A Rare Case of Anca Positivity and Antiphospholipid Antibodies in a Patient with Takayasu Arteritis: Case Report and Review of the Literature.

Takayasu arteritis (TA) is a chronic large-vessel vasculitis characterized by immune-mediated panarteritis, which predominantly affects the aorta and its main branches and is most prevalent in young women. TA is unusually associated with the presence of antiphospholipid antibodies. We present a case report of a 48-year-old Caucasian woman with acute aortic dissection as an initial feature of TA, where detailed clinical, imaging and laboratory studies were performed. Computed tomography angiography (CTA) of the chest and abdomen revealed aortic dissection DeBakey I. Bentall and De Bono surgery was performed. Additional immunological tests revealed positive antineutrophil cytoplasmic antibodies (ANCAs) with the simultaneous presence of pANCA and cANCA antibodies on indirect immunofluorescence, along with anti-MPO+PR3+antibodies positivity in the absence of a clinically relevant disease. Surprisingly, antiphospholipid antibodies (aPLs) were detected. Then, we performed a thorough review of the current literature. The coexistence of aPL antibodies and dual specificity for MPO and PR3 in a patient diagnosed with Takayasu arteritis is unusual and poses a diagnostic challenge. The presented case report outlines a rare case of aortic dissection as a presenting symptom of TA, along with atypical ANCA positivity and positive APL antibodies.

Quality of life and disease activity of patients with rheumatoid arthritis on tofacitinib and biologic disease-modifying antirheumatic drug therapies.

The aim of this study was to analyze the therapeutic results of rheumatoid arthritis (RA) therapy with different biologic disease-modifying antirheumatic drugs (bDMARDs) and the first Janus-activated kinase (JAK) inhibitor in real-life clinical settings. This is a prospective, observational, longitudinal study at the largest rheumatology clinic in Bulgaria conducted during the period 2012-2020. One hundred seventy-four patients were followed up for a period of one year. Patients naïve to biological therapy were consecutively assigned on the available at the time bDMARDs (infliximab, etanercept, adalimumab, rituximab, golimumab, cetrolizumab, tocilizumab) or tofacitinib. We evaluated the disease activity score (DAS28-CRP), Health assessment questionnaires (HAQ) and short form 36 (SF-36) were applied at the initiation of biological therapy, after 6, and 12 months of follow-up. We analyze the changes in the two major subgroups of SF36-physical (MCS) and mental health (PCS). The age and gender distribution were similar between the groups on bDMARDs and tsDMARD. All observed indicators for disease control and QoL improve after the initiation of the biological or JAK inhibitor therapy. We also analyze the effect of therapies on DAS28-CRP, HAQ, SF-36 (PCS, MCS). Dispersion analysis for the effect of therapy measured through DAS28 between 1st and 3rd measurement shows a statically significant difference in between the average effect of therapies (p = 0.005). According to the average change in DAS28 between the first and third measurement the most effective is the golimumab (Median difference = 2.745), followed by rituximab (median = 2.305) and etanercept (median = 2.070). According to the average change in HAQ between first and third the most effective is tofacitinib (median 0.563), followed rituximab and infliximab (median 0.500 for both). Less effective in term of HAQ changes between the first and third measurement appears to be etanercept (median difference 0.250). All differences are statistically significant (p < 0.05). Regarding the changes in the QoL measured with SF-36 MCS and PCS there is no statistically significant differences in the average effect of different therapeutic agents. Tofacitinib is non-inferior in comparison to bDMARDs and improve both-disease activity and QoL in patients with RA.

Olokizumab, a monoclonal antibody against interleukin 6, in combination with methotrexate in patients with rheumatoid arthritis inadequately controlled by methotrexate: efficacy and safety results of a randomised controlled phase III study.

