Trial of Anti-BDCA2 Antibody Litifilimab for Cutaneous Lupus Erythematosus.

BACKGROUND: Blood dendritic cell antigen 2 (BDCA2) is a receptor that is exclusively expressed on plasmacytoid dendritic cells, which are implicated in the pathogenesis of lupus erythematosus. Whether treatment with litifilimab, a humanized monoclonal antibody against BDCA2, would be efficacious in reducing disease activity in patients with cutaneous lupus erythematosus has not been extensively studied. METHODS: In this phase 2 trial, we randomly assigned adults with histologically confirmed cutaneous lupus erythematosus with or without systemic manifestations in a 1:1:1:1 ratio to receive subcutaneous litifilimab (at a dose of 50, 150, or 450 mg) or placebo at weeks 0, 2, 4, 8, and 12. We used a dose-response model to assess whether there was a response across the four groups on the basis of the primary end point, which was the percent change from baseline to 16 weeks in the Cutaneous Lupus Erythematosus Disease Area and Severity Index-Activity score (CLASI-A; scores range from 0 to 70, with higher scores indicating more widespread or severe skin involvement). Safety was also assessed. RESULTS: A total of 132 participants were enrolled; 26 were assigned to the 50-mg litifilimab group, 25 to the 150-mg litifilimab group, 48 to the 450-mg litifilimab group, and 33 to the placebo group. Mean CLASI-A scores for the groups at baseline were 15.2, 18.4, 16.5, and 16.5, respectively. The difference from placebo in the change from baseline in CLASI-A score at week 16 was -24.3 percentage points (95% confidence interval [CI] -43.7 to -4.9) in the 50-mg litifilimab group, -33.4 percentage points (95% CI, -52.7 to -14.1) in the 150-mg group, and -28.0 percentage points (95% CI, -44.6 to -11.4) in the 450-mg group. The least squares mean changes were used in the primary analysis of a best-fitting dose-response model across the three drug-dose levels and placebo, which showed a significant effect. Most of the secondary end points did not support the results of the primary analysis. Litifilimab was associated with three cases each of hypersensitivity and oral herpes infection and one case of herpes zoster infection. One case of herpes zoster meningitis occurred 4 months after the participant received the last dose of litifilimab. CONCLUSIONS: In a phase 2 trial involving participants with cutaneous lupus erythematosus, treatment with litifilimab was superior to placebo with regard to a measure of skin disease activity over a period of 16 weeks. Larger and longer trials are needed to determine the effect and safety of litifilimab for the treatment of cutaneous lupus erythematosus. (Funded by Biogen; LILAC ClinicalTrials.gov number, NCT02847598.).

Elderly-Onset Rheumatoid Arthritis: Characteristics and Treatment Options.

Elderly-onset rheumatoid arthritis (EORA) is a distinct clinical entity defined as the onset of rheumatoid arthritis (RA) in individuals aged over 60 years. EORA presents unique clinical features, including a more equitable distribution of sexes, a potential predilection for male involvement, a higher incidence of acute onset characterized by constitutional symptoms, a propensity for systemic manifestations, elevated sedimentation rates at disease onset, a reduced occurrence of rheumatoid factor positivity, increased titers of anti-citrullinated protein antibodies, a preference for involvement of large joints, elevated disease activity, the presence of bone erosions, and heightened patient disability. RA is recognized to consist of three partially overlapping subsets. One subset mirrors the classical RA clinical presentation, while the remaining subsets exhibit either a polymyalgia rheumatica-like phenotype or present with remitting seronegative symmetrical synovitis accompanied by pitting edema syndrome. In the initial stages of EORA management, non-steroidal anti-inflammatory drugs (NSAIDs) are not typically the first-line treatment choice, because seniors are much more prone to develop side effects due to NSAIDs, and the use of NSAIDs is in reality contraindicated to the majority of seniors due to comorbidities. Disease-modifying antirheumatic drugs (DMARDs), frequently methotrexate, are introduced immediately after the diagnosis is made. In cases where elderly patients demonstrate resistance to conventional DMARD therapy, the introduction of biological or targeted synthetic DMARDs becomes a viable treatment option. EORA presents a unique clinical profile, necessitating tailored treatment strategies. Our study emphasizes the challenges of NSAID use in seniors, highlighting the imperative shift toward DMARDs such as methotrexate. Future research should explore personalized DMARD approaches based on disease activity, comorbidities, and safety considerations, aiming to optimize treatment outcomes and minimize glucocorticoid reliance, thereby enhancing the quality of care for EORA patients.

