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Systemic vasculitis is a group of heterogeneous diseases characterized by inflammation of the vascular wall. They can be primary or arise in the context of another disease. Blood vessels of different sizes are affected, being mainly divided into small, medium and large vessels. Takayasu's arteritis is a vasculitis of the large blood vessels, most often affecting the aorta and its branches, subclavian arteries, iliac, femoral arteries and others. The presented clinical case concerns a woman with non-specific symptoms - low fever, sweating, weight loss, easy fatigue. After excluding an infectious genesis of the complaints, a diagnosis of Takayasu's Arteritis was made in the early phase of the disease as a result of Positron emission tomography. Corticosteroid and immunosuppressive therapy was started. When conducting a control PET, 20 months after the start of the therapy, a significant regression to absence of the findings from the imaging study was observed.

A 47-year-old female patient with active Systemic lupus erythematosus (SLE) - skin, joint, hematological, and renal involvement was admitted for rapidly progressive renal failure at the background of very high anti-dsDNA and pANCA antibodies. Active pathogenetic treatment was started pulse therapy with methylprednisolone, intravenous immunoglobulins (IVIG) and cyclophosphamide, blood transfusions were performed, symptomatic treatment with infusions ad diuretic was initiated. Due to progression of renal failure with volume overload and increase in urea and creatinine levels renal-replacement therapy was initiated. The patient developed E. faecalis and E. durans sepsis with disseminated intravascular coagulation and ground-glass-type lung changes and the condition further deteriorated to fatal multiorgan failure. The authors discuss the role of pANCA antibodies in SLE with renal and lung involvement.

Fossil deposit first described by Franz Toula in 1890, in the Garnyovitsa area near Kotel is estimated as a geosite of a national significance with historical value for the Bulgarian geology. Here is cropping out a huge marl olistolith embedded among Middle Jurassic turbidites of the Kotel Olistostrome Formation. It contains Late Triassic (Norian) hydrozoa and corals, identified by the first explorers of the Bulgarian lands as early as the end of the 19th century. Given the high geodiversity of the area and the proximity to Kotel, this geosite has great potential for geotourism within the future geopark “East Balkan”.

The pathogenesis of spondyloarthritis (SpA) is multifactorial and involves multiple immune cells and cytokines that are signaled by Janus kinase (JAK). Inhibition of JAK signaling pathways has emerged as a new therapeutic option for patients with inflammatory joint diseases. Despite the proven effect of treatment with anti-IL-17, as well as TNFα inhibitors, some patients with ankylosing spondylitis cannot reach minimal disease activity or remission. This necessitated the development of a new class of molecules, and in recent years more and more clinical studies have proven their role in the treatment of both rheumatoid arthritis and ankylosing spondylitis. JAK inhibition is a promising therapeutic strategy for the treatment of SpA and its application has potential in patients with axial, polyarticular, or extraarticular manifestations of the disease in psoriatic arthritis and ankylosing spondylitis. The present literature review aims to highlight the new therapeutic options offered by this class of target synthetic disease-modifying antirheumatic drugs and to summarize the clinical trial data for tofacitinib, upadacitinib and filgotinib reported to date.

With the onset of the global pandemic due to the new virus SARS-CoV-2 and the development of vaccines against it, various adverse events have been reported to them. We present a clinical case of a 53-year-old Caucasian woman who presented one week after Pfizer vaccination against SARS-CoV-2 with severe muscle weakness, myalgia in upper and lower extremities, alopecia 2 cm in diameter, and two mucosal ulcerations on lower lip. No deviations from the hematological, biochemical and immunological indicators were found from the laboratory tests carried out. Two weeks later, the patient developed total alopecia on the scalp. Due to the causal relationship with the administered vaccine, the patient was not given a second dose and a diagnosis of Systemic Connective Tissue Disease was not accepted. Six months later, recovery and partial hair growth was observed in the affected areas of the capillitium. Alopecia areata is autoimmune in nature, with literature reporting initial or recurrent alopecia after vaccination. It is important that adverse events after vaccination are properly evaluated in order to choose a proper therapeutic approach.

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.

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

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. 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. 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. 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.

Not applicable.

