iTRAQ-based mass spectrometry screen to identify serum biomarkers in systemic lupus erythematosus.

OBJECTIVE: Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disorder with no reliable serum biomarkers currently available other than autoantibodies. METHODS: In the present study, isobaric tags for relative and absolute quantitation-based mass spectrometry was used to screen the sera of patients with SLE to uncover potential disease biomarkers. RESULTS: 85 common proteins were identified, with 16 being elevated (≥1.3) and 23 being decreased (≤0.7) in SLE. Of the 16 elevated proteins, serum alpha-1-microglobulin/bikunin precursor (AMBP), zinc alpha-2 glycoprotein (AZGP) and retinol-binding protein 4 (RBP4) were validated in independent cross-sectional cohorts (Cohort I, N=52; Cohort II, N=117) using an orthogonal platform, ELISA. Serum AMBP, AZGP and RBP4 were validated to be significantly elevated in both patients with inactive SLE and patients with active SLE compared with healthy controls (HCs) (p<0.05, fold change >2.5) in Cohort I. All three proteins exhibited good discriminatory power for distinguishing active SLE and inactive SLE (area under the curve=0.82-0.96), from HCs. Serum AMBP exhibited the largest fold change in active SLE (5.96) compared with HCs and correlated with renal disease activity. The elevation in serum AMBP was validated in a second cohort of patients with SLE of different ethnic origins, correlating with serum creatinine (r=0.60, p<0.001). CONCLUSION: Since serum AMBP is validated to be elevated in SLE and correlated with renal disease, the clinical utility of this novel biomarker warrants further analysis in longitudinal cohorts of patients with lupus and lupus nephritis.

Effect of Community Treatment Orders on Mental Health Service Usage, Emergency Visits, and Violence: a Systematic Review and Meta-Analysis.

INTRODUCTION: Community treatment orders (CTOs) enable patients to actively engage in mental health services while being supervised in the community outside the hospital setting. However, the efficacy of CTOs remains controversial in terms of mental health services usage or service contacts, emergency visits, and violence. METHODS: The databases PsychINFO, Embase, and Medline were searched on 11 March 2022 by 2 independent reviewers through the Covidence website (www.covidence.org). Randomised or non-randomised case-control studies and pre-post studies were included if they examine the effect of CTOs on service contacts, emergency visits, and violence in individuals with mental illnesses by comparing with control groups or pre-CTO conditions. Conflicts were resolved by consultation of the third independent reviewer. RESULTS: Sixteen studies provided sufficient data in the target outcome measures and were included in analysis. Variability in the risk of bias was high among studies. Meta-analyses were conducted separately for case-control studies and pre-post studies. For service contacts, a total of 11 studies with 66,192 patients reported changes in the number of service contacts under CTOs. In 6 case-control studies, a small non-significant increase in service contacts was observed in those under CTOs (Hedge's g = 0.241, z = 1.535, p = 0.13). In 5 pre-post studies, a large and significant increase in service contacts was noted after CTOs (Hedge's g = 0.830, z = 5.056, p < 0.001). For emergency visits, a total of 6 studies with 930 patients reported changes in the number of emergency visits under CTOs. In 2 case-control studies, a small non-significant increase in emergency visits was noted in those under CTOs (Hedge's g = -0.196, z = -1.567, p = 0.117). In 4 pre-post studies, a small significant decrease in emergency visits was noted after CTOs (Hedge's g = 0.553, z = 3.101, p = 0.002). For violence, a total of 2 pre-post studies reported a moderate significant reduction in violence after CTOs (Hedge's g = 0.482, z = 5.173, p < 0.001). CONCLUSION: Case-control studies showed inconclusive evidence, but pre-post studies showed significant effects of CTOs in promoting service contacts and reducing emergency visits and violence. Future studies on cost-effectiveness analysis and qualitative analysis for specific populations with various cultures and backgrounds are warranted.

Lipocalin-2 is a pathogenic determinant and biomarker of neuropsychiatric lupus.