Depression/anxiety symptoms in axial spondyloarthritis and psoriatic arthritis patients in Serbia: a pilot study.

To assess prevalence and change of depression/anxiety symptoms in spondyloarthritis patients and feasibility of depression/anxiety questionnaires. 43 Patients with axial spondyloarthritis (axSpA) and 27 patients with psoriatic arthritis (PsA) were consecutively recruited. There were 34 patients on biologics and 36 patients on nonbiologics. Patients were not previously treated for depression. The demographic variables, pain, patient global assessment, laboratory, clinical findings, diseases activity scores, Beck Depression Inventory (BDI) and Depression Anxiety and Stress Scale-short version (DASS-21) were collected. The study visits were at the beginning, after 1 month, after 3 and after 6 months. In axSpA and PsA patients on biologics, BDI and DASS-21 were significantly lower compared to nonbiologics group during time. The axSpA patients on biologics had significantly lower BDI and depression severity by BDI at each time point and lower DASS-21 after 1, 3 and 6 months. BDI in PsA patients who received biological therapy was significantly lower after 3 and 6 months. In biologics groups, BDI significantly decreased after 3 months in axSpA patients and after 1 month in PsA patients. In axSpA patients, there was a medium correlation between BDI and axial pain, patient global assessment and disease activity scores. The biological therapy significantly affected the depression/anxiety symptoms in axSpA and PsA during time. BDI moderately correlated with pain and disease activity in axSpA. BDI and DASS-21 are easy to use in daily practice.

Correction to: Endorsement by Central European experts of the revised ESCEO algorithm for the management of knee osteoarthritis.

In the Original Publication, the e-mail address of the author Milan Petronijevic is incorrect. The correct e-mail address is milanpetronijevic@yahoo.com.

Endorsement by Central European experts of the revised ESCEO algorithm for the management of knee osteoarthritis.

Osteoarthritis (OA) is characterized by deterioration of the joints and associated with considerable pain and disability. OA is a chronic disease that requires intervention with both non-pharmacological and pharmacological treatment modalities and, inevitably, disease progression may necessitate successive treatments throughout the course of the disease. There is increasing data on the shortfalls of current pharmacological treatment of OA, and safety concerns associated with analgesic therapy use in OA arising from increasing evidence of gastrointestinal, cardiovascular, hepatic and renal adverse events with paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs). Consequently, symptomatic slow-acting drugs for OA (SYSADOAs) may now be considered as a first-line treatment for knee OA, with a particular emphasis placed on the outstanding benefit: risk ratio of pharmaceutical-grade glucosamine and chondroitin sulfate formulations. In this short communication we review recent publications concerned with the safety of paracetamol, NSAIDs and SYSADOAs. Greater understanding of the benefits and limitations of current medications will lead to better disease management in OA. Furthermore, adherence to guideline recommendations across Europe and internationally, such as those from the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO), will promote evidence-based medicine and patient-centric care, ultimately leading to greater physician and patient satisfaction.

Construct validity and sensitivity to change of Belgrade Ultrasound Enthesitis Score in patients with spondyloarthritis: a pilot study.

