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The aim of the study was to assess the cli­nical performance of the model combining areal bone mineral density (aBMD) at spine and microarchitecural texture (TBS) for the detection of the osteoporo­tic fracture. The Eastern European Study is a multicenter study (Serbia, Bulgaria, Romania and Ukraine) evaluating the role of TBS in routine clinical practice as a complement to aBMD. All scans were acquired on Holo­gic Disco­very and GE Prodigy densitometers in a routine clinical manner. The additional clinical values of aBMD and TBS were analyzed using a two steps classification tree approach (aBMD followed by TBS tertiles) for all type of osteoporotic fracture (All-OP Fx). Sensitivity, specifi­city and accuracy of fracture detection as well as the Net Reclassification Index (NRI) were calculated. This study involves 1031 women subjects aged 45 and older recrui­ted in east European countries. Clinical centers were cross-calibrated in terms of BMD and TBS. As expe­cted, areal BMD (aBMD) at spine and TBS were only mo­derately correlated (r2 = 0.19). Prevalence rate for All-OP Fx was 26%. Subjects with fracture have significant lower TBS and aBMD than subjects without fracture (p

This review explores the link between immune interactions and chronic pain, offering new perspectives on treatment. It focuses on Janus kinase (JAK) inhibitors' potential in pain management. Immune cells' communication with neurons shapes neuroinflammatory responses, and JAK inhibitors' effects on pain pathways are discussed, including cytokine suppression and microglial modulation. This review integrates studies from rheumatoid arthritis (RA) pain and central sensitization to highlight connections between immune interactions and pain. Studies on RA joint pain reveal the shift from cytokines to sensitization. Neurobiological investigations into central sensitization uncover shared pathways in chronic pain. Clinical evidence supports JAK inhibitors' efficacy on pain-related outcomes and their effects on neurons and immune cells. Challenges and future directions are outlined, including interdisciplinary collaboration and dosing optimization. Overall, this review highlights JAK inhibitors' potential to target immune-mediated pain pathways, underscoring the need for more research on immune-pain connections.

Introduction: Post-menopausal women with osteoporosis > 70 years of age at high risk of fracture urgently require treatment for fracture prevention. Moreover, persistence with osteoporosis therapy is critical for real-world effectiveness. We estimated persistence with denosumab in older women at high fracture risk in clinical practice in Bulgaria., Methods: Eligible participants were post-menopausal women, > 70 years of age, diagnosed with osteoporosis (T-score ≤ - 2.5) and at high risk of fracture (≥ 3% for hip and ≥ 20% for major osteoporotic fracture) who received at least one denosumab injection before enrollment. Planned follow-up was 24 months. The primary endpoint was persistence to denosumab at 12, 18, and 24 months (defined as receiving all denosumab injections within 6 months ± 60 days of the previous injection)., Results: 250 women were enrolled across 12 Bulgarian endocrinology/rheumatology practices; median follow up, 736 days. Mean (SD) age was 75.8 (4.2) years; mean (SD) FRAX ® was 13.1 (8.6) for hip and 26.1 (9.5) for major osteoporotic fracture; 47 (18.8%) women had prior osteoporosis therapy and 104 (41.6%) had prior fracture. Denosumab persistence was high: 98.0%, 92.4%, and 84.4% at 12, 18, and 24 months, respectively. A total of 42 (16.8%) women discontinued denosumab during follow-up, mostly for financial reasons [25/42 (59.5%)] or loss to follow-up [8/42 (19.0%)]. After 24 months of denosumab treatment, BMD T-score improvement to the range of osteopenia (- 2.5 ≤ T < - 1.5) was achieved by 42.4% at the femoral neck, 23.6% at the lumbar spine, and 49.2% at the total hip; complete recovery (T-score ≥ - 1.5) was observed in 9.0%, 26.4%, and 23.0% respectively. New fracture was reported in 5 patients (2%)., Conclusions: Even in an elderly population, persistence with denosumab was high despite the challenge imposed by the 50% co-pay in Bulgaria., Trial Registration: Bulgarian Drug Agency, №HИП-0009 (registered 28.06.2017); Central Ethics Commission: №КИ-41 (registered 16.05.2017).