OBJECTIVE: To evaluate the efficacy and safety of olokizumab (OKZ) in patients with active rheumatoid arthritis despite treatment with methotrexate (MTX). METHODS: In this 24-week multicentre, placebo-controlled, double-blind study, patients were randomised 1:1:1 to receive subcutaneously administered OKZ 64 mg once every 2 weeks, OKZ 64 mg once every 4 weeks, or placebo plus MTX. The primary efficacy endpoint was the proportion of patients achieving an American College of Rheumatology 20% (ACR20) response at week 12. The secondary efficacy endpoints included percentage of subjects achieving Disease Activity Score 28-joint count based on C reactive protein <3.2, Health Assessment Questionnaire Disability Index at week 12, ACR50 response and Clinical Disease Activity Index ≤2.8 at week 24. Safety and immunogenicity were assessed throughout the study. RESULTS: A total of 428 patients were randomised. ACR20 responses were more frequent with OKZ every 2 weeks (63.6%) and OKZ every 4 weeks (70.4%) than placebo (25.9%) (p<0.0001 for both comparisons). There were significant differences in all secondary efficacy endpoints between OKZ-treated arms and placebo. Treatment-emergent serious adverse events (TESAEs) were reported by more patients in the OKZ groups compared with placebo. Infections were the most common TESAEs. No subjects developed neutralising antidrug antibodies. CONCLUSIONS: Treatment with OKZ was associated with significant improvement in signs, symptoms and physical function of rheumatoid arthritis without discernible differences between the two regimens. Safety was as expected for this class of agents. Low immunogenicity was observed. Trial registration number NCT02760368.

Clinical Management of Women with Newly Diagnosed Osteoporosis: Data from Everyday Practice in Bulgaria.

INTRODUCTION: The real duration of osteoporosis treatment in clinical practice is still not well described. The primary objective is to estimate the proportion of patients who stayed on treatment during a 4-year follow-up, and the secondary objective is to estimate the proportion of patients who switched treatment and the reasons for switch or discontinuation. METHODS: This was a national retrospective chart review, based on routine clinical data. Data were collected electronically from medical records in 33 representative primary care physicians' sites. Inclusion criteria were women with postmenopausal osteoporosis that have received initial treatment prescription following diagnosis by DXA between January 1, 2012 and December 31, 2014, and at least a 12-month database history after the index date. Exclusion criteria were women receiving treatment for osteoporosis and follow-up at secondary care physicians' sites only. All statistical analyses were performed with the R statistical package. RESULTS: A total of 1206 female patients with newly diagnosed osteoporosis and treatment initiation were followed for 4 years. The majority (88.3%) had no history of previous fractures. Bone mineral density data were available in 70.1%. Endocrinology was the most common specialty among prescribing specialists (40.0%), followed by rheumatology (30.3%). Bisphosphonates (BPs) were the most common initial treatment (72.7%), followed by denosumab (20.1%). Ibandronate (70.2%) and alendronate (24.2%) constituted the majority of all prescribed BPs; 731 patients remained on treatment during the second year (60.6%), 524 during the third year (43.4%) and 403 (33.4%)-at study end (fourth year). In all groups, except that on denosumab, the most common reason for switching to another treatment was presumed lack of effect. The main reasons for treatment discontinuation were financial on the patient's part. CONCLUSIONS: The duration of osteoporosis treatment in real-world clinical practice is far from optimal: < 3-4 years irrespective of fracture risk. Factors other than medical considerations are at play, mainly limitations set by the Health Insurance Fund. The health authorities should be aware of this.

Comparisons of +3179G/A insulin-like growth factor 1 receptor gene distribution between two inflammatory arthritides and healthy adults.

OBJECTIVES: This study aims to investigate whether single nucleotide polymorphisms (SNPs) at the +3179G/A insulin-like growth factor 1 receptor (IGF-1R) locus were associated with rheumatoid arthritis (RA) and ankylosing spondylitis (AS) genetic susceptibility and also explore age and sex distribution of the rs2229765 in healthy adults. PATIENTS AND METHODS: This cross-sectional study was conducted between September 2012 and October 2014. Seventy patients with RA (7 males, 63 females; mean age: 54±1 years; range, 32 to 78 years) and 56 with AS (44 males, 12 females; mean age: 38±9 years; range, 22 to 57 years) were genotyped using polymerase chain reaction-restriction fragment length polymorphism method. The genotype and allele frequencies of the rs2229765 polymorphism in both patient groups were compared to those in 308 healthy donors (141 males, 167 females; mean age: 35±19 years; range, 18 to 75 years) who were further subjected to analysis of sex- and age-related genetic variation. RESULTS: We identified the homozygous genotype AA (22.9% vs. 14.1%; odds ratio [OR]=2.33, p=0.034) and A-allele (47.9% vs. 37.5%; OR=1.53, p=0.032) associated with increased risk for RA, but not AS. The same genotype AA was non-significantly more common in healthy males than females, and the frequency of the A-allele was markedly higher in younger males (46% vs. 40%; p=0.039). The overall percentage of healthy carriers of the AA gene variant was 18%. CONCLUSION: We primarily present an inverse effect of the +3179G/A IGF-1R polymorphism on disease susceptibility to RA and AS, confirming the distinctly different immune pathways involved in the pathogenesis of both inflammatory arthritides. In addition, we could also show trends regarding age- and sex-specific patterns of the rs2229765 genotype distribution in the general population.

