Development of prediction model for alanine transaminase elevations during the first 6 months of conventional synthetic DMARD treatment.

Frequent laboratory monitoring is recommended for early identification of toxicity when initiating conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). We aimed at developing a risk prediction model to individualize laboratory testing at csDMARD initiation. We identified inflammatory joint disease patients (N = 1196) initiating a csDMARD in Turku University Hospital 2013-2019. Baseline and follow-up safety monitoring results were drawn from electronic health records. For rheumatoid arthritis patients, diagnoses and csDMARD initiation/cessation dates were manually confirmed. Primary endpoint was alanine transaminase (ALT) elevation of more than twice the upper limit of normal (ULN) within 6 months after treatment initiation. Computational models for predicting incident ALT elevations were developed using Lasso Cox proportional hazards regression with stable iterative variable selection (SIVS) and were internally validated against a randomly selected test cohort (1/3 of the data) that was not used for training the models. Primary endpoint was reached in 82 patients (6.9%). Among baseline variables, Lasso model with SIVS predicted subsequent ALT elevations of > 2 × ULN using higher ALT, csDMARD other than methotrexate or sulfasalazine and psoriatic arthritis diagnosis as important predictors, with a concordance index of 0.71 in the test cohort. Respectively, at first follow-up, in addition to baseline ALT and psoriatic arthritis diagnosis, also ALT change from baseline was identified as an important predictor resulting in a test concordance index of 0.72. Our computational model predicts ALT elevations after the first follow-up test with good accuracy and can help in optimizing individual testing frequency.

Predictors of ASDAS-CRP inactive disease in axial spondyloarthritis during treatment with TNF-inhibitors: Data from the EuroSpA collaboration.

OBJECTIVES: In patients with axial spondyloarthritis (axSpA) initiating their first tumor necrosis factor alpha-inhibitor (TNFi), we aimed to identify common baseline predictors of Ankylosing Spondylitis Disease Activity Score (ASDAS-CRP) inactive disease (primary objective) and clinically important improvement (CII) at 6 months, and drug retention at 12-months across 15 European registries. METHODS: Baseline demographic and clinical characteristics were collected. Outcomes were investigated per registry and in pooled data using logistic regression analyses on multiply imputed data. RESULTS: The consistency of baseline predictors in individual registries justified pooling the data. In the pooled dataset (n = 21,196), the 6-month rates for ASDAS inactive disease and ASDAS CII were 26% and 51%, and the 12-month drug retention rate 65% in patients with available data (n = 9,845, n = 6,948 and n = 21,196, respectively). Nine common baseline predictors of ASDAS inactive disease, ASDAS CII and 12-month drug retention were identified, and the odds ratios (95%-confidence interval) for ASDAS inactive disease were: age, per year: 0.97 (0.97-0.98), men vs. women: 1.88 (1.60-2.22), current vs. non-smoking: 0.76 (0.63-0.91), HLA-B27 positive vs. negative: 1.51 (1.20-1.91), TNF start year 2015-2018 vs. 2009-2014: 1.24 (1.06-1.45), CRP>10 vs. ≤10 mg/l: 1.49 (1.25-1.77), one unit increase in health assessment questionnaire (HAQ): 0.77 (0.58-1.03), one-millimeter (mm) increase in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) fatigue and spinal pain: 0.99 (0.99-1.00) and 0.99 (0.99-1.99), respectively CONCLUSION: Common baseline predictors of treatment response and adherence to TNFi could be identified across data from 15 European registries, indicating that they may be universal across different axSpA populations.

68Ga-Citrate PET of Healthy Men: Whole-Body Biodistribution Kinetics and Radiation Dose Estimates.