Neuropsychiatric manifestations in lupus (NPSLE) affect ∼20-40% of patients. In the central nervous system, lipocalin-2 (LCN2) can promote injury through mechanisms directly linked to NPSLE, including brain barrier disruption, neurotoxicity, and glial activation. Since LCN2 is elevated in lupus and has been implicated in neuroinflammation, we investigated whether LCN2 is required for the pathogenesis of NPSLE. Here, we investigated the effects of LCN2 deficiency on the development of neurobehavioral deficits in the B6.Sle1.Sle3 (Sle1,3) mouse lupus model. Sle1,3 mice exhibited depression-like behavior and impaired spatial and recognition memory, and these deficits were attenuated in Sle1,3-LCN2KO mice. Whole-brain flow cytometry showed a significant increase in brain infiltrating leukocytes in Sle1,3 mice that was not reduced by LCN2 deficiency. RNA sequencing on sorted microglia revealed that several genes differentially expressed between B6 and Sle1,3 mice were regulated by LCN2, and that these genes are key mediators of the neuroinflammatory cascade. Importantly, LCN2 is upregulated in the cerebrospinal fluid of NPSLE patients across 2 different ethnicities. Our findings establish the Sle1,3 strain as an NPSLE model, demonstrate that LCN2 is a major regulator of the detrimental neuroimmune response in NPSLE, and identify CSF LCN2 as a novel biomarker for NPSLE.

Systemic lupus erythematosus: what should family physicians know in 2018?

Systemic lupus erythematosus (SLE) is a complex multi-systemic autoimmune disease with considerable clinical and immunological heterogeneity. Family physicians should be familiar with the protean manifestations of SLE to aid early diagnosis and monitoring of disease progression. The role of family physicians in SLE includes education, counselling, psychological support, management of mild disease, and recognition of the need for referral to other specialists for more serious disease and complications. Surveillance of cardiovascular risk factors and osteoporosis and advice about vaccination and reproductive issues can be performed in the primary care setting under close collaboration with rheumatologists and other specialists. This review provides family physicians with the latest classification criteria for SLE, recommendations on SLE-related health issues, and pharmacological therapies for SLE.

Long-term immunogenicity of a quadrivalent human papillomavirus vaccine in systemic lupus erythematosus.

OBJECTIVES: To evaluate the 5-year immunogenicity of a quadrivalent human papillomavirus (HPV) vaccine (GARDASIL) in patients with systemic lupus erythematosus (SLE). METHODS: Female SLE patients and controls, aged 18-35 years, who received GARDASIL in 2011 and sero-converted 12 months post-vaccination were followed for persistence of immunogenicity. Antibody measurement to HPV serotypes 6, 11, 16, 18 was repeated at 5 years. The rate of sero-reversion was compared between patients and controls, and factors associated with sero-reversion of the anti-HPV antibodies were studied. RESULTS: 50 SLE patients and 50 controls were vaccinated with GARDASIL. Among subjects who sero-converted at 1 year and consented for this study, antibodies to HPV serotypes 6, 11, 16 and 18 at 5 years were persistent in 24/27 (89%), 26/31 (84%), 32/34 (94%) and 24/25 (96%) of the SLE patients; and 32/33 (97%), 32/33 (97%), 32/32 (100%) and 23/24 (96%) of the controls, respectively. Antibody titers to HPV-6 and 16 were significantly lower in patients than controls. Seven (21%) SLE patients had sero-reversion of ≥1 anti-HPV antibodies. Sero-reverted patients experienced significantly more SLE flares, particularly renal, and had received significantly higher cumulative doses of prednisolone, mycophenolate mofetil and tacrolimus than those with persistent immunogenicity. The cumulative doses of prednisolone correlated inversely and significantly with the anti-HPV 6, 11, and 16 titers at 5 years. CONCLUSIONS: Immunogenicity of the quadrivalent HPV vaccine was retained in a high proportion of SLE patients at 5 year. Patients with more SLE renal flares and had received more immunosuppression were more likely to have sero-reversion of the anti-HPV antibodies. CLINICAL TRIAL REGISTRATION NUMBER: US ClinicalTrials.gov (NCT00911521 & NCT02477254).

Effect of immunosuppressive therapies on survival of systemic lupus erythematosus: a propensity score analysis of a longitudinal cohort.

