Sleep characteristics in type 1 diabetes and associations with glycemic control: systematic review and meta-analysis.

OBJECTIVES: The association between inadequate sleep and type 2 diabetes has garnered much attention, but little is known about sleep and type 1 diabetes (T1D). Our objectives were to conduct a systematic review and meta-analysis comparing sleep in persons with and without T1D, and to explore relationships between sleep and glycemic control in T1D. METHODS: Studies were identified from Medline and Scopus. Studies reporting measures of sleep in T1D patients and controls, and/or associations between sleep and glycemic control, were selected. RESULTS: A total of 22 studies were eligible for the meta-analysis. Children with T1D had shorter sleep duration (mean difference [MD] = -26.4 minutes; 95% confidence interval [CI] = -35.4, -17.7) than controls. Adults with T1D reported poorer sleep quality (MD in standardized sleep quality score = 0.51; 95% CI = 0.33, 0.70), with higher scores reflecting worse sleep quality) than controls, but there was no difference in self-reported sleep duration. Adults with TID who reported sleeping >6 hours had lower hemoglobin A1c (HbA1c) levels than those sleeping ≤6 hours (MD = -0.24%; 95% CI = -0.47, -0.02), and participants reporting good sleep quality had lower HbA1c than those with poor sleep quality (MD = -0.19%; 95% CI = -0.30, -0.08). The estimated prevalence of obstructive sleep apnea (OSA) in adults with TID was 51.9% (95% CI = 31.2, 72.6). Patients with moderate-to-severe OSA had a trend toward higher HbA1c (MD = 0.39%, 95% CI = -0.08, 0.87). CONCLUSION: T1D was associated with poorer sleep and high prevalence of OSA. Poor sleep quality, shorter sleep duration, and OSA were associated with suboptimal glycemic control in T1D patients.

Angiotensin-converting enzyme gene polymorphism in Thai patients with systemic lupus erythematosus.

OBJECTIVE: To determine the association between angiotensin-converting enzyme (ACE) I/D polymorphism and the presence of systemic lupus erythematosus (SLE) disease and lupus nephritis (LN), including the association with disease severity in a Thai population. METHOD: In this retrospective study, 187 SLE patients followed up for (at least) 7 years in a rheumatology clinic of an academic hospital were enrolled. Disease severity and damage score at diagnosis and every 6 months, including treatment outcome of the first episode of LN were retrieved from medical records. The ACE genotype of SLE patients were determined by polymerase chain reaction and compared with ACE genotype in 687 controls from a database of a Thai surveillance cohort. RESULT: There was an association between ACE I/D polymorphism and the presence of SLE disease and LN (P < 0.001). Unexpectedly, the prevalence of DD genotype in SLE patients was lower than controls (OR 0.44 [95% CI 0.23-0.84], P = 0.013). The prevalence of ID genotype was not different between SLE patients and controls (OR 1.44 [95%CI 0.93-2.24], P = 0.102), but was higher in LN patients compared to controls (OR 1.77 [95% CI 1.14-2.72], P = 0.01). However, the ACE I/D polymorphism is not associated with SLE disease severity, either in patients with or without nephritis. CONCLUSION: The DD genotype could not be used as a poor prognostic marker for SLE and LN susceptibility in a Thai population. However, ID genotype may be associated with risk to develop LN.

APLAR rheumatoid arthritis treatment recommendations.

AIMS: Rheumatoid arthritis is a chronic inflammatory condition that affects approximately 1% of the world's population. There are a wide number of guidelines and recommendations available to support the treatment of rheumatoid arthritis; however, the evidence used for these guidelines is predominantly based on studies in Caucasian subjects and may not be relevant for rheumatoid arthritis patients in the Asia-Pacific region. Therefore, the Asia Pacific League of Associations for Rheumatology established a Steering Committee in 2013 to address this issue. MATERIALS AND METHODS: The AGREE II instrument and the ADAPTE Collaboration framework were applied to systematically identify, appraise, synthesize, and adapt international rheumatoid arthritis guidelines for use in the Asia-Pacific region. RESULTS: Forty rheumatoid arthritis treatment recommendations, based on evidence and expert opinion, were drafted and are presented in this report. CONCLUSION: The Asia Pacific of Associations for Rheumatology rheumatoid arthritis treatment recommendations are intended to serve as a reference for best practice management of rheumatoid arthritis in Asia-Pacific, focusing on local issues to ensure the delivery of basic care for these patients, and to improve their outcomes. In addition, the document will serve as a reference for national rheumatology associations in Asia-Pacific for developing guidelines in their respective countries.