68Ga-citrate has one of the simplest chemical structures of all 68Ga-radiopharmaceuticals, and its clinical use is justified by the proven medical applications using its isotope-labeled compound 67Ga-citrate. To support broader application of 68Ga-citrate in medical diagnosis, further research is needed to gain clinical data from healthy volunteers. In this work, we studied the biodistribution of 68Ga-citrate and subsequent radiation exposure from it in healthy men. Methods: 68Ga-citrate was prepared with an acetone-based radiolabeling procedure compliant with good manufacturing practices. Six healthy men (age 41 ± 12 y, mean ± SD) underwent sequential whole-body PET/CT scans after an injection of 204 ± 8 MBq of 68Ga-citrate. Serial arterialized venous blood samples were collected during PET imaging, and the radioactivity concentration was measured with a γ-counter. Urinary voids were collected and measured. The MIRD bladder-voiding model with a 3.5-h voiding interval was used. A model using a 70-kg adult man and the MIRD schema was used to estimate absorbed doses in target organs and effective doses. Calculations were performed using OLINDA/EXM software, version 2.0. Results: Radioactivity clearance from the blood was slow, and relatively high radioactivity concentrations were observed over the whole of the 3-h measuring period. Although radioactivity excretion via urine was rather slow (biologic half-time, 69 ± 24 h), the highest decay-corrected concentrations in urinary bladder contents were measured at the 90- and 180-min time points. Moderate concentrations were also seen in kidneys, liver, and spleen. The source organs showing the largest residence times were muscle, liver, lung, and heart contents. The heart wall received the highest absorbed dose, 0.077 ± 0.008 mSv/MBq. The mean effective dose (International Commission on Radiological Protection publication 103) was 0.021 ± 0.001 mSv/MBq. Conclusion: PET imaging with 68Ga-citrate is associated with modest radiation exposure. A 200-MBq injection of 68Ga-citrate results in an effective radiation dose of 4.2 mSv, which is in the same range as other 68Ga-labeled tracers. This suggests the feasibility of clinical studies using 68Ga-citrate imaging in humans and the possibility of performing multiple scans in the same subjects across the course of a year.

First-in-Humans Study of 68Ga-DOTA-Siglec-9, a PET Ligand Targeting Vascular Adhesion Protein 1.

Sialic acid-binding immunoglubulinlike lectin 9 (Siglec-9) is a ligand of vascular adhesion protein 1. A 68Ga-labeled peptide of Siglec-9, 68Ga-DOTA-Siglec-9, holds promise as a novel PET tracer for imaging of inflammation. This first-in-humans study investigated the safety, tolerability, biodistribution, and radiation dosimetry of this radiopharmaceutical. Methods: Six healthy men underwent dynamic whole-body PET/CT. Serial venous blood samples were drawn from 1 to 240 min after intravenous injection of 162 ± 4 MBq of 68Ga-DOTA-Siglec-9. In addition to γ-counting, the plasma samples were analyzed by high-performance liquid chromatography to detect intact tracer and radioactive metabolites. Radiation doses were calculated using the OLINDA/EXM software, version 2.2. In addition, a patient with early rheumatoid arthritis was studied with both 68Ga-DOTA-Siglec-9 and 18F-FDG PET/CT to determine the ability of the new tracer to detect arthritis. Results:68Ga-DOTA-Siglec-9 was well tolerated by all subjects. 68Ga-DOTA-Siglec-9 was rapidly cleared from the blood circulation, and several radioactive metabolites were detected. The organs with the highest absorbed doses were the urinary bladder wall (0.38 mSv/MBq) and kidneys (0.054 mSv/MBq). The mean effective dose was 0.022 mSv/MBq (range, 0.020-0.024 mSv/MBq). Most importantly, however, 68Ga-DOTA-Siglec-9 was comparable to 18F-FDG in detecting arthritis. Conclusion: Intravenous injection of 68Ga-DOTA-Siglec-9 was safe and biodistribution was favorable for testing of the tracer in larger group of patients with rheumatoid arthritis, as is planned for the next phase of clinical trials. The effective radiation dose of 68Ga-DOTA-Siglec-9 was within the same range as the effective radiation doses of other 68Ga-labeled tracers. Injection of 150 MBq of 68Ga-DOTA-Siglec-9 would expose a subject to 3.3 mSv. These findings support the possible repeated clinical use of 68Ga-DOTA-Siglec-9, such as in trials to elucidate the treatment efficacy of novel drug candidates.