The objective of this study was to determine the construct validity and sensitivity to change of Belgrade Ultrasound Enthesitis Score (BUSES) in spondyloarthritis patients. Seventy-six spondyloarthritis patients with enthesitis were included in this pilot, prospective, double-blinded ultrasound study. Thirty-four patients received biological and forty-two patients received non-biological therapy. BUSES was determined at the beginning, after 1, 3, and 6 months. Spearman's correlation coefficient was calculated between BUSES and baseline characteristics. Brunner-Langer mixed non-parametric ANOVA was used to examine sensitivity to change of BUSES and effect of biological therapy on BUSES. Effect of time on the presence of each of the ultrasound enthesitis signs (increased thickness, hypoehogenicity, Power Doppler, enthesophytes, and erosions) was assessed using Cochran Q test. There was a weak, positive correlation between BUSES and disease duration, clinical enthesitis score, BASFI, BASDAI, and ASDAS-ESR/CRP. BUSES was higher at the beginning than after 1 month (p = 0.004), after 3 months (p < 0.001) and after 6 months (p < 0.001), as well as BUSES was higher after 1 month than after 3 months (p < 0.001) and after 6 months (p = 0.002). There is no difference in efficiency between non-biological and biological therapies on BUSES. Increased thickness, hypoechogenicity, and Power Doppler have decreased on Achilles tendon's and plantar fascia's enthesis over time. BUSES has a certain degree of construct validity because of the weak, positive correlation with parameters referring to severity of spondyloarthritis. BUSES demonstrated sensitivity to change over time due to decreasing of ultrasound acute enthesitis signs in treated spondyloarthritis patients. BUSES could be useful for monitoring the progression of enthesitis and effectiveness of the treatment.

Matrix Metalloproteinases-3 Baseline Serum Levels in Early Rheumatoid Arthritis Patients without Initial Radiographic Changes: A Two-Year Ultrasonographic Study.

OBJECTIVE: To investigate the association of high baseline serum levels of metalloproteinases-3 (MMP-3) with structural damage to hand and feet joints, assessed by ultrasonography (US), in patients with early, treatment-naïve rheumatoid arthritis (RA), without initial X-ray-visible erosions, during 24 months follow-up. METHODS: Sixty-three early RA (European League Against Rheumatism/American College of Rheumatology 2010), disease-modifying anti-rheumatic drugs/glucocorticoid naïve patients (mean age 53.4 ± 14.1) with symptom duration ≤12 months, had baseline serum levels of MMP-3 tested. OMERACT US group definition was used to detect the presence, as well as longitudinal diameter of erosions by US at study entry and after 24 months, at the level of wrists, metacarpophalangeal (MCP2/MCP5) joints of both hands, and fifth metatarsophalangeal joints. RESULTS: Complete data were collected from 52 out of 63 patients. High baseline serum levels of MMP-3 (MMP-3-positive) were found in 46/63 patients. 122 bone erosions in total (1.9 bone erosions/patients) were detected by US at baseline visit and 213 erosions (4.3/patients) after 24 months. MMP-3 positive patients had significantly higher total number of erosions than MMP-3-negative (p = 0.039) and higher increase in size of bone erosions in the feet but not in the hand joints after follow-up (OR 4.82 [1.23-18.9], p = 0.024; OR 1.17 [0.320-4.26], p = 0.816 respectively). CONCLUSION: After 2 years of follow-up, US assessment showed a higher number of new bone erosions in MMP-3-positive compared to MMP-3-negative patients with early RA and no visible initial radiographic changes. High baseline levels of MMP-3 predict significantly higher structural damage progression at the level of feet, but not at the level of hand joints.

Polymorphisms of the eNOS gene are associated with disease activity in rheumatoid arthritis.

Nitric oxide (NO) is a mediator in autoimmune responses and thus involved in the pathogenesis of a variety of rheumatic diseases. Genetic factors that influence the expression of the enzyme endothelial nitric oxide synthase (eNOS) that catalyzes NO synthesis are important for the control of NO level and consequently its activity. We have analyzed three functionally relevant polymorphisms of eNOS gene: T-786C, G894T and VNTR (4a/b), to investigate whether they are predisposing factors in pathogenesis of RA in Serbian population and to evaluate their role in clinical manifestations of RA. We performed genotyping of 196 patients with RA and the control group of 132 healthy individuals from Serbian population, using PCR and polymerase chain reaction-restriction fragment length polymorphism methods. Disease activity was prospectively assessed using number of tender joints, number of swollen joints and 28-joints disease activity score (DAS28). There were no differences between the patients and control groups in the genotypes and alleles frequencies of the three analyzed SNPs. Our results showed statistically significant differences in all three analyzed parameters of disease severity between 786TT/786CT and 786CC genotypes and between 894GG/894GT and 894TT genotypes. In the case of 4a/b polymorphism, carriers of minor allele had significantly lower DAS28 values. In conclusion, our results do not support the implication of analyzed eNOS gene polymorphisms in susceptibility to RA but associate them with the disease activity and give assumption that minor alleles are indicators of better clinical course.