The synergistic role of TNFA - 308G/A and IL10 - 1082A/G polymorphisms in ankylosing spondylitis.

OBJECTIVE: Genetic polymorphisms of the cytokine genes could alter their protein expression, thus creating a genetic basis of dysregulated cytokine production and function, which render them as excellent candidates predisposing to autoimmune diseases. We investigated single nucleotide polymorphisms (SNPs) at TNFA - 308G/A and IL10 - 1082A/G locus to identify their involvement, separately or in combination, in determining susceptibility to ankylosing spondylitis (AS), as well as their functional connections with relevant serum cytokines and associations with disease characteristics. METHODS: Eighty-one AS patients and 215 healthy controls were genotyped by polymerase chain reaction-based method; 76 patients and sex-matched controls were also subjected to analysis of serum TNF-α and IL-10 levels by enzyme-linked immunosorbent assay. RESULTS: We identified the homozygous genotype GG of the TNFA-308 significantly more common in patients than controls; whereas the - 308 minor A-allele predicts a threefold decreased risk against developing AS and shows associations with milder radiographic spinal impairments and functional limitations. This protective effect was multiplied by fivefold in synergistic interaction with the homozygous - 1082AA genotype of the IL10 which acts as a modifying factor, since IL10 - 1082A/G SNPs by itself did not have a significant impact on AS genetic susceptibility. In comparison with controls, AS patients had significantly elevated mean serum TNF-α levels and decreased mean IL-10 concentrations not restricted to any particular genotype. CONCLUSION: TNFA - 308 A-allele is essential for reducing susceptibility to AS, with a considerable synergistic protective effect of the combined TNF-α - 308 (GA/AA)/IL-10 - 1082AA genotypes. In addition, the presence of this variant allele is associated with more benign clinical phenotype of the disease. No conclusive statements on the functional relevance of both gene variants on cytokines production should be made.

Serum levels of matrix metalloproteinase-3 as a prognostic marker for progression of cartilage injury in patients with knee osteoarthritis.

OBJECTIVE: To evaluate serum matrix metalloproteinase (MMP)-3 levels as a prognostic marker for the progression of cartilage damage in patients with knee osteoarthritis (KOA). METHODS: Fifty-six patients, aged 40 to 80 years (62.59 ± 10.11 years) who met the ACR criteria for KOA, were included in a one-year observational prospective clinical study. Complete baseline and follow-up data were collected from 50 out of 56 patients. X-ray and magnetic-resonance images were carried out at baseline and after 12 months. They were evaluated according to the Kellgren-Lawrence and Whole-Organ magnetic Resonance iMaging Score (WORMS) semi-quantitative scales, respectively. Progression of cartilage damage in the medial tibiofemoral compartment was registered at the end of the follow-up using the change in WORMS. Serum levels of MMP-3 were measured during the baseline visit, using enzyme-linked immunosorbent assay. RESULTS: Significantly higher values of baseline MMP-3 levels were observed in patients with a registered progression of cartilage injury in the medial tibiofemoral compartment of the knee compared with patients with no progression (p = 0.005). Binary logistic regression analysis showed that levels of serum MMP-3 (ng/ml) were an independent predictor of subsequent progression of cartilage injury in the medial tibiofemoral compartment of the index knee (assessed by MRI) (OR = 1.042, CI 95%: 1.002-1.084). Receiver operating characteristic analysis was performed to delineate progressors from non-progressors. CONCLUSION: Serum MMP-3 levels may serve as a potential prognostic biomarker for cartilage injury in patients with KOA.