Low-avidity anticitrullinated protein antibodies (ACPA) are associated with a higher rate of joint destruction in rheumatoid arthritis.

OBJECTIVES: Anticitrullinated protein antibodies (ACPA) are specific for rheumatoid arthritis (RA) and have been implicated in disease pathogenesis. Previously we have shown that ACPA display a considerably lower avidity as compared with antibodies against recall antigens. Nonetheless, ACPA-avidity did vary between patients. As antibody mediated effects are influenced by antibody-avidity, we now investigated ACPA-avidity in relation to biological activity and clinical outcome. METHODS: We determined the avidity of ACPA and related this with severity of joint damage in two Dutch early-RA cohorts containing 199 and 132 patients respectively. Differences in effector functions of low- and high-avidity ACPA were studied. RESULTS: Extensive variation in ACPA-avidity between patients was observed. This allowed the analysis of the relationship between avidity and severity. The presence of low-avidity ACPA is associated with a higher rate of joint destruction. This finding was replicated in an independent cohort. Analysis of the properties of low-versus high-avidity ACPA revealed that low-avidity ACPA are less hampered in their ability to bind 'new' citrullinated antigens. Although no differences could be observed regarding cellular activation via Fc-γ receptors, low-avidity ACPA were more potent in activating the complement system. CONCLUSIONS: Patients with low-avidity ACPA display a higher rate of joint destruction. Low-avidity ACPA display a higher potency to interact with more citrullinated antigens in time and show that low-avidity ACPA are more potent in complement activation. These data indicate that (low) avidity impacts on the biological activity of ACPA and associates with a worse radiological outcome.

Risk of tuberculosis with anti-tumor necrosis factor-α therapy: substantially higher number of patients at risk in Asia.

AIM: To assess the potential risk of tuberculosis (TB) in patients treated with anti-tumor necrosis factor-alpha (TNF-α) agents in Asia. METHODS: Absolute risk increase (ARI) of TB was estimated for three widely used anti-TNF-α therapies using published standardized incidence ratios (SIR) from the French Research Axed on Tolerance of bIOtherapies registry and incidence (absolute risk [AR]) of TB in Asia. Assuming an association of increased TB risk with anti-TNF-α therapy and country TB AR (incidence), the ARI of TB by country was calculated by multiplying the SIR of the anti-TNF-α therapy by the country's TB AR. The numbers needed to harm (NNH) for each anti-TNF-α agent and numbers needed to treat (NNT) to reduce one TB event using etanercept therapy instead of adalimumab or infliximab were also calculated for each country. RESULTS: The ARI of TB with anti-TNF-α therapies in Asian countries is substantially higher than Western Europe and North America and the difference between etanercept versus the monoclonal antibodies becomes more evident. The NNH for Asian countries ranged from 8 to 163 for adalimumab, 126 to 2646 for etanercept and 12 to 256 for infliximab. The NNT to reduce one TB event using etanercept instead of adalimumab therapy ranged from 8 to 173, and using etanercept instead of infliximab therapy the NNT ranged from 13 to 283. CONCLUSION: Higher numbers of patients are at risk of developing TB with anti-TNF-α therapy in Asia compared with Western Europe and North America. The relative lower risk of TB with etanercept may be particularly relevant for Asia, an endemic area for TB.

Predictors for low disease activity and remission in rheumatoid arthritis patients treated with biological DMARDs.