Diagnosis of Raynaud's phenomenon by 99mTc-pertechnetate hand perfusion scintigraphy: a pilot study.

We assess the usefulness of 99mTc-pertechnetate hand perfusion scintigraphy in patients with Raynaud's phenomenon (RP). The study population consisted of 18 patients with primary RP, 25 patients with secondary RP within systemic sclerosis (SSc), and ten healthy individuals. Gamma camera dynamic first-pass study during the first 60 s and a static scintigraphy after 5 min were recorded following a bolus injection of 99mTc-pertechnetate via a cubital vein. Regions of interest were drawn on the summed images around the fingers and the palmar region. The fingers-to-palm ratios were then calculated. The mean fingers-to-palm ratio for dynamic study (blood flow) was 0.58 ± 0.19 for the healthy group, 0.45 ± 0.18 for the primary RP, and 0.43 ± 0.21 for the SSc patients. The mean fingers-to-palm ratio for static study (blood pool) was 0.44 ± 0.06 for the healthy group, 0.42 ± 0.06 for the primary RP, and 0.36 ± 0.07 for the SSc patients. Analysis of variance showed these differences to be significant (p = 0.039 from blood flow and p = 0.004 from blood pool). The receiver operating characteristic curve showed sensitivity of 80% and a specificity of 60% when using cutoff values of 0.40 for blood flow and sensitivity of 79% and a specificity of 70% when using cutoff values of 0.37 for blood pool. Our method is able to differentiate between patients with normal and those with abnormal microcirculation of the hands. Dynamic study separates the healthy subjects from patients with RP, while static study separates primary from secondary RP.

Repetitive Transcranial Magnetic Stimulation in Fibromyalgia: Exploring the Necessity of Neuronavigation for Targeting New Brain Regions.

Fibromyalgia and osteoarthritis are among the most prevalent rheumatic conditions worldwide. Nonpharmacological interventions have gained scientific endorsements as the preferred initial treatments before resorting to pharmacological modalities. Repetitive transcranial magnetic stimulation (rTMS) is among the most widely researched neuromodulation techniques, though it has not yet been officially recommended for fibromyalgia. This review aims to summarize the current evidence supporting rTMS for treating various fibromyalgia symptoms. Recent findings: High-frequency rTMS directed at the primary motor cortex (M1) has the strongest support in the literature for reducing pain intensity, with new research examining its long-term effectiveness. Nonetheless, some individuals may not respond to M1-targeted rTMS, and symptoms beyond pain can be prominent. Ongoing research aims to improve the efficacy of rTMS by exploring new brain targets, using innovative stimulation parameters, incorporating neuronavigation, and better identifying patients likely to benefit from this treatment. Summary: Noninvasive brain stimulation with rTMS over M1 is a well-tolerated treatment that can improve chronic pain and overall quality of life in fibromyalgia patients. However, the data are highly heterogeneous, with a limited level of evidence, posing a significant challenge to the inclusion of rTMS in official treatment guidelines. Research is ongoing to enhance its effectiveness, with future perspectives exploring its impact by targeting additional areas of the brain such as the medial prefrontal cortex, anterior cingulate cortex, and inferior parietal lobe, as well as selecting the right patients who could benefit from this treatment.

Wearable Movement Exploration Device with Machine Learning Algorithm for Screening and Tracking Diabetic Neuropathy-A Cross-Sectional, Diagnostic, Comparative Study.