Objectives The aim of this study was to study the relationship between immunosuppressive drug treatment and survival in patients with systemic lupus erythematosus (SLE). Methods Patients who fulfilled four or more American College of Rheumatology criteria for SLE were followed longitudinally. Clinical characteristics, use of immunosuppressive agents and mortality were reviewed. Cox regression was used to study the relationship between immunosuppressive treatment and survival, adjusted for age, sex, vascular risk factors, organ damage, the anti-phospholipid antibodies and a propensity score for the indication of individual immunosuppressive agent derived from separate regression models. Results A total of 803 SLE patients were studied (92% women; age of SLE onset 33.2±14 years; follow-up time 10.8±7.7 years). The frequencies of ever use of immunosuppressive agents were: high-dose prednisolone (≥0.6 mg/kg/day for ≥4 weeks) (85%), azathioprine (63%), cyclophosphamide (25%), mycophenolate mofetil (27%), the calcineurin inhibitors (23%) and hydroxychloroquine (69%). Ninety-seven patients (12%) died and 56 (7%) patients were lost to follow-up. The causes of death were infection (44%), cerebrovascular events (12%), cardiovascular events (10%) and malignancy (8.2%). Cox regression revealed that the ever use of high-dose prednisolone, mycophenolate mofetil, calcineurin inhibitors or cyclophosphamide was not significantly associated with improved survival. However, the ever use of hydroxychloroquine (hazard ratio 0.59 (0.37-0.93); P=0.02) and azathioprine (hazard ratio 0.46 (0.28-0.75); P=0.002) was significantly associated with reduced mortality (41% and 54%, respectively) after adjustment for the propensity score and other confounding factors. A similar beneficial effect of hydroxychloroquine and azathioprine on survival was also observed in patients with lupus nephritis. Conclusions In this longitudinal cohort of Chinese SLE patients, the ever use of hydroxychloroquine and azathioprine was significantly associated with a probability of better survival. Treatment with high-dose prednisolone, cyclophosphamide, mycophenolate mofetil or the calcineurin inhibitors was not associated with long-term survival benefit.

Disease-specific quality of life in patients with lupus nephritis.

Background Patient-reported outcomes in lupus nephritis (LN) are not well studied. Studies with disease-targeted PRO tool in LN do not exist. Herein, we describe quality of life (QOL: HRQOL & non-HRQOL) among LN patients using LupusPRO. Methods International, cross-sectional data from 1259 patients with systemic lupus erythematosus (SLE) and LupusPRO were compared, stratified by (a) presence of LN (ACR classification criteria (ACR-LN)) at any time and, (b) active LN (on SLEDAI) at study visit. Damage was assessed by SLICC/ACR-SDI. Multivariate regression analyses for QOL against ACR-LN (active LN) after adjusting for age, gender, ethnicity and country of recruitment were performed. Results Mean (SD) age was 41.7 (13.5) yrs, 93% were women. Five hundred and thirty-nine of 1259 SLE patients had ACR-LN. ACR-LN group was younger, were more often on immunosuppressive medications, had worse QOL on lupus medications and procreation than non-ACR-LN patients. HRQOL and non-HRQOL scores were similar in both groups. One hundred and twenty-nine of 539 ACR-LN patients had active LN. Active LN group was younger, had greater disease activity and had worse HRQOL and non-HRQOL compared to patients without active LN. Specific domains adversely affected were lupus symptoms, lupus medications, procreation, emotional health, body image and desires-goals domains. Patients with ACR-LN and active LN fared significantly worse in lupus medications and procreation HRQOL domains, even after adjusting for age, ethnicity, gender and country of recruitment. Conclusions Lupus nephritis patients have poor QOL. Patients with active LN have worse HRQOL and non-HRQOL. Most domains affected are not included in the generic QOL tools used in SLE. LN patients must receive discussion on lupus medications and procreation issues. Patients with active LN need comprehensive assessments and addressal of QOL, along with treatment for active LN.

Towards new avenues in the management of lupus glomerulonephritis.