Background: In the randomized, phase III, global SELECT-COMPARE study, upadacitinib 15 mg demonstrated efficacy at week 12 versus placebo and adalimumab with methotrexate (MTX) in patients with rheumatoid arthritis and inadequate response to MTX, which was maintained over 48 weeks. This post hoc analysis of SELECT-COMPARE reports the efficacy and safety of upadacitinib in Central and Eastern European (CEE) patients., Methods: Patients were randomized 2:2:1 to upadacitinib 15 mg once daily, placebo, or adalimumab 40 mg every other week, and continued MTX. Efficacy and safety were assessed through 48 weeks. Primary endpoints were the achievement of ≥20% improvement in American College of Rheumatology response criteria and Disease Activity Score in 28 joints with C-reactive protein <2.6 responses at week 12 for upadacitinib versus placebo. No statistical comparisons were conducted., Results: A total of 596 patients from 12 CEE countries were randomized. At week 12, a numerically greater proportion of patients receiving upadacitinib versus placebo or adalimumab achieved ≥20% improvement in American College of Rheumatology response criteria (72% versus 33% and 59%), Disease Activity Score in 28 joints with C-reactive protein <2.6 (26% versus 4% and 11%), low disease activity and remission, and improved physical function, with results maintained over 48 weeks. Upadacitinib treatment numerically inhibited structural progression versus placebo at week 26. Serious infection and herpes zoster rates were numerically higher with upadacitinib versus adalimumab (2.7 versus 1.7 and 2.3 versus 1.1 events/100 patient-years, respectively) over 48 weeks., Conclusion: Consistent with the global population of patients with rheumatoid arthritis and an inadequate response to MTX, in CEE patients, upadacitinib 15 mg demonstrated clinical and functional improvements versus placebo and adalimumab, radiographic improvements versus placebo, and reasonable safety, over 48 weeks., Competing Interests: Disclosure and potential conflicts of interest: Karel Pavelka has received honoraria from AbbVie, Amgen, BMS, Egis, Hospira, Medac, MSD, Pfizer, Roche, and UCB. Zoltán Szekanecz has received consulting fees and honoraria from AbbVie, Amgen, BMS, Gedeon Richter, Lilly, MSD, Pfizer, Roche, Sanofi, and UCB. Nemanja Damjanov has received grants and research support from AbbVie, Pfizer, and Roche, and consulting fees and honoraria from AbbVie, Gedeon Richter, Merck, Novartis, Pfizer, and Roche. Branimir Anić has nothing to disclose. Matija Tomšič has received research grants, consulting fees, and honoraria from AbbVie, Amgen, Biogen, Celltrion, Lilly, Novartis, Pfizer, Roche, and Sanofi. Vadim Mazurov has nothing to disclose. Marija Maksimovic and Orsolya Nagy are employees of AbbVie Ltd and may own AbbVie stock. Jerzy Świerkot has received honoraria from AbbVie, Amgen, BMS, Egis, Gedeon Richter, Lilly, MSD, Pfizer, Roche, Novartis, and UCB. Tzvetanka Petranova has received consulting fees and honoraria from AbbVie, Amgen, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi, and UCB. Tiina Veldi has nothing to disclose. Asta Baranauskaitė has received research funding, consulting fees, and honoraria from AbbVie. Catalin Codreanu has received consulting fees and honoraria from AbbVie, Amgen, BMS, Egis, MSD, Pfizer, Roche, Sanofi, and UCB. Daina Andersone has received grants and consulting fees from AbbVie, Amgen, BMS, Janssen, Novartis, Pfizer, and Roche. Roy Fleischmann has received grants and consulting fees from AbbVie, Amgen, BMS, Gilead, Lilly, Novartis, and Pfizer, and grants from EMD-Serono, Genentech, Roche, Sanofi, and UCB. The International Committee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests form for the authors is available for download at: https://www.drugsincontext.com/wp-content/uploads/2020/09/dic.2020-7-5-COI.pdf, (Copyright © 2020 Pavelka K, Szekanecz Z, Damjanov N, Anić B, Tomšič M, Mazurov V, Maksimovic M, Nagy O, Jerzy Świerkot J, Petranova T, Veldi T, Asta Baranauskaitė A, Codreanu C, Andersone D, Fleischmann R.)