Coronavirus disease 2019 (COVID-19) during pregnancy in patients with rheumatic diseases.

The novel coronavirus outbreak induces many concerns about the management of pregnancy, as well as rheumatic and musculoskeletal diseases. The very rapid spread of the infection throughout all inhabited continents leads to a fast-growing number of infected with SARS-CoV-2 and requires answers and special recommendations to the most vulnerable group of people: pregnant woman and patients on immunomodulatory or immunosuppressive treatment. A systematic literature search was performed in Embase, MEDLINE, and Scopus database for studies describing COVID-19 infection in pregnant women diagnosed with rheumatic and musculoskeletal diseases. From the 1,115 initially identified articles, we selected 29 publications in the English language, from which 18 were eligible according to the inclusion criteria. Limited number of cases and further researches are required to evaluate the risk of transmission of SARS-CoV-2 from mother to her infant as well as clinical features of infection in pregnant women. The conclusions of different authors, despite the small number of cases, suggest that there is no vertical transmission in women diagnosed with COVID-19 pneumonia. Although the World Health Organization recently reported that pregnant patients do not have a higher risk of infection than the rest of the population, Royal College of Obstetricians & Gynecologists and The Royal College of Midwives for COVID-19 infection in pregnancy published Guidelines for pregnant women with suspected SARS-CoV-2 infection.Considerations about patients with rheumatic diseases on the immunosuppressive treatment required European League Against Rheumatism, American College of Rheumatology, British Society for Rheumatology, and Australian Rheumatology Association to publish recommendations for patients with rheumatic diseases and COVID-19. These algorithms are very important to the medical society, but many concerns, absence of experience, and many questions are still unanswered and need time to be resolved and proceed successfully in this global pandemic situation.

High interleukin-18 and low FOXP3 mRNAs in peripheral blood of women with severe systemic lupus erythematosus: a cross-sectional study.

Gene expression analysis of peripheral blood cells may provide valuable information about the triggered molecular processes in systemic lupus erythematosus (SLE). The study aimed to quantify the mRNA in peripheral blood of seven target genes, including inflammatory cytokine genes (IL23A, IL12B, TNFA, IL18), and T regulatory-related genes (FOXP3, TGFB1, IL10) in patients with SLE and to correlate expression levels with disease activity and/or clinical manifestations. The relative quantification of target genes was performed using real-time polymerase chain reaction in peripheral blood obtained from 28 adult SLE females and 17 healthy women. The highest up-regulation in the blood of SLE patients was observed for IL23A with a median 9.54 (p < 0.0001), followed by TGFB1 (median: 2.07; p = 0.047) and IL10 (median: 1.84; p = 0.013). IL12B and TNFA were significantly down-regulated in patients compared to controls (median: 0.521; p = 0.0023, and median: 0.519; p = 0.0003, respectively). FOXP3 mRNA was lower among patients with higher degree of disease activity (median: 0.338; p = 0.029) and showed inverse correlation with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). IL18 mRNA correlated positively with the SLEDAI and was highly expressed during severe flares (median: 1.216; p = 0.021). IL18 up-regulation was associated with anti-dsDNA antibody positivity, while FOXP3 down-regulation with lupus nephritis. Our study pointed out the relationship of SLE disease activity and particular clinical manifestations with IL18 and FOXP3 expression, and the significant contribution of IL23A in the SLE immunopathogenesis. Hence, the peripheral blood cytokine mRNAs should be exploited as novel prognostic and diagnostic biomarkers.

Impact of IL12B Polymorphisms on Genetic Susceptibility and IL-12p40 and IL-23 Serum Levels in Rheumatoid Arthritis.