Renal involvement in systemic lupus erythematosus (SLE) carries substantial morbidity and mortality. Conventional immunosuppressive agents (cyclophosphamide and azathioprine) have suboptimal efficacy and substantial toxicity. Mycophenolate mofetil has emerged as an alternative agent for both induction and maintenance therapy in lupus nephritis because of its reduced gonadal toxicity, despite its failure to demonstrate superiority over cyclophosphamide in pivotal studies. The calcineurin inhibitor tacrolimus has equivalent efficacy to cyclophosphamide and mycophenolate mofetil for inducing remission of lupus nephritis. Although rituximab has shown promise in refractory lupus nephritis, combining rituximab with mycophenolate mofetil as initial therapy offers no additional benefit. Considerable interethnic variation is evident in the efficacy and tolerability of the various immunosuppressive regimens, which necessitates individualized treatment and comparison of the efficacy of new regimens across different ethnic groups. For example, low-dose combinations of tacrolimus and mycophenolate mofetil seem to be more effective than pulse cyclophosphamide as induction therapy in Chinese patients. The same regimen has also been used successfully to treat refractory proliferative and membranous lupus nephritis in patients of various ethnic groups. Finally, novel serum and urinary biomarkers are being validated for diagnosis, prognostic stratification and early recognition of flares in lupus nephritis.

Effect of golimumab and pamidronate on clinical efficacy and MRI inflammation in axial spondyloarthritis: a 48-week open randomized trial.

OBJECTIVES: To compare the effect of golimumab (GLM) and pamidronate (PAM) on clinical efficacy and magnetic resonance imaging (MRI) inflammation in axial spondyloarthritis (aSpA). METHOD: Patients who fulfilled the Assessment of SpondyloArthritis Society (ASAS) criteria for aSpA and had active disease [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score ≥ 4] were randomized in a 2:1 ratio to receive either GLM (50 mg) or PAM (60 mg) 4 weekly for 48 weeks. Clinical efficacy was assessed at intervals. Inflammation of the spine and sacroiliac joints (SIJs) on MRI was graded by the Spondyloarthritis Research Consortium of Canada (SPARCC) scoring system. RESULTS: Twenty patients were assigned to GLM and 10 to PAM (83% men; age 33.4 ± 10.9 years; disease duration 4.4 ± 3.4 years). The baseline characteristics of the two groups were similar. At week 48, the proportions of patients who achieved an ASAS20 response were not significantly different between the GLM and PAM groups (65% vs. 56%; p = 0.69). Although there were no differences in BASDAI, spinal pain, and Medical Outcomes Study 36-item Short Form Health Survey (SF-36) scores between the two groups at week 48, the Ankylosing Spondylitis Disease Activity Score (ASDAS), Bath AS Functional Index (BASFI), C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) levels were significantly lower in GLM-treated patients. The SPARCC scores of the spine and SIJs decreased significantly in GLM- but not in PAM-treated patients. The differences in SPARCC scores between the two groups at week 48 were statistically significant. The frequency of adverse events (AEs) was similar in both arms. CONCLUSIONS: In patients with aSpA, the clinical response rate and improvement in pain and quality of life (QoL) were similar between GLM and PAM groups after 48 weeks. However, significant reduction in inflammatory markers and MRI inflammation was only observed with GLM treatment.

Functioning and health-related quality of life in Chinese patients with systemic sclerosis: a case-control study.

The objective of the study was to study the functioning and health-related quality of life (HRQoL) in patients with systemic sclerosis (SSc) and its associated factors. Consecutive SSc patients and an equal number of age- and gender-matched healthy controls were recruited for the assessment of functioning and HRQoL by the Health assessment questionnaire disability index (HAQ-DI) and Medical Outcomes Study Short Form 36 (SF-36), respectively. The extent of skin involvement of SSc was assessed by the modified Rodnan skin score (mRSS), and disease severity was assessed by the Medsger severity index. Factors associated with functioning and HRQoL in SSc patients were studied by linear regression. Seventy-eight Chinese SSc patients were studied (87 % women; age 50.2 ± 12.1 years; disease duration 7.8 ± 6.5 years; 81 % limited cutaneous subtype). The median mRSS of the patients was 8 (IQR 0-10). Patients with SSc had significantly higher HAQ-DI (0.69 ± 0.69 vs 0.04 ± 0.18; p < 0.001) but lower SF36 scores (p < 0.05 in all domains) than matched controls. Linear regression revealed that the mRSS was inversely associated with the physical component (beta = -0.39; p = 0.001) and mental component scores (beta = -0.27; p = 0.031) of the SF36 but positively correlated with the HAQ-DI score (beta = 0.51; p < 0.001) adjusted for age, sex, and disease duration. The SF36 and HAQ-DI scores also correlated significantly with the Medsger SSc severity index in the general, peripheral vascular, skin, tendon/joint, and heart domains. SSc patients had impaired physical and social functioning and poorer HRQoL than healthy individuals. The extent of skin involvement, tendon/joint contracture, damage in the heart, and peripheral vascular system were associated with poorer functioning and HRQoL.