BACKGROUND: Optimal outcome of treatment in rheumatoid arthritis (RA) is early clinical remission to delay joint damage. Therefore, severe RA patients with inadequate response to conventional disease modifying anti-rheumatic drugs (cDMARDs) need highpotency drug as biological DM4RDs (bDMARDs). In general, one-third of RA patient could not get into disease remission with cDMARDs, and half ofthem are still suffering from severe arthritis. However, high cost of this agent is the major barrier for patient engagement, and it is affordable to only 5-10% of patients. We need a good strategy to distribute bDMARDs to patients, especially in limited resource situation. OBJECTIVE: We explored the characteristics ofRA patients who were currently using biologic agents in Ramathibodi Hospital to determine the favorable treatment outcome. MATERIAL AND METHOD: The studied patients were RA patients classified according to ACR/EULAR 2010 criteria and using any biologic agents, between 2010 and2012. Demographic data and treatment outcome (low disease activity and remission) were retrievedfrom patient records. Univariate analysis and generalized estimating equation (GEE) were used to analyze predicting factors to control disease at one year. Kaplan-Meier and log rank test were used to analyze time to disease remission or low disease activity. RESULTS: Patients treated with bDMARDs in Ramathibodi Hospital demonstrated long disease duration (mean 130.7 months) and severe disease activity (mean DAS28 5.37). At 1-year after treatment, 19.4% and 12.9% ofpatients achieved low disease activity (low DAS) and disease remission, respectively. At 3-years after treatment, 88.9% and 45.2% of patients attained low DAS and remission. Patients who started bDMARDs after 2010 had significantly shorter time to control disease when compared to patients who started bDMARDs before 2010 (10 months vs. 34 months). Moreover, we observed that patient who started bDMARDs after 2010 using more cDMARDs (2.5 vs. 1.7, p = 0.02) and higher dose of methotrexate (10.7 vs. 6.5, p = 0.03). There were no association between disease control status and treatment (methotrexate, prednisolone, biologic agent) or disease duration. However the exposedstatus ofbiologic agent was associated with low DAS or remission at the first year of observation (p = 0.004 and 0.04, respectively). CONCLUSION: Chance to control rheumatoid arthritis in the level of remission or low disease activity is predicted by time of bDAMRDs exposure. This result is mainly influenced by dose ofmethotrexate and number of cDMARDs.

Anti-citrullinated protein antibodies (ACPA) in early rheumatoid arthritis.

Autoantibodies with the highest specificity for rheumatoid arthritis (RA) are the antibodies directed to citrulline-containing epitopes, so-called anti-citrullinated peptide/protein antibodies (ACPA). During the past decade it became clear that the presence of these antibodies was highly predictive of and specific for RA, and illustrating the importance of ACPA. Therefore, the presence of these antibodies is one of the new American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 2010 criteria for RA. Apart from the presence of these antibodies, the composition of this antibody response matures during RA development. This review summarizes the current knowledge of the characteristics of ACPA in RA development.

The fine specificity of IgM anti-citrullinated protein antibodies (ACPA) is different from that of IgG ACPA.

INTRODUCTION: The antigen recognition pattern of immunoglobulin M (IgM) could, when directed against protein antigens, provide an indication of the antigenic moieties triggering new B cells. The half-life of IgM is short and memory B cells against T-cell-dependent protein antigens typically produce IgG and not IgM antibodies. In this study, we analyzed whether a difference exists between the fine specificity of IgM versus IgG anti-citrullinated protein antibodies (ACPAs). METHODS: We determined the fine specificity of IgM and IgG ACPAs in 113 ACPA-positive rheumatoid arthritis patients with IgM cyclic citrullinated peptide 2 (CCP2) levels above 100 AU/ml. Fine specificity was assessed by performing ELISA using citrullinated peptides derived from vimentin, fibrinogen-ß, fibrinogen-α and α-enolase, as well as citrullinated proteins fibrinogen and myelin basic protein. The arginine counterparts were used as controls. RESULTS: Recognition of defined citrullinated antigens by IgM ACPA was confined to samples that also displayed recognition by IgG ACPA. However, the IgM ACPA response displayed a more restricted antigen recognition profile than IgG ACPA (OR = 0.26, P < 0.0001). CONCLUSION: Our data show that several defined citrullinated antigens are recognized only by IgG ACPA, whereas others are also recognized by IgM ACPA. These observations suggest that not all citrullinated antigens are able to activate new B cells despite concurrent recognition by IgG ACPA.

Primary prophylaxis for Pneumocystis jirovecii pneumonia in patients with connective tissue diseases.