BACKGROUND: Diabetic neuropathy is one of the most common complications of diabetes mellitus. The aim of this study is to evaluate the Moveo device, a novel device that uses a machine learning (ML) algorithm to detect and track diabetic neuropathy. The Moveo device comprises 4 sensors positioned on the back of the hands and feet accompanied by a mobile application that gathers data and ML algorithms that are hosted on a cloud platform. The sensors measure movement signals, which are then transferred to the cloud through the mobile application. The cloud triggers a pipeline for feature extraction and subsequently feeds the ML model with these extracted features. METHODS: The pilot study included 23 participants. Eleven patients with diabetes and suspected diabetic neuropathy were included in the experimental group. In the control group, 8 patients had suspected radiculopathy, and 4 participants were healthy. All participants underwent an electrodiagnostic examination (EDx) and a Moveo examination, which consists of sensors placed on the feet and back of the participant's hands and use of the mobile application. The participant performs six tests that are part of a standard neurological examination, and a ML algorithm calculates the probability of diabetic neuropathy. A user experience questionnaire was used to compare participant experiences with regard to both methods. RESULTS: The total accuracy of the algorithm is 82.1%, with 78% sensitivity and 87% specificity. A high linear correlation up to 0.722 was observed between Moveo and EDx features, which underpins the model's adequacy. The user experience questionnaire revealed that the majority of patients preferred the less painful method. CONCLUSIONS: Moveo represents an accurate, easy-to-use device suitable for home environments, showing promising results and potential for future usage.

Association of the TYMS 3G/3G genotype with poor response and GGH 354GG genotype with the bone marrow toxicity of the methotrexate in RA patients.

PURPOSE: Gamma-glutamyl hydrolase (GGH), cyclin D1 (CCND1) and thymidylate synthase (TS) genes encode enzymes that are involved in methotrexate (MTX) action. In a group of 184 RA patients treated with MTX, we have investigated whether selected polymorphisms in these genes modulate MTX efficacy and/or have impact on adverse drug effects (ADEs). METHODS: The efficacy of the MTX therapy has been estimated using the disease activity score in 28 joints (DAS28-ESR) based on EULAR criteria and relative DAS28 values (rDAS28). All adverse drug events were recorded. Patients were genotyped for selected polymorphisms of the GGH (-354 G > T and 452 C > T), CCND1 (870 A > G) and TYMS (variable number of tandem repeats, VNTR, and G to C substitution of triple repeat, 3R allele) gene. Association studies have been performed between obtained genotypes and the efficacy and toxicity of MTX. RESULTS: According to the EULAR response criteria, 146 RA patients (79.3 %) were classified as responders (good/moderate response) and 38 (20.7 %) as non-responders (poor response). Higher frequency of the TYMS 3 G/3 G genotype has been found among non-responders as compared to individuals with remaining genotypes (p = 0.02). ADEs were recorded in 53 patients. Among those patients eight experienced bone marrow toxicity, all of them carried GGH -354GG genotype (p = 0.003). No other significant association were observed. CONCLUSION: The 3 G/3 G genotype of the TYMS gene may indicate predisposition of poor response to MTX and GG genotype of GGH -354 T > G polymorphism may have high predictive value for myelosuppression in RA patients.

Late appearance and exacerbation of primary Raynaud's phenomenon attacks can predict future development of connective tissue disease: a retrospective chart review of 3,035 patients.

To assess the prognostic value of the age at onset of Raynaud's (RP) and of a history of exacerbation of RP attacks for the development of connective tissue disease (CTD) in patients initially found to have primary Raynaud's. 3,035 patients with primary RP (2,702 women and 333 men) were followed for an average of 4.8 years (range from 1 to 10 years). At baseline and every 6 months, they were screened for signs and symptoms of CTD. At 4.8 years of follow-up, 54.7 % patients remained as primary RP, 8.1 % had developed suspected secondary RP, and 37.2 % had developed a definite CTD. Primary RP patients had an earlier onset of RP (mean age of 32.2 years) than those with suspected (mean age 36.5 years, P = .007) or definite secondary RP associated with CTD (mean age of 39.8 years, P = .004). RP beginning before the age of forty was not significantly associated with the development of CTD. Conversely, the appearance of RP after the age of 40 was significantly associated with the development of CTD (P = .00001). Worsening of RP attacks predicted the development of CTD, especially systemic sclerosis (relative risk [RR] of 1.42), scleroderma overlap syndrome (RR of 1.18), and mixed CTD (RR of 1.18). Patients whose onset of RP occurred past 40 years of age and those with worsening RP attacks were at risk for the future development of CTD.