18F-FDG positron emission tomography/computed tomography of cardiac implantable electronic device infections.

BACKGROUND: The diagnosis of cardiac implantable electronic device (CIED) infection is challenging because of its variable presentations. We studied the value of 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in the detection of CIED infection. METHODS AND RESULTS: Thirty patients with suspected CIED infection underwent 18F-FDG-PET/CT. The control group was ten patients with asymptomatic CIED who underwent cancer-related 18F-FDG-PET/CT. 18F-FDG-PET/CT was evaluated visually, semiquantitatively as maximum standardized uptake value (SUVmax) and target-to-background ratio (TBR). Final diagnosis of CIED infection was based on clinical and bacteriological data. 18F-FDG-PET/CT was visually positive in all 9 patients with recent (≤ 8 weeks) implantation of CIED, but only 4 had confirmed CIED infection. 18F-FDG-PET/CT was true positive in 9 out of 21 cases with remote implantation of CIED and false positive in 3 (14.3%) cases. 18F-FDG-PET/CT was also false positive in 3 (30%) cases of control group. The SUVmax of the pocket area was significantly higher in patients with CIED infection than in the control group (4.8 ± 2.4 vs 2.0 ± .8, P < .001). By using the cut-off value of TBR ≥ 1.8, sensitivity of 18F-FDG-PET/CT for the diagnosis of CIED infection in patients with remote implantation was 90% and specificity 73%, PPV 75%, and NPV 89%. CONCLUSIONS: 18F-FDG-PET/CT is a sensitive but nonspecific method in the diagnosis of CIED infection.

The Delay and Costs of Diagnosing Systemic Vasculitis in a Tertiary-Level Clinic.

INTRODUCTION: The diagnosis of systemic vasculitis is a challenge because of the heterogeneity of clinical manifestations. The aim of this study is to analyze the diagnostic delay in systemic vasculitis, the total costs during the first year of care, and how the diagnostic delay affects the costs in a tertiary health care facility. METHODS: Patients with a new diagnosis of systemic vasculitis between 2010 and 2018 were identified from hospital records. The diagnostic delay and health care costs were evaluated during the diagnostic period and within 12 months after the first contact with tertiary health care. Vasculitis-related costs were recorded as true costs charged. A total of 317 patients fulfilled the study criteria. The diagnoses were grouped into three clinically relevant groups: IgA vasculitis and other small-vessel vasculitis (n = 64), ANCA-associated vasculitis (AAV) (n = 112), and large-vessel vasculitis (LVV) (n = 141). RESULTS: The diagnostic delay from the first referral to tertiary-level clinic was shortest in the LVV group and longest in the AAV group. Total costs during the diagnostic period were the highest in the AAV group (median = €6754 [IQR €8812]) and lowest in the LVV group (median = €3123 [IQR €4517]), p < 0.001. There was a significant positive correlation between the diagnostic delay and total costs during the diagnostic period and 12 months (rs = 0.38, p < 0.001 and rs = 0.34, p < 0.001, respectively). In a linear model, the inpatient days and the number of laboratory tests were the strongest predictors (p < 0.001) of a higher treatment cost during the diagnostic period. CONCLUSIONS: There is a substantial diagnostic delay that correlates significantly with the costs in tertiary-level health care when diagnosing systemic vasculitis.

Prosthetic Valve Candida Endocarditis: A Case Report with 18F-FDG-PET/CT as Part of the Diagnostic Workup.

Diagnosis of Candida spp. infective endocarditis (IE) is challenging, and diagnostic delays are common. We describe two patients with Candida spp. prosthetic valve endocarditis (PVE) and 18fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) as a part of diagnostic workup. We also refer to 5 other cases we found from the published literature. These cases highlight that 18F-FDG-PET/CT can improve diagnostic accuracy in prosthetic valve Candida endocarditis.

Evaluation of a New Skeletal Troponin I Assay in Patients with Idiopathic Inflammatory Myopathies.