OBJECTIVES: The aim of our study was to examine the primary prophylactic effect of sulfamethoxazole/trimethoprim single strength (SMZ/TM SS) against Pneumocystis jirovecii pneumonia (PCP) in connective tissue disease (CTD) patients with immune dysfunction induced by the long-term use of prednisolone. Prevalence of adverse drug reactions (ADRs) to sulfonamide in these patients was the secondary outcome. METHODS: This was a retrospective cohort study. Medical records of CTD patients who were treated with prednisolone ≥20 mg per day or equivalent doses of corticosteroid for more than 2 weeks and were followed for at least 12 weeks after receiving this dosage of corticosteroids at the Rheumatology clinic of Ramathibodi Hospital between October 2006 and September 2007 were reviewed. Information regarding clinical status, laboratory features, and clinical course of the enrolled subjects was recorded. RESULTS: There were 138 episodes of PCP risk in 132 CTD patients; 59 episodes received SMZ/TM SS, while 79 episodes did not. All 6 PCP cases developed in patients without prophylaxis with an overall incidence of 4.3%. The incidence of PCP between the 2 groups was significantly different (P = 0.038). Absolute risk reduction and relative risk reduction were 7.3% and 100%, respectively. All ADR developed in 5 systemic lupus erythematosus patients (8.5%): 4 had drug rashes and 1 had mild hepatitis. There was no correlation between the use of, or allergic reactions to, SMZ/TM and lupus flare. CONCLUSIONS: Sulfamethoxazole/trimethoprim single strength can be used effectively as a primary prophylaxis against PCP in high-risk CTD patients. Only mild ADR developed at this dosage. Further evaluations in larger groups of CTD patients are warranted.

Autoantibodies recognizing carbamylated proteins are present in sera of patients with rheumatoid arthritis and predict joint damage.

Autoimmune responses against posttranslationally modified antigens are a hallmark of several autoimmune diseases. For example, antibodies against citrullinated protein antigens (ACPA) have shown their relevance for the prognosis and diagnosis of rheumatoid arthritis (RA), and have been implicated in disease pathogenesis. It is conceivable that other autoantibody systems, recognizing other posttranslationally modified proteins, are also present in RA. Here, we describe the presence of an autoantibody system that discriminates between citrulline- and homocitrulline-containing antigens in the sera of RA-patients. IgG antibodies recognizing carbamylated (homocitrulline-containing) antigens were present in sera of over 45% of RA-patients. Likewise, anticarbamylated protein (anti-CarP) IgA antibodies were observed in 43% of RA-sera. ACPA and anti-CarP antibodies are distinct autoantibodies because, in selected double-positive patients, the anti-CarP antibody binding to carbamylated antigens could be inhibited by carbamylated antigens, but not by control or citrullinated antigens. Similarly, ACPA-binding to citrullinated antigens could only be inhibited by citrullinated antigens. In line with this observation, 16% of ACPA-negative RA-patients, as measured by a standard ACPA assay, harbored IgG anti-CarP antibodies, whereas 30% of these patients tested positive for IgA anti-CarP antibodies. The presence of anti-CarP antibodies was predictive for a more severe disease course in ACPA-negative patients as measured by radiological progression. Taken together, these data show the presence of a unique autoantibody system recognizing carbamylated, but not citrullinated, protein antigens. These antibodies are predictive for a more severe clinical course in ACPA-negative RA-patients, indicating that anti-CarP antibodies are a unique and relevant serological marker for ACPA-negative RA.

Are anti-citrulline autoantibodies better serum markers for rheumatoid arthritis than rheumatoid factor in Thai population?

The aim of the study is to evaluate the prevalence of anti-citrulline antibodies (anti-CCP) versus rheumatoid factor (RF) in a cohort of Thai patients with rheumatoid arthritis (RA), a variety of rheumatic diseases other than RA and healthy controls. The association between anti-CCP and RA disease activity was also examined. Serum from 125 RA patients, 60 from other rheumatic diseases (non-RA) and 60 from healthy controls were tested for IgM RF and second generation anti-CCP. The association between anti-CCP, RF, the Disease Activity Score (DAS 28) and other relevant laboratory tests (CBC, ESR and CRP) were assessed. The sensitivity and specificity of anti-CCP antibody were 58.7 and 100% when compared with 63.5 and 98.3% for RF. These differences were not statistically significant. The anti-CCP outperformed RF in terms of the positive-predictive values (100 vs. 97.6%); however, the negative-predictive values were 72.4% for RF and 69.6% for anti-CCP. The sensitivity when either anti-CCP or RF was positive increased to 71.2%. Nine out of 45 RF-negative patients had a positive anti-CCP test. Anti-CCP was significantly correlated with parameters of inflammation, but not with DAS 28. In conclusion, although anti-CCP is better than RF in distinguishing RA from other rheumatic diseases, its cost, which is 3.3 times higher than the RF test precludes it from replacing RF as a serum marker for Thai patients with RA. The treatment decisions cannot be based on the test alone, as it has no correlation with DAS 28. Its usefulness is in patients with suspected RA who have had a negative RF test.

