultured with serum from 45 ankylosing spondylitis patients, 30 healthy controls, or 45 rheumatoid arthritis patients. The relative PPARD, fra-1, MMP7, OPG and RANKL mRNA levels were measured using quantitative real-time polymerase chain reaction. Associations between gene expression and patient demographics and clinical assessments were then analyzed. RESULTS: MG63 cells treated with serum from ankylosing spondylitis patients had higher PPARD, fra-1, MMP7 and OPG gene expression than did cells treated with serum from controls or rheumatoid arthritis patients (all p<0.05). RANKL expression was higher in MG63 cells treated with serum from patients with ankylosing spondylitis or rheumatoid arthritis than in those treated with serum from controls (both p<0.05). The OPG/RANKL ratio was also higher in MG63 cells treated with serum from ankylosing spondylitis patients than in those treated with serum from controls (p<0.05). No associations were found between the expression of the five genes and the patient demographics and clinical assessments (all p>0.05). CONCLUSIONS : Serum from ankylosing spondylitis patients increases PPARD, fra-1, MMP7, OPG and RANKL expression and the OPG/RANKL ratio in MG63 cells; these effects may be due to the stimulatory effect of the serum on the Wnt pathway.

The relationship between disease activity measured by the BASDAI and psychological status, stressful life events, and sleep quality in ankylosing spondylitis.

Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) is a standard instrument regularly used to assess disease activity of patients with ankylosing spondylitis (AS). However, the well-being of a patient is also affected by impairment of function as well as psychological status and other factors. The objective of this study was to evaluate if psychological status, stressful life events, and sleep quality contribute significantly to BASDAI. Six hundred eighty-three AS patients satisfying the Modified New York Criteria for AS were recruited from the rheumatology clinics of seven hospitals in China. Patients with other concomitant disorders were excluded. Participants were requested to complete a set of clinical examinations and the following questionnaires: Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Zung Self-Rating Anxiety Scale (SAS), Zung Self-Rating Depression Scale (SDS), Pittsburgh Sleep Quality Index Questionnaire (PSQI), Health Assessment Questionnaire for Spondyloarthropathies (HAQ-S), and Social Readjustment Rating Scale (SRRS). Spearman correlation analysis showed that BASDAI was highly associated with degree and duration of morning stiffness, overall pain, nocturnal back pain, overall back pain, anxiety, and BASFI (all P < 0.001), but were not associated with education, HAQ-S, and sleep medication in PSQI (P > 0.05). Multiple stepwise regression analysis indicated that overall pain was the maximal statistical contribution in predicting disease activity (standardized coefficient, 0.335). In hierarchic multiple regression analysis, psychological variables added an only additional 2.7% to the overall R(2) beyond that accounted for by demographic and medical variables, resulting in a final R(2) of 53.5%. Although BASDAI is a very good measurement of pain and stiffness and to a certain extent effect of functional impairment in AS, it barely takes into account psychological status, stress life events, and sleep quality These factors should be evaluated by other modalities.

Costs and work limitation of patients with ankylosing spondylitis in China.

OBJECTIVES: To access the annual direct, indirect costs and work limitation of AS patients in Chinese population and explore the determinants of cost. METHODS: A retrospective, cross-sectional study was performed in 257 patients with AS in China. The participants completed questionnaires about disease characteristics, quality of life and direct and indirect costs. Only the patients with paid-work completed the Work Limitation Questionnaire (WLQ), a 25-item questionnaire that accesses the impact of chronic health conditions on job performance and productivity. Functional impairment and disease activity were assessed using the Bath Ankylosing Spondylitis Functional Index (BASFI) and the Bath Akylosing Spondylitis Disease Activity Index (BASDAI). Quality of life was measured by the Short Form-36. RESULTS: Of the 257 patients who completed the questionnaires, the mean age was 28.5 (SD=0.5) with mean disease duration of 6.52 years (SD=0.44). The mean BASDAI and BASFI score was 3.28 and 1.3, respectively. Among the 257 patients, 21.8% are students, 64.2% have a paid job and 10.5% without a job because of AS. 165 participants finished the WLQ with a mean WLQ index of 0.19 which corresponds to a 17% decrease in productivity. The annual estimated costs of each patient was $2714.18 while the indirect cost accounted for 64.7%. The annual direct cost significantly correlated with disease activity. CONCLUSIONS: Our research is the first to provide information about the burden of AS and the work status of AS patients in mainland China, which may help to establish the treatment strategy and a policy of support.