The aim of this study was to evaluate the possible association of IL12B gene polymorphisms with serum levels of IL-12p40, IL-23 and genetic susceptibility to rheumatoid arthritis (RA) in the Bulgarian population. Genotyping for IL12Bpro (rs17860508) and IL12B A/C - 3' UTR (rs3212227) polymorphisms was performed by polymerase chain reaction (PCR)-based methods in 125 RA patients and 239 healthy controls. The IL-23 and IL-12p40 serum levels were measured by enzyme-linked immunosorbent assay (ELISA). An association was established between the rs17860508 polymorphism and RA susceptibility in Bulgarian population with an increased frequency of rs17860508 minor allele-2 and homozygous genotype-22 in RA patients. The rs17860508 risk RA genotype-22 was also significantly correlated to elevated serum IL-23 in RA patients. Although, there was no association between the rs3212227 and genetic predisposition to RA, significantly increased serum levels of both Il-12p40 and IL-23 were observed in RA patients with the rs3212227 AA genotype. Furthermore, the distribution of haplotypes and genotype combination in our cohort indicated increased RA risk in individuals carrying the rs17860508/rs3212227 2/A haplotype or 2.2/AC+CC combination, while 1/A haplotype or 1.1/AA combination may be protective for RA. In conclusion, our study demonstrates a functional effect of IL12B polymorphisms on IL-12p40 and IL-23 cytokine levels in RA patients and suggests a leading role for IL12B rs17860508 in the genetic predisposition to RA, while IL12B rs3212227 significantly modify the RA risk in Bulgarian population.

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.

Secretory factors produced by adipose mesenchymal stem cells downregulate Th17 and increase Treg cells in peripheral blood mononuclear cells from rheumatoid arthritis patients.

We aimed to assess the immunoregulatory effects of secretory factors produced by adipose tissue-derived MSC (AT-MSC) on Th17 and Treg subsets from patients with rheumatoid arthritis (RA). 17 patients with active disease matching the ACR/EULAR 2010 criteria for RA were included. Patients' peripheral blood mononuclear cells (PBMC) were cultured in AT-MSC-conditioned medium (AT-MSCcm) and in control medium. The cytokine production of AT-MSC and PBMC was quantified by ELISA. Th17 and Treg were determined by flow cytometry. AT-MSCcm contained: IL-6, IL-17, IL-21, CCL2, CCL5, IL-8, sVEGF-A and PGE2. Cultivation of patients' PBMC with AT-MSCcm increased TGF-ß1 (8318 pg/ml; IQR 6327-11,686) vs control medium [6227 pg/ml (IQR 1681-10,148, p = 0.013)]. PBMC cultivated with AT-MSCcm downregulated TNF-α, IL-17A, and IL-21 compared to control PBMC: 5 pg/ml IQR (1.75-11.65) vs 1 pg/ml (IQR 0.7-1.9), p = 0.001; 4.2 pg/ml (IQR 3.1-6.1) vs 2.3 pg/ml (IQR.75-5.42), p = 0.017; 66.9 pg/ml (IQR 40.6-107.2) vs 53 pg/ml (IQR 22-73), p = 0.022. Th17 decreased under the influence of AT-MSCcm: 10.13 ± 3.88% vs 8.98 ± 3.58%, p = 0.02. CD4+FoxP3+, CD4+CD25-FoxP3+, and CD4+CD25+FoxP3+ was 11.35 ± 4.1%; 7.13 ± 3.12% and 4.22 ± 2% in control PBMC. Accordingly, CD4+FoxP3+, CD4+CD25-FoxP3+, and CD4+CD25+FoxP3+ significantly increased in PBMC cultured with AT-MSCcm: 15.6 ± 6.1%, p = 0.001; 9.56 ± 5.4%, p = 0.004 and 6.04 ± 3.6%, p = 0.001. All these effects could define MSC-based approaches as adequate avenues for further treatment development in RA.

Genetic variations in the IL-12B gene in association with IL-23 and IL-12p40 serum levels in ankylosing spondylitis.