Effect of raloxifene on disease activity and vascular biomarkers in patients with systemic lupus erythematosus: subgroup analysis of a double-blind randomized controlled trial.

OBJECTIVES: The purpose of this study was to identify the effect of raloxifene on disease activity and vascular biomarkers in patients with systemic lupus erythematosus (SLE). METHODS: Subgroup data were analyzed for postmenopausal female SLE patients who participated in a randomized controlled trial of raloxifene on glucocorticoid-induced osteoporosis. Patients who were receiving a stable daily dose of prednisolone (≤10 mg) for ≥6 months were assigned to receive raloxifene (60 mg/day) or placebo on top of calcium and vitamin D. Disease activity was assessed by the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA), SLE disease activity index (SLEDAI) and physicians' global assessment (PGA) every three months. Lupus flares were assessed by the SELENA flare instrument. Serial serum levels of homocysteine, high-sensitivity C-reactive protein (hsCRP) and soluble thrombomodulin (sTM) were measured. RESULTS: A total of 62 patients (30 raloxifene, 32 placebo) were studied (age 52.5 ± 6.7 years; SLE duration 9.3 ± 7.6 years; menopause duration 7.2 ± 6.6 years). The SLEDAI at entry was 1.8 ± 2.3 (SLEDAI ≥ 6 in 8%). After 12 months, a significant gain in bone mineral density (BMD) of the lumbar spine (1.6%, p = 0.02), and reduction in bone resorption and formation markers was observed in the raloxifene but not in the placebo treated patients. The SELENA-SLEDAI and PGA scores area under the curve over 12 months were not significantly different between the two groups. There were three episodes of mild/moderate lupus flares (33% musculoskeletal, 33% dermatological) in the raloxifene group, compared to nine episodes of mild/moderate flares (27% musculoskeletal, 45% dermatological) in the placebo group (p = 0.11). The low density lipoprotein (LDL) cholesterol level increased significantly in the placebo but not raloxifene treated patients. No significant changes in homocysteine, hsCRP and sTM levels were observed in either group of patients. CONCLUSIONS: Raloxifene significantly improves lumbar spine BMD in SLE patients but does not cause an increase in lupus activity or flares.

Referral strategy for early recognition of axial spondyloarthritis: consensus recommendations from the Hong Kong Society of Rheumatology.

Low back pain is one of commonest problems prompting a visit to the family physician. Up to 5% of patients with chronic low back pain in the primary care setting are diagnosed as having spondyloarthritis, which includes the prototype disease ankylosing spondylitis. Making a diagnosis of ankylosing spondylitis is often delayed for years, leading to significant pain, impairment of quality of life, disability and productivity loss. A recent breakthrough in the treatment of spondyloarthritis is the anti-tumor necrosis factor-alpha biologics, which lead to rapid relief of pain and inflammation, and improvement in all clinical parameters of the disease. Patients with early spondyloarthritis often respond better than those with late established disease. With proper recognition of inflammatory back pain, and the use of magnetic resonance imaging, spondyloarthritis can now be diagnosed much earlier before features are evident on plain radiographs. Referral to the rheumatologist based on onset of back pain (> 3 months) before the age of 45 years, and an inflammatory nature of the pain, or the presence of human leukocyte antigen-B27, or sacroiliitis by imaging, have been confirmed in multi-center international studies to be a pragmatic approach to enable early diagnosis of spondyloarthritis. This referral strategy has recently been adopted by the Hong Kong Society of Rheumatology for primary care physicians and non-rheumatology specialists.