The short-term effect of glucosamine-sulfate, nonanimal chondroitin-sulfate, and S-adenosylmethionine combination on ultrasonography findings, inflammation, pain, and functionality in patients with knee osteoarthritis: A pilot, double-blind, randomized, placebo-controlled clinical trial.

Objectives: This study aimed to investigate the efficacy of glucosamine-sulfate (GS), nonanimal chondroitin-sulfate (naCS), and S-adenosylmethionine (SAMe) combination on ultrasound findings, inflammation, pain, and functionality in knee osteoarthritis. Patients and methods: In the prospective, randomized, double-blind, placebo-controlled pilot study conducted between August 2019 and November 2019, 120 participants (28 males, 92 females; mean age: 66.4±7.9 years; range, 42.4 to 74.5 years) were randomized at a 1:1:1 ratio to the placebo group, the first experimental group (a combination of GS, naCS, and SAMe was administered to the experimental groups. The first experimental group received 375 mg of GS, 300 mg of naCS, and 100 mg of SAMe, whereas the second experimental group received 750 mg of GS, 600 mg of naCS, and 200 mg of SAMe). Laboratory (erythrocyte sedimentation rate, C-reactive protein, tumor necrosis factor alpha, interleukin [IL]-1ß, IL-6, IL-17), clinical (Visual Analog Scale [VAS], short form health survey [SF-36], the Western Ontario and McMaster Universities Arthritis Index [WOMAC], and the Tegner Lysholm Knee Scoring Scale [TLKS]), and musculoskeletal ultrasound (MSUS) assessments were performed at baseline and after three and six months. Results: A minor increase was observed in the second experimental group after six months using ultrasonography to evaluate articular cartilage thickness (p<0.05). The investigational product's superiority in reducing osteoarthritis ultrasonographic findings was not proven. A moderately negative association was found between cartilage thickness and VAS scores at baseline (ρ=-0.36, p<0.01), while the presence of massive osteophytes on MSUS showed a low to moderate association with all clinical outcomes. There was no difference in the delta changes between groups for the VAS, TLKS, WOMAC, and SF-36. The only serum inflammatory marker outside the reference range was IL-1ß, but no significant changes were observed after six months. Conclusion: According to the results of our investigation, treatment for knee osteoarthritis should be evaluated using more objective outcomes. The most important conclusion of our study is that IP may result in a slight increase in articular cartilage thickness, which was associated with a decrease in pain intensity at baseline. Clarification of the potential influence of this combination on radiographic progression and laboratory markers of inflammation requires further exploration.

Antiphospholipid Antibodies and Vascular Thrombosis in Patients with Severe Forms of COVID-19.

Antiphospholipid antibodies (aPLA) are a laboratory criterion for the classification of antiphospholipid syndrome (APS) and are known to cause clinical symptoms such as vascular thrombosis or obstetric complications. It is suggested that aPLA may be associated with thromboembolism in severe COVID-19 cases. Therefore, we aimed to combine clinical data with laboratory findings of aPLA at four time points (admission, worsening, discharge, and 3-month follow-up) in patients hospitalized with COVID-19 pneumonia. In 111 patients with COVID-19 pneumonia, current and past history of thrombosis and pregnancy complications were recorded. Nine types of aPLA were determined at four time points: anticardiolipin (aCL), anti-ß2-glycoprotein I (anti- ß2GPI), and antiphosphatidylserine/prothrombin (aPS/PT) of the IgM, IgG, or IgA isotypes. During hospitalization, seven patients died, three of them due to pulmonary artery thromboembolism (none were aPLA positive). Only one of the five who developed pulmonary artery thrombosis was aPLA positive. Out of 9/101 patients with a history of thrombosis, five had arterial thrombosis and none were aPLA positive at admission and follow-up; four had venous thrombosis, and one was aPLA positive at all time points (newly diagnosed APS). Of these 9/101 patients, 55.6% were transiently aPLA positive at discharge only, compared to 26.1% without a history of thrombosis (p = 0.041). Patients with severe forms of COVID-19 and positive aPLA should receive the same dose and anticoagulant medication regimen as those with negative aPLA because those antibodies are mostly transiently positive and not linked to thrombosis and fatal outcomes.