In the present study, we evaluated the implication of IL12Bpro (rs17860508) and IL12B 3' UTR A/C single nucleotide polymorphisms (SNPs) (rs3212227) for the ankylosing spondylitis (AS) development and the impact of IL12B genetic variations on IL-23 and IL-12p40 production and musculoskeletal disease characteristics. 80 patients with AS and 242 healthy controls were studied. Genotyping for the rs3212227 was performed by restriction fragment length polymorphisms-polymerase chain reaction (PCR) and for the rs17860508 by allele-specific PCR. Cytokines were measured by an enzyme-linked immunosorbent assay (ELISA). Clinical status was evaluated by calculation of the Ankylosing Spondylitis Disease Activity Score (ASDAS) using the C-reactive protein (CRP) level, the Bath Ankylosing Spondylitis Functional Index (BASFI) and the Bath Ankylosing Spondylitis Metrology Index (BASMI). An association was found for the rs17860508 polymorphism with AS under the allelic, the dominant, and the co-dominant models. Rs3212227 was not attributable to AS susceptibility by itself, but the carriage of C allele in the genotype amplifies the genetic risk for AS in the carriers of the high-risk IL12Bpro 2-allele, especially in homozygosity. Circulating IL-23 and IL-12p40 were raised among AS patients, as some of the genotypes of both IL12B polymorphisms positively regulate their expression. Carriage of the IL12Bpro genotype 2.2 has been linked to a worsened functional disability, while 3' UTR CC genotype-with severe disease activity. IL12B polymorphisms can impact AS susceptibility and modulate IL-23 and IL-12p40 production levels, and have a contribution to the disease phenotype.

Bulgarian rheumatology: science and practice in a cost-constrained environment.

Our aim was to appraise publications from Bulgaria, to assess their global impact, and to describe features and challenges unique to the rheumatology practice in Bulgaria characterized by stringent cost constraints. The Scopus database was queried on 25th July 2018 and data on the number of published documents, their Hirsch-indices and citations number were extracted. Published Bulgarian guidelines for the management of rheumatic diseases and the presented data on Bulgarian Rheumatology Society were identified based on prior knowledge of the authors. From all the identified 1082 document the most extensively researched areas were rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), osteoporosis, and osteoarthritis (OA). For the last five years (from Jan 2013 to 25th July 2018) the number of publications was 293. We found that Bulgaria's international scientific collaboration in the field of rheumatology is focused on a handful of countries mainly from Europe. Although Bulgarian rheumatologists have access to costly biologic agents for treating their patients with rheumatic diseases, their funding may not be granted according to the current recommendations of European League against Rheumatism (EULAR) and national guidelines for the management of rheumatic diseases. Although the western world clearly dominates the production of scientific publications in rheumatology, Bulgarian rheumatology may present another perspective for diagnosis and management of patients with rheumatic diseases in a cost-stringent environment. Nevertheless, both rheumatology science and practice in Bulgaria still have a long way to go to take its deserved place among the other European countries.

Real World Experience of Disease Activity in Patients With Rheumatoid Arthritis and Response to Treatment With Varios Biologic DMARDs.

The current study investigate the disease activity and effectiveness of treatment in patients with RA on biological disease modifying antirheumatic drugs (bDMARDs) in combination with a conventional synthetic DMARD (csDMARD) and determine whether or not the benefits of different therapies were sustained over a follow up period of 1 year. 124 patients were selected with a mean age 55.26 ± 13, 18SD years, meeting the 1987 ACR and /or ACR/ EULAR (2010) classification criteria for Rheumatoid arthritis (RA). Patients were arranged according to treatment regimens: Tocilizumab (TCL) - 30 patients, Certolizumab (CZP) - 16, Golimumab (GOL) - 22, Etanercept (ETN) 20, Adalimumab (ADA) 20, Rituximab (RTX) - 16. Disease activities was the primary concern. Independent joint assessor evaluated 28 joints on baseline, 6th and 12th month's thereafter. C-reactive protein (CRP) was used to measure the inflammatory process. DAS28-CRP, clinical disease activity index (CDAI) and simplified disease activity index (SDAI) were calculated. On baseline all of the patients' groups had severe disease activity (mean DAS28-CRP > 5.2, mean CDAI > 22, mean SDAI > 26. It was noted that, during the 6th month follow-up period all of the treatment groups significantly decreased DAS28-CRP, CDAI, SDAI and reach moderate disease activity. After 6th and 12th months of treatment all of the groups on bDMARDs had significantly lower disease activity. The GOL group reach remission only according to DAS28-CRP: 2.49 ± 0.76, and low disease activity as measured by CDAI: 6.78 ± 4.51 and SDAI 7.80 ± 5.67. The other 5 groups after 12 months reach the level of low disease activity according to the three activity parameters: DAS28-CRP (TCL 3.07 ± 0.73, CZP 3.06 ± 0.65, ETN 2.85 ± 0.55, ADA 3.15 ± 0.82, RTX 2.90 ± 0.70), CDAI (TCL 9.80 ± 4.91, CZP - 9.33 ± 4.22, ETN 7.97 ± 3.80, ADA 10.00 ± 5.25, RTX 7.48 ± 2.99) and SDAI (TCL 10.45 ± 5.14, CZP 9.94 ± 4.43, ETN 9.03 ± 4.25, ADA 10.50 ± 5.61, RTX 8.08 ± 3.24). The therapy with different bDMARDs added to a csDMARD led to very similar results - a minimal disease activity and a state of remission in the GOL treatment group only as per DAS28-CRP.