Болестта на Стил при възрастни представлява рядко системно автоинфламаторно заболяване с недобре изяснена етиология, характеризиращо се с ежедневни температурни пикове, полиартрит и преходен макуло-папулозен обрив с цвят на сьомга. Екстремно високи нива на феритин се наблюдават при голям процент от болните, което го прави важен лабораторен тест при поставяне на диагнозата. Болестта на Стил при възрастни е важен диагностичен и терапевтичен проблем, който в редица случаи остава неразпознат поради рядкостта в популацията и разнообразната клинична картина. Представяме ви клиничен случай на 34-годишна жена, с първа изява - обрив по дорзалната повърхност на двете гривнени стави и в областта на двете коленни стави, по време на първа бременност в 6-та гестацинонна седмица. При гинекологичен преглед се установява интраутеринна смърт на плода, което е наложило преждевременно прекъсване на бременността в 8-ма гестационна седмица. По същото време пациентката съобщава за поява на фебрбилитет до 39°C. На фона на започната комбинирана антибиотична терапия, при болната се наблюдават персистиращи фебрилни епизоди с втрисане и тенденция към повишаване на острофазовите показатели. Пациентката е хоспитализирана в нефрологично отделение в увредено общо състояние, където е проведена комбинирана антибиотична и кортикостероидна терапия без задоволителен ефект. При пациентката е установен двукратно отрицателен резултат от PCR-тест за COVID-19. От проведените микробиологични изследвания за бактериални, вирусологични и гъбични инфекции, се доказа повишен титър на IgG- антитела за бруцелоза. Инфекцията е потвърдена от положителен PCR-тест в Клиника по инфекциозни болести и назначен 2-месечен антибиотичен курс с Доксициклин 200мг/дневно, на фона на който фебрилитетът персистира. Болната се хоспитализира в Клиника по Ревматология “ УМБАЛ “ Св. Ив. Рилски” в увредено общо състояние, с неясно фебрилно състояние до 39°С, полиартралгии, полимиалгии, макулозен еритемен обрив в областта на гърдите, левкоцитоза, тромбоцитоза, повишени LDH, феритин, ГГТ, острофазови показатели, микроцитна, хипохромна анемия, отрицателни имунологични изследвания (анти-MCV, анти-ССР, ANA-screen, ANA-blot, anti-dsDNA, ANCA, anti-MPO, anti-PR3, аCL, antiB2GPI, anti-Protrombin), Quantiferon (-) отр. При пациентката се прие диагноза Болест на Стил и се започна лечение с Метилпреднизолон 60 мг/дневно, на фона на който се наблюдава трайно афебрилно състояние и значително подобрение в клиничното състояние и лабораторните показатели.

През последните години вниманието на специалистите пулмолози и ревматолози е фо- кусирано върху връзката между интерстициалната белодробна болест (ILD) и системните забо- лявания на съединителната тъкан (CTD). Изработването на прецизни критерии се превърна в ос- новна цел поради нарастващия брой пациенти с диагностицирана ILD, разнообразие от антитела и признаци, характерни за различни ревматични болести. Диагностицирането на интерстициал- на белодробна болест, асоциирана със системно заболяване на съединителната тъкан, както и идентифицирането на идиопатична интерстициална пневмония, са все още предизвикателство поради множеството нозологични единици, при които се срещат, и значителната хетерогенност във фенотипа на заболяването между различните популации. Имунологичните изследвания играят важна роля за разпознаването на подлежащо CTD при пациентите с ILD, особено при наличие на дискретнo кожнo, ставнo или мускулно ангажиране. Въпреки това липсва изграден алгоритъм или консенсус по въпроса с кои имунологични изследвания трябва да се започне диагностичният процес. През 2015 г. European Respiratory Society/American Thoracic Society приема термина „интерстициал- на пневмония с автоимунна характеристика“ за класифициране на пациентите, които са клинично неопределени и не могат да бъдат включени в никаква група. Предложените класификационни кри- терии бяха обсъждани задълбочено от мултидисциплинарни екипи, но и към настоящия момент все още подлежат на широка дискусия и се актуализират с времето.

Chikungunya virus (CHIKV) is an arthritogenic arbovirus infection transmitted through the mosquitoes Aedes aegypti and Aedes albopictus. The clinical picture is diverse - from mildly flowing, almost asymptomatic forms to characteristic episodes of fever, polymyalgia, polyarthralgia, and arthritis. Globalization of the world is increasing the chances of infection spreading outside known endemic areas. This necessitates a broad differential diagnosis, especially in cases that mimic inflammatory joint diseases such as rheumatoid arthritis. The presented clinical case is of a patient who has returned from a trip to the Maldives and is the first in the Republic of Bulgaria as far as we know, and is established after a detailed literature reference has been made. Rheumatologists, even in non-CHIKV-endemic regions, should consider CHIKV in their evaluation of symmetric polyarthritis lasting above six weeks, especially in case of anamnesis for a trip to the endemic regions to CHIKV that are likely to expand in the near future. However, demonstrating positive antibodies to the Chikungunya virus is the rheumatologist‘s primary help in distinguishing the two diseases.