The role of Doppler ultrasound in rheumatic diseases.

The use of Doppler techniques, including power, colour and spectral Doppler, has greatly increased in rheumatology in recent years. This is due to the ability of Doppler US (DUS) to detect pathological vascularization within joints and periarticular soft tissues, thereby demonstrating the presence of active inflammation, which has been reported to be correlated with the local neo-angiogenesis. In synovitis, DUS showed a high correlation with histological and MRI findings, thus it is considered a valid tool to detect pathological synovial vascularization. Moreover, it is more sensitive than clinical examination in detecting active joint inflammation and in the evaluation of response to treatment. In addition, DUS may be considered as a reference imaging modality in the assessment of enthesitis, MRI being not sensitive and histology not feasible. Moreover, it has been demonstrated to be able to detect changes in asymptomatic enthesis. In conclusion, DUS is a useful and sensitive tool in the evaluation and monitoring of active inflammation. Its widespread use in clinical rheumatological practice is recommended. The aim of this article is to review the current literature about the role of DUS in rheumatic diseases, analysing its validity, reliability and feasibility.

Ultrasonography of major salivary glands could be an alternative tool to sialoscintigraphy in the American-European classification criteria for primary Sjogren's syndrome.

OBJECTIVE: To test the diagnostic accuracy of modified American-European classification criteria (AEC) for primary SS (pSS) by replacing sialoscintigraphy (sSC) with ultrasonography of the major salivary glands. METHODS: One hundred and ninety subjects were evaluated for the diagnosis of pSS, including US of the salivary glands. We tested the diagnostic accuracy of the three different sets of five diagnostic criteria for pSS. Each set combined these four criteria (ocular symptoms, oral symptoms, Schirmer-I test and auto-SS-A antibody) and one of the following: US (US set), sSC (sSC set) or biopsy (Biopsy set). The area under the receiver operating characteristics curve (AUC-ROC) was used to evaluate the diagnostic accuracy of each set of criteria. RESULTS: Out of 190 subjects examined, 140 subjects fulfilled the AEC for the diagnosis of pSS, whereas 50 subjects were classified as non-pSS subjects. US score was positive in 129 (92%), sSC in 123 (88%) and biopsy in 93 (66%) of 140 pSS patients. Among 140 patients with pSS, 88 (63%) patients fulfilled the criteria of the US set, 85 (61%) patients of the sSC set and 71 (51%) patients of the Biopsy set. None of the subjects from the non-pSS group fulfilled any of the sets of criteria. Diagnostic accuracy of each of the three sets of criteria was high and similar [AUC-ROC (s.e.) for the US set was 0.99 (0.00), followed by the sSC set at 0.98 (0.00) and the Biopsy set at 0.97 (0.00)]. CONCLUSION: US finding of major salivary gland involvement could replace sSC in AEC for the diagnosis of pSS.

Construct validity and reliability of ultrasound disease activity score in assessing joint inflammation in RA: comparison with DAS-28.

OBJECTIVE: To investigate the construct validity and reliability of US DAS compared with 28-joint DAS (DAS-28) in assessing joint inflammation and in prediction of structural damage in patients with RA. METHODS: Ninety patients with active RA were prospectively recruited and followed up during the 6 months of treatment. The patients underwent clinical, laboratory and X-ray assessment, along with blinded power Doppler US (PDUS) and grey-scale (GS) US (GSUS) examination at baseline and 6 months. A subgroup of 25/90 randomly assigned patients underwent MRI examination of their hands at baseline. A PDUS examination of 22 joints and GSUS examination for effusion/hypertrophy (E/H) of 28 joints were performed by two independent examiners, blinded to clinical findings. E/H was qualitatively assessed as absent or present, and PD signal was semi-quantitatively graded from 0 to 3. PDUS score for synovitis in 22 joints and GS score for E/H in 28 joints were included in US DAS calculation. Clinical scoring, PDUS and GSUS inter-observer reliability were evaluated. RESULTS: Strong correlation was found between US DAS and standard assessment of disease activity such as the DAS-28, ESR and CRP levels. Correlation between US DAS and patients' and physicians' visual analogue scale of activity was moderate, whereas correlations of US DAS with Health Assessment Questionnaire - Disability Index (HAQ-DI) and Short Form 36 Health Survey (SF-36) were weak to moderate. US DAS correlated with X-ray, MRI and US parameters and rates of joint damage. CONCLUSION: US DAS better anticipated future joint damage than standard DAS-28.