A retrospective population-based survey was undertaken in a region of Bulgaria to determine the incidence of hip fracture. The estimated number of hip fractures nationwide for 2015 was 9322 and is predicted to increase to 11,398 in 2050. The hip fracture rates were used to create a FRAX model., Objective: To describe the epidemiology of hip fractures in Bulgaria, which was then used to develop the country-specific fracture prediction FRAX® tool., Methods: We carried out a retrospective population-based survey in Stara Zagora, Bulgaria, representing approximately 4.6% of the country's population. We identified hip fractures occurring in 2015, 2016 and 2017 from hospital registers and primary care sources held by the regional health insurance agency. Age- and sex-specific incidence of hip fracture and national mortality rates were incorporated into a FRAX model for Bulgaria. Fracture probabilities were compared with those from neighbouring countries having FRAX models., Results: The incidence of hip fracture applied nationally suggested that the estimated number of hip fractures nationwide in persons over the age of 50 years for 2015 was 9322 and is predicted to increase to 11,398 in 2050. FRAX-based probabilities were higher in Bulgaria than those in Serbia or Romania, lower than those in Turkey and similar to those in Greece., Conclusion: The FRAX model should enhance accuracy of determining fracture probability among the Bulgarian population and help guide decisions about treatment.

Persistence with osteoporosis therapy is critical for fracture risk reduction. This observational study evaluated medication-taking behaviour of women with postmenopausal osteoporosis receiving denosumab or oral ibandronate in real-world clinical practice in Bulgaria. Compared with ibandronate, densoumab was associated with a lower discontinuation rate and greater increases in bone mineral density., Purpose: Persistence with osteoporosis therapy is critical for fracture risk reduction and the effectiveness of such treatments may be reduced by low persistence. Alternative therapies such as denosumab may improve persistence. This study aimed to describe medication-taking behaviour in women with osteoporosis, prescribed denosumab or oral ibandronate, in Bulgarian clinical practice., Methods: This retrospective, observational, multicentre chart review (with up to 24 months follow-up) enrolled postmenopausal women initiating 6-monthly denosumab injection or monthly oral ibandronate treatment for osteoporosis between 1 October 2011 and 30 September 2012., Results: Overall, 441 women were enrolled (224 had initiated denosumab, 217 had initiated ibandronate). At baseline, more women in the denosumab group than in the ibandronate group had a previous fracture (25.5 vs 17.5%; p = 0.043) and past exposure to osteoporosis therapy (19.6 vs 12.0%; p = 0.028). At 24 months, 4.5% of women receiving denosumab had discontinued therapy compared with 56.2% of women receiving ibandronate. Median time to discontinuation was longer in the denosumab group (729 days; interquartile range (IQR), 728.3-729.0) than in the ibandronate group (367 days; IQR, 354.0-484.8; p < 0.001). At 24 months, there were significantly greater changes in BMD T-scores at the lumbar spine (p < 0.001) and femoral neck (p < 0.001) in patients receiving denosumab than in those receiving ibandronate. At 24 months, persistence with denosumab was 98.7%., Conclusion: This real-world study demonstrates there is a low discontinuation rate and high persistence with denosumab. Denosumab was associated with greater BMD increases than ibandronate, which could reduce fracture risk.