BACKGROUND: The current biomarkers for diagnosis and monitoring of injured and diseased skeletal muscles, such as creatine kinase (CK), have limited tissue specificity and incapability to differentiate between pathological and physiological changes. Thus, new biomarkers with improved diagnostic accuracy are needed. Our aim was to develop and validate a novel assay for skeletal troponin I (skTnI), and to assess its clinical performance in patients with idiopathic inflammatory myopathies (IIM). METHODS: A two-step fluoroimmunoassay was used to analyze samples from healthy reference individuals (n = 140), patients with trauma (n = 151), and patients with IIM (n = 61). RESULTS: The limit of detection was 1.2 ng/mL, and the upper reference limit (90th percentile) was 5.2 ng/mL. The median skTnI concentrations were

Granulocyte colony-stimulating factor- and chemotherapy-induced large-vessel vasculitis: six patient cases and a systematic literature review.

OBJECTIVE: Patients receiving chemotherapy are prone to neutropoenic infections, presenting with non-specific symptoms such as a high fever and elevated inflammatory parameters. Large-vessel vasculitis (LVV) may have a similar clinical presentation and should be included in differential diagnostics. A few published case reports and adverse event reports suggest a causal association between LVV and the use of granulocyte colony-stimulating factor (G-CSF) and chemotherapy. Our objective was to evaluate the relationship between LVV, G-CSF and chemotherapy. METHODS: Between 2016 and 2018, we identified six patients in Finland with probable drug-induced LVV associated with G-CSF and chemotherapy. All six patients had breast cancer. A systematic literature review was performed according to PRISMA guidelines using comprehensive search terms for cancer, chemotherapy, G-CSF and LVV. RESULTS: The literature search identified 18 similar published case reports, of which most were published after 2014. In all patients combined (n = 24), the time delay from the last drug administration to the LVV symptoms was on average 5 days with G-CSF (range = 1-8 days) and 9 days with chemotherapy (range = 1-21 days). Common symptoms were fever (88%), neck pain (50%) and chest pain (42%). Based on imaging, 17/24 (71%) had vascular inflammation in the thoracic aorta and supra-aortic vessels, but 5/24 (21%) reportedly had inflammation limited to the carotid area. CONCLUSION: This review suggests that LVV may be a possible serious adverse event associated with G-CSF and chemotherapy. Successful management of drug-induced LVV requires early identification, through diagnostic imaging, and discontinuation of the drug.

Automated Text Message-Enhanced Monitoring Versus Routine Monitoring in Early Rheumatoid Arthritis: A Randomized Trial.

OBJECTIVE: Frequent monitoring of patients with early rheumatoid arthritis (RA) is required for achieving good outcomes. This study was undertaken to investigate the influence of text message (SMS)-enhanced monitoring on early RA outcomes. METHODS: We randomized 166 patients with early, disease-modifying antirheumatic drug-naive RA to receive SMS-enhanced follow-up or routine care. All patients attended visits at 0, 3, and 6 months, and a follow-up visit at 12 months. Treatment was at the physicians' discretion. The intervention included 13 SMSs during weeks 0-24 with questions concerning medication problems (yes/no) and disease activity (patient global assessment [PtGA], scale 0-10). Patients were contacted if response SMSs indicated medication problems or PtGA exceeded predefined thresholds. Primary outcome was 6-month Boolean remission (no swollen or tender joints and normal C-reactive protein levels). Quality of life (QoL; measured by the Short Form 36 survey) and Disease Activity Score in 28 joints (DAS28) were assessed. RESULTS: Six and 12-month follow-up data were available for 162 and 157 patients, respectively. In the intervention group, 46% of the patients (38 of 82) reported medication problems and 49% (40 of 82) reported text message PtGAs above the alarm limit. Remission rates at 6 months (P = 0.34) were 51% in the intervention group and 42% in the control group. These rates were 57% and 43% at 12 months (P = 0.17) in the intervention and control groups, respectively. The respective mean ± SD DAS28 scores for the intervention and control groups were 1.92 ± 1.12 and 2.22 ± 1.11 at 6 months (P = 0.09); and 1.79 ± 0.91 and 2.08 ± 1.22 at 12 months (P = 0.28). No differences in QoL were observed. CONCLUSION: The study did not meet the primary outcome despite a trend favoring the intervention group. This may be explained by the notably high overall remission rates.