Combined low-dose mycophenolate mofetil and tacrolimus for lupus nephritis with suboptimal response to standard therapy: a 12-month prospective study.

OBJECTIVE: The objective of this paper is to evaluate the efficacy of combined mycophenolate mofetil (MMF) and tacrolimus (TAC) for lupus nephritis with suboptimal response to standard therapy. METHODS: Inclusion criteria for patients: (1) biopsy-confirmed active lupus nephritis; and (2) inadequate response to ≥ 2 immunosuppressive regimens. While prednisolone (≤ 10 mg/day) and angiotensin-converting enzyme inhibitors were continued, immunosuppressive agents were replaced by combined MMF (1 g/day) and TAC (4 mg/day). Patients were followed every 2 months for the clinical response and adverse events at 12 months. RESULTS: Twenty-one patients were recruited (20 women; age 35.8 ± 9.2 years; systemic lupus erythematosus (SLE) duration 111 ± 51 months). The histological classes of lupus nephritis were: IV/III (33%), V+III/IV (33%) and pure V (33%). The creatinine clearance (CrCl), urine protein-to-creatinine ratio (uP/Cr) and serum albumin was 82.4 ± 33 ml/min (<90 ml/min in 57%), 3.27 ± 1.5 and 30.1 ± 5.9 g/l, respectively. Thirteen (62%) patients had active urinary sediments and 17 (81%) patients had active lupus serology. At 12 months, eight (38%) patients had very good response, one (5%) patient had good response and five (24%) patients had partial response. Significant improvement in uP/Cr, albumin, complement C3 and anti-dsDNA titer, and stabilization of CrCl was observed in the responders. Thirty-three adverse events were reported in 18 patients: major infection requiring hospitalization (6%), infection not requiring hospitalization (27%), herpes infection (9%), diarrhea (12%), cramps (9%), dyspepsia (6%), transient increase in serum Cr (6%), alopecia (4%), facial twitching (3%), tremor (3%) and diabetes mellitus (3%). None of these had led to protocol withdrawal. CONCLUSIONS: Combined low-dose MMF and TAC is an option for lupus nephritis that fails to respond adequately to standard regimens, with two-thirds of patients improving after 12 months. Longer-term observation is needed to confirm its efficacy and safety.

Development of systemic lupus erythematosus in a male-to-female transsexual: the role of sex hormones revisited.

Systemic lupus erythematosus (SLE) predominantly affects women of childbearing age. The infrequency of SLE in men and disease onset in prepubertal or postmenopausal women suggests a role of estrogen in the predisposition to the disease. Patients with hypergonadotrophic hypogonadism are prone to the development of SLE, and the use of exogenous estrogens in women increases the relative risk of SLE onset and disease flares. These observations provide indirect evidence for an opposite role of estrogens and androgens in the pathogenesis of SLE. We report on a male-to-female transsexual who developed SLE 20 years after sex-reassignment surgery and prolonged estrogen therapy. The role of sex hormones in SLE is revisited.

Drug levels, anti-drug antibodies, and clinical efficacy of the anti-TNFα biologics in rheumatic diseases.

The objectives of this study are to evaluate the effect of anti-drug antibodies on the clinical efficacy and withdrawal rate of the anti-TNFα biologics in patients with rheumatic diseases. Consecutive patients with rheumatic diseases recently commenced on anti-TNFα biologics were recruited. Serum samples were collected for assay of drug level and antibody titer against the corresponding biologics. Comparison of the clinical efficacy and drug retention rate was performed between patients with and without anti-drug antibodies. Fifty-eight Chinese patients were studied (64 % women; age 47.8 ± 12.9 years; disease duration 6.7 ± 6.4 years). The proportion of patients using infliximab (IFX), adalimumab (ADA), and etanercept (ETN) was 41, 28, and 31 %, respectively. Antibodies against IFX, ADA, and ETN were demonstrated in 12(50 %), 5(31 %) and 0(0 %) patients, respectively. Patients who developed anti-drug antibodies had significantly lower levels of the corresponding drugs (IFX level: 0.004 ± 0.01 vs 3.81 ± 3.49 µg/ml; p = 0.002; ADA level: 0.0 vs 7.6 ± 8.3 µg/ml; p = 0.008). Anti-drug antibody-positive patients had a significantly higher cumulative drug withdrawal rate due to inefficacy (64.7 and 71.8 % vs 10.3 and 10.3 % at month 12 and month 24, respectively; p < 0.001). In rheumatoid arthritis and psoriatic arthritis, non-responders was significantly more frequent in antibody-positive patients (54 vs 13 %; p = 0.01). In spondyloarthritis, the improvement in ankylosing spondylitis disease activity score was significant in patients without antibodies (3.89 ± 0.82 to 2.22 ± 0.86; p = 0.01) but not in those with anti-drug antibodies (3.40 ± 1.67 to 3.23 ± 1.40; p = 0.73). We concluded that the presence of neutralizing antibodies is associated with lower serum levels of the anti-TNFα biologics, leading to lower efficacy and higher withdrawal rate.