Evaluation of Assessment of Spondyloarthritis International Society classification criteria for axial spondyloarthritis in Chinese patients with chronic back pain: results of a 2-year follow-up study.

OBJECTIVE: To evaluate the diagnotic value of the Assessment of Spondyloarthritis International Society (ASAS) classification criteria for axial spondyloarthritis (SpA) in Chinese patients with chronic back pain and without radiographic sacroiliitis in a 2-year follow-up study. METHODS: Patients with chronic back pain ≥ 3 months, onset age ≤ 45 years and without radiographic sacroiliitis were enrolled, and then received 2-year follow-up. All the clinical parameters associated with SpA were recorded. The patients were followed for 2 years and the final diagnosis of axial SpA or non-SpA was confirmed by rheumatologists. Diagnostic concordance between the initial classification according to three classification criteria (ASAS criteria for axial SpA, European Spondylarthropathy Study Group (ESSG) criteria and Amor criteria) and final diagnosis was compared. Diagnostic sensitivity and specificity were compared between the two subsets of ASAS criteria (set 1: sacroiliitis plus more than one SpA feature; set 2: HLA-B27 plus two more SpA features). RESULT: One thousand and sixty-eight patients entered the study and 867 completed the 2-year follow-up (455 axial SpA and 412 non-SpA). The concordance of ASAS criteria was better than ESSG and Amor criteria. Three hundred and thirty-three patients and 335 patients were classified as axial SpA according to the ASAS set 1 and set 2 of criteria, respectively. Further, set 1 of criteria (318/333) showed higher specificity than set 2 critera (279/335) (P = 0.000). CONCLUSION: The ASAS classification criteria for axial SpA showed good concordance in diagnosing Chinese axial SpA patients in this prospective study. Set 1 criteria involving sacroiliitis plus more than one SpA feature had better diagnosing value.

Limitations of lumbar spine MRI in the diagnosis of ankylosing spondylitis.

OBJECTIVES: To assess the value of inflammatory and fatty lesions in the lumbar spine on magnetic resonance imaging (MRI) in differentiating ankylosing spondylitis (AS) from non-inflammatory chronic back pain. METHODS: We reviewed the lumbar spine MR images of 192 consecutive AS patients and 208 non-AS subjects with non-inflammatory chronic back pain. Lesions including vertebral corner inflammatory lesions (CIL), inflammation in posterior elements (PE) of the spine, and fatty deposition lesions (FDL) seen on lumbar spine MRI were scored in a blinded manner. RESULTS: The frequencies of CIL and FDL in AS patients were higher than that in non-AS patients (both p<0.01), but there was no significant difference in the positive rate of inflammation in PE of the spine between two groups. AS patients had higher scores of all three types of lesions than non-AS patients (all p<0.01). Positive likelihood ratio increased as the cut-off score for distinguishing AS from other diseases increased (ranged from 1.14 to 18.42). But the biggest value of area under the receiver operating characteristic curve of all types of lesions was only 62.58%. We also summarised some features of these lesions that may help to distinguish AS from non-inflammatory chronic back pain. CONCLUSIONS: Our study found that the value of inflammatory and fatty lesions (including CIL, inflammation in PE and FDL) seen on lumbar spine MRI in the diagnosis of AS was limited. But the diagnosis of AS would be more convincing if patients had high scores of these three types of lesions (CIL ≥16, and/or inflammation in PE of the spine ≥5, and/or FDL ≥2).

Adalimumab significantly reduces inflammation and serum DKK-1 level but increases fatty deposition in lumbar spine in active ankylosing spondylitis.