The Clinical Impact of Using 18F-FDG-PET/CT in the Diagnosis of Suspected Vasculitis: The Effect of Dose and Timing of Glucocorticoid Treatment.

18F-Fluorodeoxyglucose positron-emission tomography (18F-FDG-PET) with computed tomography (CT) is effective for diagnosing large vessel vasculitis, but its usefulness in accurately diagnosing suspected, unselected vasculitis remains unknown. We evaluated the feasibility of 18F-FDG-PET/CT in real-life cohort of patients with suspicion of vasculitis. The effect of the dose and the timing of glucocorticoid (GC) medication on imaging findings were in special interest. 82 patients with suspected vasculitis were evaluated by whole-body 18F-FDG-PET/CT. GC treatment as prednisolone equivalent doses at the scanning moment and before imaging was evaluated. 38/82 patients were diagnosed with vasculitis. Twenty-one out of 38 patients had increased 18F-FDG accumulation in blood vessel walls indicating vasculitis in various sized vessels. Vasculitis patients with a positive vasculitis finding in 18F-FDG-PET/CT had a significantly shorter duration of GC use (median = 4.0 vs 7.0 days, P=0.034), and they used lower GC dose during the PET scan (median dose = 15.0 mg/day vs 40.0 mg/day, p=0.004) compared to 18F-FDG-PET/CT-negative patients. Vasculitis patients with a positive 18F-FDG-PET/CT result had significantly higher C-reactive protein (CRP) than patients with a negative 18F-FDG-PET/CT finding (mean value = 154.5 vs 90.4 mg/L, p=0.018). We found that 18F-FDG-PET/CT positivity was significantly associated with a lower dose and shorter duration of GC medication and higher CRP level in vasculitis patients. 18F-FDG-PET/CT revealed clinically significant information in over half of the patients and was effective in confirming the final diagnosis.

Case report: bilateral Mooren ulcer in association with hepatitis C.

BACKGROUND: Mooren ulcer has been considered as an idiopathic autoimmune keratitis. However, it has been in some cases suggested to be associated with hepatitis C, although the evidence is very vague. CASE PRESENTATION: We present a case of a man who was diagnosed with a primary Mooren ulcer in his right eye. The eye became blind despite of intensive treatment with local medications and extensive surgical procedures. After 10 years, the patient was diagnosed with the same disease, now in his left, previously healthy eye. There was no history that would suggest a secondary Mooren ulcer, but a chronic hepatitis C infection was detected. Treatment was targeted against hepatitis C (ribavirin and interferon) in addition to immunosuppressive medical and surgical treatment which resulted in a full and more than 6 years lasting remission of the disease. CONCLUSIONS: Whether the immunomodulatory and immunosuppressive medication against hepatitis C was the key reason for the good results in the treatment of the second eye, remains elusive. The causality of hepatitis C with respect to the pathogenesis of Mooren ulcer on this patient remains open, but should be considered as one of the possible etiological factors of the disease.

Head-to-Head Comparison of 68Ga-Citrate and 18F-FDG PET/CT for Detection of Infectious Foci in Patients with Staphylococcus aureus Bacteraemia.