The main aim was to gain structured insight into the use of musculoskeletal ultrasonography (MSUS) in routine rheumatology practices in Central and Eastern European (CEE) countries. In a cross-sectional, observational, international, multicenter survey, a questionnaire was sent to investigational sites in CEE countries. Data on all subsequent routine MSUS examinations, site characteristics, MSUS equipment, and investigators were collected over 6 months or up to 100 examinations per center. A total of 95 physicians at 44 sites in 9 countries provided information on a total of 2810 MSUS examinations. The most frequent diagnoses were rheumatoid arthritis (RA) and spondyloarthritis (34.8 and 14.9 % of cases, respectively). Mean number of joints examined was 6.8. MSUS was most frequently performed for diagnostic purposes (58 %), particularly in patients with undifferentiated arthritis, suspected soft tissue disorders, or osteoarthritis (73.0-85.3 %). In RA patients, 56.3 % of examinations were conducted to monitor disease activity. Nearly all investigations (99 %) had clinical implications, while the results of 78.6 % of examinations (51.6-99.0 %) were deemed useful for patient education. This first standardized multicountry survey performed in CEEs provided a structured documentation of the routine MSUS use in participating countries. The majority of MSUS examinations were performed for diagnostic purposes, whereas one-third was conducted to monitor disease activity in RA. A majority of examinations had an impact on clinical decision making and were also found to be useful for patient education.

Osteoporosis is a key health problem in postmenopausal women with high social and economic impact. Decreased bone mineral density (BMD) and deterioration of bone microarchitecture may occur also as a result of long-term glucocorticoid treatment (GCT) of autoimmune or inflammatory conditions. Denosumab specifically inhibits the binding of the receptor activator of nuclear factor-κB to its ligand, thus preventing osteoclast activation and bone resorption. The efficacy and safety of denosumab, administered subcutaneously as 60 mg, once every six months for 12 months, were evaluated in 60 patients with postmenopausal osteoporosis (PMO) divided into two groups. The GCT group included 30 patients receiving concomitant glucocorticoid therapy and the non-GCT group included 30 patients that did not receive GCT. In the non-GCT group, the 12-month treatment with denosumab resulted in BMD increase of 6.1% and 2.8% in lumbar spine and hip, respectively. T-score increased by 13.1% and 5.6% in both, the lumbar spine and hip. A slight rise in the Trabecular Bone Score (TBS) of 0.3% was observed. Bone pain was markedly reduced by 56.2%. In the GCT group, denosumab therapy increased BMD with 5.8% and 2.3% in lumbar spine and hip, respectively. T-score of lumbar spine and hip significantly increased by 14.0% and 4.4%, and the TBS rose by 5%. Bone pain was reduced by 53.6%. These data confirm the available knowledge on denosumab efficacy and safety in women with PMO and also provide new insights into its therapeutic potential in patients with osteoporosis related to a long-term corticosteroid treatment.

The aim of the study was to assess the clinical performance of the model combining areal bone mineral density (aBMD) at spine and microarchitecural texture (TBS) for the detection of the osteoporotic fracture. The Eastern European Study is a multicenter study (Serbia, Bulgaria, Romania and Ukraine) evaluating the role of TBS in routine clinical practice as a complement to aBMD. All scans were acquired on Hologic Discovery and GE Prodigy densitometers in a routine clinical manner. The additional clinical values of aBMD and TBS were analyzed using a two steps classification tree approach (aBMD followed by TBS tertiles) for all type of osteoporotic fracture (All-OP Fx). Sensitivity, specificity and accuracy of fracture detection as well as the Net Reclassification Index (NRI) were calculated. This study involves 1031 women subjects aged 45 and older recruited in east European countries. Clinical centers were cross-calibrated in terms of BMD and TBS. As expected, areal BMD (aBMD) at spine and TBS were only moderately correlated (r (2) = 0.19). Prevalence rate for All-OP Fx was 26 %. Subjects with fracture have significant lower TBS and aBMD than subjects without fracture (p < 0.01). TBS remains associated with the fracture even after adjustment for age and aBMD with an OR of 1.27 [1.07-1.51]. When using aBMD T-score of -2.5 and the lowest TBS tertile thresholds, both BMD and TBS were similar in terms of sensitivity (35 vs. 39 %), specificity (78 vs. 80 %) and accuracy (64 vs. 66 %). aBMD and TBS combination, induced a significant improvement in sensitivity (+28 %) and accuracy (+17 %) compared to aBMD alone whereas a moderate improvement was observed in terms of specificity (+9 %). The overall combination gain was 36 % as expressed using the NRI. aBMD and TBS combination decrease significantly the number of subjects needed to diagnose from 7 for aBMD alone to 2. In a multi-centre Eastern European cohort, we have shown that the use of TBS in addition to the aBMD permit to reclassified correctly more than one-third of the overall subjects. Furthermore, the number of subjects needed to diagnose fell to 2 subjects. Economical studies have to be performed to evaluate the gain induced by the use of TBS for the healthcare system.