Effect of renal disease on the standardized mortality ratio and life expectancy of patients with systemic lupus erythematosus.

OBJECTIVE: To study the effect of renal disease on the standardized mortality ratio (SMR) and life expectancy of patients with systemic lupus erythematosus (SLE). METHODS: Patients whose diagnosis met ≥4 American College of Rheumatology criteria for SLE were longitudinally followed up from 1995 to 2011. The cumulative survival rate, SMR, and life expectancy were calculated, and the effect of renal involvement, histologic class of lupus nephritis, renal damage, and end-stage renal disease (ESRD) on these parameters was evaluated. RESULTS: Of the 694 SLE patients studied, 368 (53%) had renal disease, and the distribution of histologic classes (among 285 patients) was class I (1%), class II (6%), class III (19%), class IV (47%), class III/IV + class V (10%), and class V (16%). Renal damage was present in 79 patients (11%), and 24 (3%) developed ESRD. The age- and sex-adjusted hazard ratios (HRs) of mortality in SLE patients with renal disease, those with renal damage, and those with ESRD, as compared to those without, were 2.23 (95% confidence interval [95% CI] 1.29-3.85), 3.59 (95% CI 2.20-5.87), and 9.20 (95% CI 4.92-17.2), respectively. Proliferative lupus nephritis (adjusted HR 2.28, 95% CI 1.22-4.24), but not the pure membranous type (adjusted HR 1.09, 95% CI 0.38-3.14), was associated with a significant increase in mortality. The age- and sex-adjusted SMRs of SLE patients without renal involvement, those with lupus nephritis, those with proliferative nephritis, those with pure membranous nephritis, those with renal damage, and those with ESRD were 4.8 (95% CI 2.8-7.5), 9.0 (95% CI 6.7-11.9), 9.8 (95% CI 6.5-14.1), 6.1 (95% CI 2.0-14.1), 14.0 (95% CI 9.1-20.5), and 63.1 (95% CI 33.6-108.0), respectively. The life expectancy of SLE patients with renal disease and those with renal damage was reduced by 15.1 years and 23.7 years, respectively, compared to the general population. CONCLUSION: The presence of renal disease, in particular proliferative nephritis causing renal insufficiency, significantly reduces the survival and life expectancy of SLE patients.

Anti-müllerian hormone and ovarian reserve in systemic lupus erythematosus.

OBJECTIVE: To study the level of anti-müllerian hormone (AMH) and its relationship to age and previous exposure to cyclophosphamide (CYC) in patients with systemic lupus erythematosus (SLE). METHODS: Consecutive female patients ages 18-52 years who had menses at least once during the preceding 12 months and fulfilled ≥4 American College of Rheumatology criteria for SLE were recruited. AMH was determined using an enzyme-linked immunosorbent assay (ELISA) kit. Serum AMH levels were compared in patients with and without previous use of immunosuppressive agents. The relationship of the AMH level to the patient's age and CYC exposure was studied by linear regression and receiver operating characteristic (ROC) curve analysis. RESULTS: A total of 216 patients were studied (mean±SD age 35.1±10.1 years, mean±SD SLE duration 7.6±5.9 years). The mean±SD AMH level was significantly lower in patients previously exposed to CYC therapy than in those who had not been exposed after adjustment for age (1.58±2.92 versus 1.73±2.11 ng/ml; P=0.04). The median time interval between the AMH assay and the last dose of CYC administered was 6.7 years (interquartile range 3.4-8.5). AMH levels in users versus nonusers of other immunosuppressive agents, including mycophenolate mofetil, azathioprine, and the calcineurin inhibitors, were not statistically different. Linear regression revealed increasing age (beta -0.32, P=0.02) and each 5 gm of CYC exposure (beta -0.28, P=0.047) were independently associated with a lower AMH level. In patients ages 30 years and younger, a cumulative CYC dose cutoff of 5.9 gm yielded a sensitivity of 0.75 and a specificity of 0.80 for the prediction of undetectable AMH level on ROC curve analysis. CONCLUSION: AMH is a sensitive marker for ovarian damage due to previous CYC exposure in women with SLE.