Purpose: This study evaluated the potential of 68Ga-citrate positron emission tomography/computed tomography (PET/CT) for the detection of infectious foci in patients with Staphylococcus aureus bacteraemia by comparing it with 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) PET/CT. Methods: Four patients admitted to hospital due to S. aureus bacteraemia underwent both 18F-FDG and 68Ga-citrate whole-body PET/CT scans to detect infectious foci. Results: The time from hospital admission and the initiation of antibiotic treatment to the first PET/CT was 4-10 days. The time interval between 18F-FDG and 68Ga-citrate PET/CT was 1-4 days. Three patients had vertebral osteomyelitis (spondylodiscitis) and one had osteomyelitis in the toe; these were detected by both 18F-FDG (maximum standardised uptake value [SUVmax] 6.0 ± 1.0) and 68Ga-citrate (SUVmax 6.8 ± 3.5, P = 0.61). Three patients had soft tissue infectious foci, with more intense 18F-FDG uptake (SUVmax 6.5 ± 2.5) than 68Ga-citrate uptake (SUVmax 3.9 ± 1.2, P = 0.0033). Conclusions: Our small cohort of patients with S. aureus bacteraemia revealed that 68Ga-citrate PET/CT is comparable to 18F-FDG PET/CT for detection of osteomyelitis, whereas 18F-FDG resulted in a higher signal for the detection of soft tissue infectious foci.

Joint inflammation related citrullination of functional arginines in extracellular proteins.

We report the extent, specific sites and structural requirements of joint inflammation related citrullination in extracellular proteins. A total of 40 synovial fluid samples derived from chronically inflamed human joints were analysed by heparin-agarose fractionation and LC-MS/MS. Citrullination of 55 arginines in extracellular proteins was detected. Importantly, 20% of the sites have a characterized function related to the hallmarks of destructive joint inflammation. E.g. four arginine residues, shown here to be citrullinated, are also affected by mutations in inherited diseases causing haemolysis or blood clotting dysfunction. Citrullination of integrin ligands was selected for further studies since fibronectin R234 in isoDGR was among the most frequently citrullinated arginines in synovial fluid. Assays with synovial fibroblasts and integrin αVß3 indicated decreased affinity to the enzymatically citrullinated integrin binding sites. To conclude, our data indicate that in inflamed joints extensive citrullination affects the functional arginine residues in extracellular proteins.

Efficacy and effectiveness of tumour necrosis factor inhibitors in the treatment of rheumatoid arthritis in randomized controlled trials and routine clinical practice.

Objective: Efficacy of TNF inhibitors in the treatment of RA assessed in randomized controlled trials (RCTs) may not be fully comparable to routine care owing to the stringent inclusion criteria. The objective of this study was to observe the effectiveness of TNF inhibitors in real-world patients and assess the patients' potential eligibility for the RCTs. Methods: RA patients starting a TNF-inhibitor treatment between 2004 and 2014 were identified from the National Register for Biologic Treatment in Finland, which is a longitudinal observational cohort study. Effectiveness was measured using the ACR and EULAR response criteria and by studying the proportion of patients reaching DAS28 remission. The patients' baseline characteristics were compared against the inclusion criteria of 27 RCTs. Results: EULAR moderate and good treatment responses at 6 months were achieved by 69 and 40% of the users of the first TNF inhibitor, respectively. ACR20, ACR50 and ACR70 responses were reached by 48, 27 and 13%, respectively. DAS28 remission was reached by 47%. Only 7.6-44% of the patients would have been potentially eligible for the RCTs. The eligible patients had better treatment responses compared with the non-eligible patients. Different TNF inhibitors were mostly equipotent, but the usage of MTX co-therapy had a major influence on treatment response. Conclusion: Only a small proportion of patients would have been eligible for RCTs, and the efficacy of TNF inhibitors assessed in them cannot be generalized directly into Finnish routine health care.

18F-FDG positron emission tomography/computed tomography in infective endocarditis.

BACKGROUND: The diagnosis of infective endocarditis (IE), especially the diagnosis of prosthetic valve endocarditis (PVE) is challenging since echocardiographic findings are often scarce in the early phase of the disease. We studied the use of 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in IE. METHODS: Sixteen patients with suspected PVE and 7 patients with NVE underwent visual evaluation of 18F-FDG-PET/CT. 18F-FDG uptake was measured also semiquantitatively as maximum standardized uptake value (SUVmax) and target-to-background ratio (TBR). The modified Duke criteria were used as a reference. RESULTS: There was strong, focal 18F-FDG uptake in the area of the affected valve in all 6 cases of definite PVE, in 3 of 5 possible PVE cases, and in 2 of 5 rejected cases. In all patients with definite PVE, SUVmax of the affected valve was higher than 4 and TBR higher than 1.8. In contrast to PVE, only 1 of 7 patients with NVE had uptake of 18F-FDG by PET/CT in the valve area. Embolic infectious foci were detected in 58% of the patients with definite IE. CONCLUSIONS: 18F-FDG-PET/CT appears to be a sensitive method for the detection of paravalvular infection associated with PVE. Instead, the sensitivity of PET/CT is limited in NVE.