Quality of Life and Cost Study of Rheumatoid Arthritis Therapy With Biological Medicines.

Biological medicines are considered as a cornerstone in the therapy of rheumatoid arthritis (RA). They change the course of the disease and improve the quality of life of patients. To this date there has been no study comparing the quality of life of and cost of RA therapy in Bulgaria. This fact is what provoked our interest toward this research. The aim of this study is to analyse the cost and quality of life of patients with RA threated with biological medicines in Bulgaria. This is an observational, real life study of 124 patients treated with biological medicines during 2012-2016 at the University hospital "St. Ivan Riskli" in Sofia, specialized in rheumatology disease therapy. Patients were recruited after their consecutive transfer from non-biological to biological medicines. The yearly pharmacotherapy cost was calculated with tocilizumab (n = 30), cetrolizmab (n = 16), golimumab (n = 22), etanercept (n = 20), adalimumab (n = 20), rituximab (n = 16). Three measurements of the quality of life (QoL) were performed with EQ5D-at the beginning of the therapy, after 6 months and after 1 year of therapy. Both section of EQ5D were used-VAS and EQ5D questionnaire. Cost-effectiveness was calculated for unit of improvement in EQ5D score for a one year period and decision model was built with TreeAgePro software. The observed cost of therapy varied between 12 thousand Euros for tocilizumab to 6 thousand Euros for rituximab. All biological medicines let to substantial increase in the quality of life of the patients. Patients on tocilizumab increased their QoL from 0.43 to 0.63 after 1 year; on cetrolizumab from 0.32 to 0.56; on golimumab from 0.41 to 0.67; on etanercept from 0.45 to 0.62; on adalimumab from 0.43 to 0.57; on rhituximab from 0.46 to 0.66. The cost-effectiveness estimates of different biological therapies also varied between 66 to 30 thousand Euros for unit of improvement in the EQ5D during one the course of the year. Therapy with biological medicines improves statistically significant the quality of life of patients, measured through VAS and EQ5D scales. Despite the improvement in the quality of life all biological medicines appears not to be note cost-effective due to their high incremental cost-effectiveness ration (ICER). Rituximab's incremental ratio has (ICER) falls closer to the three times gross domestic product per capita threshold and should be considered as preferred alternatives for RA therapy. In general we can conclude that the treatment of rheumatoid arthritis with biologicals improves quality of life significantly. Only rituximab was cost-effective.

The Synergistic Effect of TNFA and IL10 Promoter Polymorphisms on Genetic Predisposition to Systemic Lupus Erythematosus.

AIMS: We investigated the individual and combined effect of functional TNFA -308G/A and IL10 -1082G/A single nucleotide polymorphisms (SNPs) and their genotypes on the susceptibility to systemic lupus erythematosus (SLE) in a Bulgarian population. MATERIALS AND METHODS: Genotyping for -1082A/G IL10 (rs1800896) and -308G/A TNFA (rs1800629) polymorphisms was performed for 154 SLE patients and 224 healthy controls. RESULTS: An association between SLE and the rs1800629 polymorphism was established under the allelic model (allele A vs. allele G; odds ratios [OR] = 2.317), the dominant model (GA+AA vs. GG; OR = 3.214), and the overdominant model (GA vs. AA+GG; OR = 3.494). There was no association between rs1800896 and SLE, although a tendency for genetic predisposition to SLE was observed for the IL10 -1082 GG genotype under the recessive genetic model (OR = 1.454). When analyzing the influence of the combined TNFA/IL10 genotypes on SLE occurrence, we found that the carriage of both high cytokine-producing genotypes of two SNPs (TNFA -308AA/GA and IL10 -1082GG) significantly increased the risk of developing SLE with OR of 9.026 (p = 0.006). CONCLUSION: Our findings suggest that the combinatorial complexity of TNFA and IL10 promoter polymorphisms impacts SLE susceptibility. Notably, we found that a TNFA promoter polymorphism is a leading risk factor for SLE susceptibility in a Bulgarian population, while the IL10 -1082 locus appears to act as a significant modifier.