Aim: To evaluate the inter- and intraobserver agreement of a group of European rheumatologist ultrasonographers in grading musculoskeletal ultrasound videoclips posted on the Internet by using a non-sophisticated electronic environment., Methods: Forty short movie clips (less than 30 secs) were made available over the Internet to all participants. Normal and pathological RA hand joints and tendons were included in the movie clips. In the first phase 30 investigators from European countries were invited to evaluate the clips and to interpret/grade them. No instruction session was held prior to the initiation of the study. For synovitis the requested scoring system included 0 to3 grades and for tenosynovitis a binary variable 0/1; separate evaluations were performed for gray scale (GS) and Power Doppler (PD) examinations. In the second phase the responders were asked to grade the same clips in a different order without having access to their first grading scale. Light's k and Cohen's k were used to analyse inter- and intraobserver reliability., Results: Twenty two European rheumatologists agreed to finalise both study phases. Mean Cohen's κ for intraobserver reliability was 0.614/0.689 for tenosynovitis GS/PD and 0.523/0.621 for synovitis GS/PD. Light's k for interobserver reliability was 0.503 for tenosynovitis evaluation and 0.455 for global (synovitis and tenosynovitis) evaluation. Mean global overall agreement was 84.95% (90.2% for global synovitis)., Conclusions: An over-the-net US evaluation and grading has shown moderate to good reliability. The results could be improved if a training session is added at the beginning of the study.

A complete physical examination of the hip is often difficult due to its size and deep position. During the last two decades, ultrasonography (US) of the hip has been widely accepted as a useful diagnostic tool in patients with hip pain and /or limited range of motion. It is commonly used in both adults and children. This technique allows evaluation of different anatomical structures and their pathological changes, such as joint recess (joint effusion, synovial hypertrophy), changes within the bursae (bursitis), tendons and muscles (tendinopathy, ruptures, calcifications), as well as changes in the bony profile of the joint surfaces, ischial tuberosity, and greater trochanter (erosions, osteophytes, calcific deposits). US is very useful for guided procedures in hip joint and periarticular soft tissues under direct visualization. The needle aspiration of synovial fluid and steroid injections are commonly-applied activities in daily rheumatology practice. The relatively limited acoustic windows available to the US beam are the principal limitations to hip US. Therefore, conducting a detailed examination of some important structures together with the interpretation of Doppler signal (sometimes undetectable) is not easy, requiring good knowledge of the modality. The aim of this review is to analyze the current literature about US of the hip and to describe the most frequently-observed normal and pathological findings.