Influence of triple disease modifying anti-rheumatic drug therapy on carotid artery inflammation in drug-naive patients with recent onset of rheumatoid arthritis.

OBJECTIVE: Increased atherosclerosis in RA is not fully explained by the ordinary risk factors, but it may be related to vascular inflammation. The aim of this study was to investigate the degree of carotid artery inflammation in drug-naive patients with early RA before and after DMARD triple therapy. METHODS: Fifteen non-diabetic patients with recently diagnosed RA [age 51 (16) years, 6 males] were examined before and at 2 and 4 weeks after the initiation of combination therapy with MTX, SSZ, HCQ and ⩽10 mg/day oral prednisolone. Eight healthy males aged 49 (6) years were examined once as controls. Inflammation in the carotid artery was quantified, using [(18)F]fluorodeoxyglucose ((18)F-FDG)-PET/CT, as the maximum standardized uptake value (SUVmax) and the maximum target-to-background ratio (TBRmax). RESULTS: Before the treatment, patients with RA had significantly higher carotid artery (18)F-FDG uptake, as compared with healthy controls [TBRmax 1.78 (0.07) vs 1.51 (0.08), P = 0.03]. The 4-week DMARD therapy reduced the TBRmax to the level of healthy controls [1.53 (0.05), P = 0.84]. Compared with the baseline, the TBRmax decreased by 12.4 (16.8)% (P = 0.01) during 4-week DMARD therapy. At baseline, the SUVmax correlated with ESR (r = 0.52, P = 0.02) and CRP (r = 0.65, P = 0.01). Change in SUVmax correlated with changes in ESR and CRP after 4 weeks of treatment, as did the changes in TBRmax and SUVmax with DAS at 12 weeks of treatment. CONCLUSION: (18)F-FDG-PET/CT revealed that drug-naive patients with early RA show carotid artery inflammation that can be efficiently reduced by 1-month DMARD triple therapy.

Extracellular citrullination inhibits the function of matrix associated TGF-ß.

In inflammatory arthritis peptidyl arginine deiminase (PAD) enzymes can citrullinate arginine residues in extracellular matrix (ECM) proteins, such as collagens and fibronectin. This may lead to the generation of anti-citrullinated protein antibodies, important diagnostic markers in rheumatoid arthritis. In addition, the citrullination may directly affect protein function. Based on structural analysis, we found that most ECM-associated growth factors (GFs) have arginine residues in their receptor recognition sites. Thus, they are potential functional targets of extracellular citrullination. To examine this further, we focused on the citrullination of transforming growth factor-ßs (TGF-ß), well-known ECM-associated GFs. PAD-treatment of CHO-LTBP1 cell derived matrix, rich with TGF-ß, decreased the level of TGF-ß activity as detected by HaCaT and MLEC-PAI-1/Lu reporter cells. Additional experiments indicated that PAD-treatment inhibits the integrin-mediated TGF-ß activation since PAD-treatment decreased the binding of integrin αVß6 ectodomain as well as integrin-mediated spreading of MG-63 and HaCaT cells to ß1-latency associated peptide (TGF-ß1 LAP). The citrullination of the RGD site, an important integrin recognition motif, was confirmed by mass spectrometry. Furthermore, the citrullination of active TGF-ß1 inhibited its binding to recombinant TGF-ß receptor II, and prevented its ability to activate TGF-ß signaling. Thus, extracellular PAD activity can affect the function of ECM-associated growth factors by different mechanisms. Importantly, the citrullination of both latent and active TGF-ß has the potency to regulate the inflammatory process.