Glucocorticoid-induced avascular bone necrosis: diagnosis and management.

Glucocorticoid use is one of the most important causes of avascular bone necrosis (AVN). The pathogenesis of glucocorticoid-induced AVN is not fully understood but postulated mechanisms include fat hypertrophy, fat emboli and intravascular coagulation that cause impedance of blood supply to the bones. Data regarding the relationship between AVN and dosage, route of administration and treatment duration of glucocorticoids are conflicting, with some studies demonstrating the cumulative dose of glucocorticoid being the most important determining factor. Early recognition of this complication is essential as the prognosis is affected by the stage of the disease. Currently, there is no consensus on whether universal screening of asymptomatic AVN should be performed for long-term glucocorticoid users. A high index of suspicion should be exhibited for bone and joint pain at typical sites. Magnetic resonance imaging (MRI) or bone scintigraphy is more sensitive than plain radiograph for diagnosing early-stage AVN. Conservative management of AVN includes rest and reduction of weight bearing. Minimization of glucocorticoid dose or a complete withdrawal of the drug should be considered if the underlying conditions allow. The efficacy of bisphosphonates in reducing the rate of collapse of femoral head in AVN is controversial. Surgical therapy of AVN includes core decompression, osteotomy, bone grafting and joint replacement. Recent advances in the treatment of AVN include the use of tantalum rod and the development of more wear resistant bearing surface in hip arthroplasty.

Concurrent psychiatric disorders are associated with significantly poorer quality of life in patients with rheumatoid arthritis.

OBJECTIVES: To study the effect of concurrent psychiatric disorders on health-related quality of life (HRQOL) in patients with rheumatoid arthritis (RA). METHODS: Consecutive Chinese patients who fulfilled the American College of Rheumatology (ACR) criteria for RA were recruited and interviewed by a psychiatrist for psychiatric disorders using the Chinese Bilingual Structured Clinical Interview for DSM-IV Axis I Disorders, Patient version (CB-SCID-I/P). HRQOL was assessed by the validated Chinese version of the 36-item Short Form Health Survey (SF-36). Sociodemographic and clinical data were also collected. Fatigue was assessed by the Functional Assessment of Chronic Illness Therapy - Fatigue scale (FACIT-F). RESULTS: Two hundred patients with RA were studied (79% women, mean age 51.4 ± 10.5 years; median RA duration 4.0 years). Forty-seven (23.5%) patients were diagnosed with a psychiatric disorder: depressive disorders in 29 patients and anxiety disorders in 26 patients. Patients with either condition had significantly higher fatigue scores (26 ± 8.8 vs. 16 ± 6.9, p < 0.001) and were more likely to be unemployed (p = 0.02) and dependent on government subsidy for living (p < 0.001) than those without. The scores of the eight domains and the physical and mental components of the SF-36 were significantly lower in RA patients with psychiatric disorders (p < 0.001 in all). In a linear regression model, the presence of either depressive or anxiety disorders (ß = -0.23, p < 0.001), older age (ß = -0.16, p = 0.006), self-perceived pain (ß = -0.25, p < 0.001) and fatigue (ß = -0.42, p < 0.001) were independently and inversely associated with the total SF-36 score after adjustment for disease activity and other sociodemographic variables. CONCLUSIONS: Concomitant depressive or anxiety disorders in RA patients are associated with significantly poorer HRQOL. Early identification and treatment of psychiatric disorders in RA patients are warranted.