Ultrasonography of the elbow is a very helpful and reliable diagnostic procedure for a broad spectrum of rheumatic and orthopedic conditions, representing a possible substitute to magnetic resonance imaging for evaluation of soft tissues of the elbow. Musculoskeletal ultrasound (US) shows many advantages over other imaging modalities, probably the most important being its capability to perform a dynamic assessment of musculoskeletal elements with patient's partnership and observation during examination. In addition, ultrasonography is cost effective, easy available, and has excellent and multiplanar capability to visualize superficial soft tissue structures. Among all imaging procedures, US is highly accepted by patients. US assessment of the elbow requires good operator experience in the assessment of normal anatomy, and suitable high-quality equipment. US of the elbow provides detailed information including joint effusions, medial and lateral epicondylitis, tears of the distal biceps and triceps tendons, radial and ulnar collateral ligament tears, ulnar nerve entrapment, cubital or olecranon bursitis and intra-articular loose bodies. The aim of this paper is to review the screening technique and the basic normal and pathological findings in elbow US.

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 (US) is a helpful imaging tool in the evaluation of the musculoskeletal system. It has some advantages over the other imaging techniques, such as plain radiography, computed tomography and magnetic resonance imaging, represented by the non-invasiveness and multiplanar imaging capability, repeatability, lack of radiation burden, good patient acceptance, and relatively limited costs. US offers an excellent resolution and a possibility for real-time dynamic examination of the joints and surrounding soft tissues, as well as enables monitoring of therapeutic response. The most common clinical indications for US examination of the shoulder are rotator cuff and biceps tendon pathology (tenosynovitis, tendinosis, complete and partial tears, and impingement) and disorders of other soft-tissue structures (joint recesses, bursae, muscles, suprascapular and axillary nerves) as well as bony cortex abnormalities. US is very useful for US-guided procedures (biopsy, joint and bursae aspirations and injections, aspiration and dissolution of calcific tendinosis). The aim of this article is to analyze the current literature about US of the shoulder and to describe both normal and pathological findings.

In the last years musculoskeletal ultrasound (US) has become a very useful imaging tool for the evaluation of rheumatic patients and a natural extension of the clinical examination of the ankle and foot. Musculoskeletal US allows the evaluation of the symptomatic and asymptomatic ankle and foot with a detailed analysis of a wide range of elementary lesions at the level of different anatomical structures and their distribution in early or long standing disease. In inflammatory pathology, it helps in the assessment of the disease activity and severity at the joint, tendon or entheseal level and in the detection of subclinical pathological features in early disease or residual activity after therapy. Moreover, US guided procedures allow accurate diagnostic and therapeutic interventions. It is a valuable imaging method that can be also used in the follow up of the treated patients (systemic and/ or local therapies or surgical procedures), being a patient friendly, non-invasive, and quick to perform method. The aim of this paper is to review the US technique of scanning and the indications of US in the analysis of the ankle and foot in rheumatic diseases.

Musculoskeletal Ultrasonography (US) is nowadays widely used for clinical grounds and for research purposes in rheumatology. US of the hand and wrist has recently developed due to the technological improvement and use of new, high resolution transducers. US is currently improving clinical examination of the rheumatic hand and wrist and it is commonly used as daily practice by many rheumatologists. The number of publications addressing this area of US scanning has grown exponentially over the last few years. The aim of this paper is to review the current literature on US of the hand and wrist in rheumatology, including US scanning techniques, as well as normal and pathological findings.

Primary Sjögren's syndrome (PSS) is an autoimmune disease of the exocrine glands that is presented with progressive ocular and oral dryness, parotid enlargement and often with systemic (extraglandular) manifestations. In patients with PSS the risk of development of non-Hodgkin's lymphoma (NHL) is 44-fold compared to healthy population. The risk is associated with certain characteristics of the disease's course: recurrent changes in the parotid glands, lymph node enlargement, skin vasculitis, peripheral neuropathy, anemia and lymphopenia. According to the morphologic and phenotypic characteristics, B-cell low-grade lymphomas prevail. This communication presents a 65-year-old woman with PSS who developed a follicular type B-cell NHL 21 years after the autoimmune disease had been diagnosed. The analysis of our case and the literature review summarize the characteristics of the course of PSS, histologic variants, and evolution and prognosis of NHL in this kind of patients.