AIM: To investigate whether adalimumab is effective for active ankylosing spondylitis (AS) patients and whether it has an impact on the formation of fatty deposition lesions (FDL) and serum Dickkopf homolog 1 (Dkk-1) level in AS patients. METHOD: This was a randomized, double-blind, placebo-controlled study. Active AS patients received 40 mg adalimumab (n = 26) or placebo (n = 20) every other week during an initial 12-week double-blind period, and all switched to adalimumab treatment for another 12 weeks. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Function Index (BASFI), C-reactive protein (CRP), Ankylosing Spondylitis Disease Activity Scores (ASDAS) and serum DKK-1 levels were measured and magnetic resonance imaging (MRI) of both the lumbar spine and sacroiliac joints were obtained at baseline, week 12 and week 24. Spinal and sacroiliac joint inflammations were evaluated using the Spondyloarthritis Research Consortium of Canada (SPARCC) MRI index, and FDL were assessed in a dichotomous manner. RESULTS: Obvious improvements in clinical assessments (BASDAI, BASFI, CRP and ASDAS reduced, all P < 0.05), as well as MRI inflammation measurements (both lumbar spine and sacroiliac joints SPARCC scores decreased, all P < 0.05) were shown in active AS patients treated by adalimumab for 12 weeks, but FDL in the lumbar spine seen by MRI increased significantly (P < 0.05) accompanied by decrease of serum DKK-1 levels (P < 0.05), while FDL remained stable after the treatment of placebo in AS patients. CONCLUSION: Our study found that adalimumab was highly effective in reducing inflammation in active AS patients, but it was accompanied by the formation of FDL in the lumbar spine and decrease in serum DKK-1 levels.

A genome-wide association study in Han Chinese identifies new susceptibility loci for ankylosing spondylitis.

To identify susceptibility loci for ankylosing spondylitis, we performed a two-stage genome-wide association study in Han Chinese. In the discovery stage, we analyzed 1,356,350 autosomal SNPs in 1,837 individuals with ankylosing spondylitis and 4,231 controls; in the validation stage, we analyzed 30 suggestive SNPs in an additional 2,100 affected individuals and 3,496 controls. We identified two new susceptibility loci between EDIL3 and HAPLN1 at 5q14.3 (rs4552569; P = 8.77 × 10(-10)) and within ANO6 at 12q12 (rs17095830; P = 1.63 × 10(-8)). We also confirmed previously reported associations in Europeans within the major histocompatibility complex (MHC) region (top SNP, rs13202464; P < 5 × 10(-324)) and at 2p15 (rs10865331; P = 1.98 × 10(-8)). We show that rs13202464 within the MHC region mainly represents the risk effect of HLA-B*27 variants (including HLA-B*2704, HLA-B*2705 and HLA-B*2715) in Chinese. The two newly discovered loci implicate genes related to bone formation and cartilage development, suggesting their potential involvement in the etiology of ankylosing spondylitis.

The Ankylosing Spondylitis Disease Activity Score is a highly discriminatory measure of disease activity and efficacy following tumour necrosis factor-α inhibitor therapies in ankylosing spondylitis and undifferentiated spondyloarthropathies in China.

OBJECTIVE: To validate the clinical value of the new Ankylosing Spondylitis Disease Activity Scores (ASDASs) in assessing the disease activity and efficacy of TNF-α inhibitor in AS and uSpA patients in China. METHODS: Two hundred and thirty patients were included in our study. They consisted of patients with active AS (n = 87) and uSpA (n = 30) participating in a double-blind placebo-controlled randomized clinical trial of etanercept and patients with active AS (n = 58) and uSpA (n = 55) treated with infliximab. The disease activity and treatment effects were assessed by ASDAS, BASDAI, patient global and the acute inflammation score of lumbar and SI joints by MRI. Discriminatory ability of all the measures was analysed by standardized mean difference and t-score. RESULTS: In both the AS and uSpA groups, ASDAS correlated well with patient global score (AS group: r = 0.65-0.72; uSpA group: r = 0.52-0.62), ESR (AS group: r = 0.57-0.81; uSpA group: r = 0.63-0.85) and CRP (AS group: r = 0.51-0.70; uSpA group: r = 0.61-0.76) both at baseline and in changes from baseline to 6 weeks after TNF-α inhibitor treatment. The ASDAS scores outperformed BASDAI, patient global score, ESR, CRP and the acute inflammation score by MRI in differentiating patients with different levels of disease activity and patients with different levels of change in both AS and uSpA groups. There was little difference in performance between the two versions of the ASDAS. CONCLUSION: The new ASDAS is a highly effective measure in assessing disease activity and a great discriminatory measurement to assess the efficacy of TNF-α inhibitor in Chinese AS patients and uSpA patients.