The infectious profiles of anti-tumor necrosis factor agents in a Thai population: a retrospective study a the university-based hospital.

AIMS: Anti-tumour necrosis factor-alpha (anti-TNF) agents represented treatment advances in a number of rheumatologic diseases. However, adverse effects of anti-TNF agents have been identified through both clinical trials and post-marketing surveillance, especially an increased risk of serious infections. This study firstly described the infectious profiles of anti-TNF agents in a Thai population. METHODS: We retrospectively reviewed all infectious incidences from 100 consecutive medical records of patients who were treated with either etanercept or infliximab for any rheumatologic and non-rheumatologic conditions. RESULTS: Indications for anti TNF-alpha agents were mainly rheumatoid arthritis (46%) and spondyloarthropathy (SpA) (41%). Seventy-seven patients were treated with etanercept and 23 with infliximab. For those whose initial treatment was etanercept, there were two events of suspected active pulmonary tuberculosis (TB) and suspected hepatitis-B virus (HBV) reactivation. Two out of 23 patients (8.7%) who were firstly treated with infliximab had herpes zoster skin infection. Incidence of overall infection before anti-TNF treatment were significantly higher in patient who started with etanercept (0.065 vs. 0.019 cases per person-years in etanercept and infliximab respectively, P < 0.0001). Incidence of overall infection post-anti-TNF treatment were 0.122 and 0.201 cases per person-years in patients who started with etanercept and infliximab with no significant difference (P > 0.05). The overall infection rates were significantly increased after infliximab treatment (P < 0.0001). CONCLUSION: Even thought there were two new events of TB and HBV reactivation after etanercept treatment, incidence of overall infection seemed to be increased after infliximab treatment. The infectious screening and monitoring with high index of suspicion as well as the pre-emptive treatment are still important whenever either etanercept or infliximab is started.

Asymptomatic avascular osteonecrosis of the hip in new patients diagnosed as systemic lupus erythematosus in Ramathibodi Hospital.

OBJECTIVE: To determine asymptomatic avascular osteonecrosis (AVN) of the hip in new patients diagnosed as Systemic Lupus Erythematosus (SLE) in Ramathibodi Hospital. MATERIAL AND METHOD: A prospective descriptive study of new SLE patients with asymptomatic hip at the Rheumatology clinic of Ramathobodi Hospital was conducted from February 2005 to November 2005. The information of steroid and immunosuppressive drug treatment was recorded Plain film (AP and frog leg views) and MR study of both hips were analyzed. RESULTS: Twenty-two hips (II patients) were enrolled in the present study (women 100%; mean age 27.8 years; range 16-50). Four hips (2 patients, 18%) had A VN, without other abnormal imaging findigs of the hips and pelvis. Seventeen hips of nine patients hadjoint effusion; none of them had AVN. No marrow edema, secondary osteoarthritis, collapsed femoral head or pelvic insufficiency fracture in allpatients is detected. In the present study, the 2 AVN patients had longest duration of steroid treatment before MR study (105 & 99 days) and rather high cumulative dose of prednisolone or its equivalent dose (4920 & 4540 mg), compared to non-AVN patients. CONCLUSION: SLE patients without hip pain may have AVN of the hips. Joint effusion and marrow edema do not necessarily associate with early AVN, and the authors found early AVN without joint effusion. Cumulative dose and duration of steroid treatment seem to relate to AVN in the present study. However a larger number of cases, prospective clinical data, and long-term follow up will help better evaluate the prevalence of asymptomatic AVN of the hips, as well as to evaluate the benefit of MRI as a screening tool for patients at risk of AVN.