Cartilage oligomeric protein, matrix metalloproteinase-3, and Coll2-1 as serum biomarkers in knee osteoarthritis: a cross-sectional study.

Biochemical markers reflecting joint remodeling in osteoarthritis (OA) are a promising diagnostic tool. The aim of this study was to investigate serum levels of candidate biomarkers in subjects with and without knee OA and assess their correlation with clinical parameters and knee structural damage. 56 patients with primary knee OA and 31 healthy controls participated in this study. Patients were separated into two groups: isolated knee OA and generalized OA. Clinical parameters were obtained by validated self-reported questionnaires and a visual analogue scale. Serum levels of cartilage oligomeric protein (COMP), matrix metalloproteinase-3 (MMP-3), and Coll2-1 were quantified by enzyme-linked immunosorbent assay. Knee structural damage was determined by plain X-ray and 1.5 T magnetic resonance imaging (MRI), using Kellgren-Lawrence (KL) grading scale and Whole-Organ Magnetic Resonance Imaging Score (WORMS), respectively. Compared to controls, patients had significantly higher median serum COMP (985 vs. 625 ng/ml; p < 0.001) and MMP-3 (36.85 vs. 22.10 ng/ml; p = 0.003) levels. Patients with radiographic evidence of KLII/III knee OA had greater median COMP levels than KLI patients (1095 vs. 720 ng/ml; p = 0.001). In the generalized OA group, mean MMP-3 levels were higher than in the isolated knee OA group (30.40 vs. 55.13 ng/ml; p < 0.001). COMP correlated positively with WORMS (r s = 0.454, p < 0.001) and MMP-3 (r s = 0.337, p = 0.003). Cut-off values for serum COMP and MMP-3 were determined. We observed higher serum COMP and MMP-3 levels in knee OA patients compared to controls. COMP may reflect knee structural damage, while MMP-3-OA "generalization".

OSKIRA-4: a phase IIb randomised, placebo-controlled study of the efficacy and safety of fostamatinib monotherapy.

OBJECTIVES: OSKIRA-4 evaluated the efficacy of fostamatinib monotherapy versus placebo on the signs and symptoms of rheumatoid arthritis over 6 weeks by Disease Activity Score C reactive protein (DAS-28(CRP)) and assessed non-inferiority to adalimumab monotherapy at Week 24 by DAS-28(CRP). METHODS: Overall, 279 patients not currently taking disease-modifying antirheumatic drugs were randomised to: (A) fostamatinib 100 mg twice daily for 24 weeks plus placebo injection every 2 weeks (PBOI); (B) fostamatinib 100 mg twice daily for 4 weeks, then 150 mg once daily up to Week 24, plus PBOI; (C) fostamatinib 100 mg twice daily for 4 weeks, then 100 mg once daily up to Week 24, plus PBOI; (D) adalimumab 40 mg every 2 weeks for 24 weeks, plus oral placebo twice daily; or (E) oral placebo twice daily for 6 weeks, plus PBOI, then a switch to arm A or B. RESULTS: Fostamatinib demonstrated a significant improvement in DAS-28(CRP) score from baseline versus placebo at Week 6 for arms A and B, but not C. Fostamatinib was significantly less effective than adalimumab at Week 24 based on DAS-28(CRP). Adverse events observed with fostamatinib treatment were consistent with those reported in previous studies, including hypertension and diarrhoea. CONCLUSIONS: Fostamatinib demonstrated efficacy as monotherapy, showing superior DAS-28(CRP) score changes between baseline and 6 weeks when compared with placebo in treatment arms A and B. However, all fostamatinib regimens demonstrated inferior responses compared with adalimumab at Week 24. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov: NCT01264770.