Association of dihydrofolate reductase (DHFR) -317AA genotype with poor response to methotrexate in patients with rheumatoid arthritis.

OBJECTIVES: Identifying genetic predictors of methotrexate (MTX) treatment response in patients with rheumatoid arthritis (RA) may have great importance for optimising drug doses required for clinical benefit without toxicity. In a group of 125 RA patients treated with MTX we investigated whether selected polymorphisms in genes relevant for MTX action (aminoimidazole-4-carboxiamide ribonucleotide transformylase, ATIC, and dihydrofolate reductase, DHFR) modulate disease activity and/or have impact on therapy side effects. METHODS: The efficacy of treatment was estimated both by the disease activity score in 28 joints (DAS28), based on EULAR criteria, and relative DAS28 (rDAS28) score. Adverse drug events (ADEs) were also recorded. RA patients were genotyped using the PCR-RFLP method, followed by an association study between ATIC -129T>G, DHFR -216T>C and DHFR -317A>G polymorphisms and the efficacy and toxicity of MTX. RESULTS: According to the EULAR response criteria, 96 RA patients (76.8%) were classified as responders (good/moderate response) and 29 (23.2%) as non-responders (poor response). rDAS28 values ranged from -0.01 to 0.80 (mean value 0.31±0.19). Among 125 patients enrolled in this study 39 experienced at least one side effect. The DHFR -317AA genotype was associated with the less favourable response (reduction in rDAS28 score, p=0.05). None of the analysed polymorphisms was associated with MTX toxicity. CONCLUSIONS: RA patients with DHFR-317AA genotype had less favourable response to MTX. Further studies in larger patient populations are necessary to confirm the relationship between the analysed polymorphisms and MTX treatment response.

Ultrasonographic measures of synovitis in an early phase clinical trial: a double-blind, randomised, placebo and comparator controlled phase IIa trial of GW274150 (a selective inducible nitric oxide synthase inhibitor) in rheumatoid arthritis.

OBJECTIVES: To test the sensitivity to change of ultrasonographic endpoints in early phase clinical trials in subjects with active rheumatoid arthritis (RA). METHODS: A double-blind, placebo and comparator controlled, randomised, two-centre study investigated the effect on synovial thickness and vascularity of 28 days repeat daily oral dosing of 60 mg of the inducible nitric oxide synthase inhibitor GW274150 or 7.5 mg prednisolone in RA. Fifty patients with DAS28 scores ≥4.0 were assigned to 3 treatment arms of 17, 19 and 14 (on placebo, GW274150 and prednisolone respectively). Synovial thickness and vascularity of all 10 metacarpophalangeal joints were assessed by ultrasonography using a semi-quantitative scale at baseline (Day 1), Day 15 and Day 28. Vascularity was also measured quantitatively by power Doppler area. RESULTS: At Day 28, the GW274150 group showed a trend towards reduction in synovial thickness compared with placebo, with an adjusted mean decrease of 33% (p=0.072); the prednisolone group decreased significantly by 44% (p=0.011). Similarly, there was a trend to reduced synovial vascularity with GW274150 by 42% compared with placebo (p=0.075); prednisolone resulted in a statistically significant decrease of 55% (p=0.012). There was a 55% decrease in power Doppler area for GW274150, compared with placebo although the result was not statistically significant (p=0.375). Prednisolone 7.5 mg resulted in a highly statistically significant decrease of 95% (p=0.003). CONCLUSIONS: This study advocates the use of ultrasonographic measures of metacarpophalangeal joint synovitis as an endpoint for clinical studies assessing therapeutic potential of new compounds in small patient cohorts over 28 days.