The onset of the pandemic caused by the new coronavirus has raised many questions in the global rheumatology society regarding the clinical course of the disease, effectiveness and complications of SARS-SoV-2 vaccination. The aim of this review is to analyze the information available up to date on the course of COVID-19 in patients with autoimmune rheumatic diseases (ARD), the frequency of complications in these patients, the effectiveness and side effects of vaccination against COVID-19. Various studies in Europe and the United States have found that the risk of severe COVID-19 in patients with ARD is similar to that in the general population. Negative prognostic factors are thought to be old age, comorbidity, moderate / high ARD activity, and corticosteroid (CS) intake at doses> 10 mg / day. Patients with systemic ARD are considered to be at higher risk of thromboembolic events due to chronic inflammation and / or the presence of antiphospholipid syndrome, as well as the nature of COVID-19 - an endothelial lesion causing thrombosis and microangiopathy. It is observed a higher risk of severe pneumonia in patients treated with Rituximab, as well as an increase in hospitalizations and deaths amongst them. The opposite trend is observed in patients treated with anti-TNF. With the development of vaccines against COVID-19, questions arise about their effectiveness in patients with ARD, as well as the frequency of complications associated with them. In these studies, slightly lower levels of neutralizing antibodies were observed in patients with ARD compared to the general population, most commonly associated with Methotrexate or targeted synthetic DMARDs. The most common side effects seen in these patients after vaccination are pain at the injection site, fatigue and headache. Complaints of the musculoskeletal system are more common in patients with ARD than in the general population. Exacerbations of the underlying disease following vaccination, requiring hospitalization, are rare.

В контекста на автоимунните възпалителни заболявания би могла да се потърси терапевтичната полза от приложението на мезенхимни стволови клетки (МСК), предвид потенциала им да осъществяват имуносупресия и да регулират имунния отговор. В опита да добием по-цялостен поглед върху механизмите на регулация, осъществявани от адипозни стволови клетки (АТ-МСК) ние изследвахме влиянието на среди от АТ-МСК върху кръвни моноцити от пациенти с ревматоиден артрит (РА). Сравнението на ефекта на разтворимите фактори, продуцирани от АТ-МСК с контролните среди за клетъчно култивиране върху периферни кръвни мононуклеарни клетки (ПКМК) показа статистически сигнификантно редукция на процента моноцити, експресиращи HLA-DR на повърхността си, 55.3% (IQR 30-65%) vs. 72% (IQR 62-81%) p=0.001, а също така и сигнификантно понижение в плътността на експресията (mean flourescent intensity, MFI) на HLA-DR върху култивираните моноцити, 265 MFI (IQR 102-896 MFI) vs. 473 MFI (IQR 160-2201 MFI), p=0.001. Под въздействие на средите от АТ-МСК върху ПКМК от болни с РА беше увеличен и процента на CD14 експресиращи моноцити, спрямо контролните среди, 11.7 % (IQR 7.6-16.5 %) vs. 6.6% (IQR 4.6-11.8 %), p=0.013 и плътността на повърхностната експресия на CD14, 2702 (IQR 1548-3418) vs. 1540 (IQR 1146-2140), p=0.05. Нивата на sVEGF-A в култури на ПКМК от пациенти с РА, култивирани с кондиционирани среди от АТ-МСК бяха сигификантно по-високи спрямо ПКМК, култивирани с контролни среди, 5012 (IQR 2516-5054 pg/ml) vs. 561 pg/ml (IQR 288-699 pg/ml), p=0.001.

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 Bulgar...

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-β1 (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.

Оценката на болестната активност е съществен фактор при избора на терапевтичен подход за превенция на инвалидизацията на пациентите с ревматоиден артрит (РА ). Целта на настоящото проучване е да се определи болестната активност, оценена чрез DAS28-CRP, CDAI, SDAI, и да се проследи повлияването u от медикаментозната терапия със сБПАРЛП и бБПАРЛП. За целите на проучването са подбрани 220 пациенти със средна възраст 55.05 ± 10.63 SD години, от- говарящи на класификационните критерии за РА на ACR от 1987 г. и ACR/EULAR от 2010 г. Паци- ентите са стратифицирани според схемите на лечение в две основни групи, съответстващи си по възраст. Лечение с конвенционални синтетични болестопроменящи антиревматични лекарствени продукти (ксБПАРЛП) провеждат 96 болни, а останалите 124 – с биологични болестопроменящи антиревматични лекарствени продукти (бБПАРЛП). Оценката на пациента за болката, свързана с болестта, глобалната оценка за общото здравословно състояние и глобалната оценка на лекаря за болестната активност са извършени чрез визуална аналогова скала (VAS) – 100 mm. Актив- ността на заболяването е основният изходен домейн. Независим ревматолог оцени 28 стави на изходния, 6-и и 12-и месец от периода на проследяване. С-реактивен протеин (CRP) беше използван за измерване на възпалителния процес. DAS28-CRP, CDAI и SDAI бяха изчислени съгласно стан- дартните формули. Статистическите обработки са направени със SPSS 13.0. Извършен е описа- телен анализ с помощта на групировки по един или няколко признака, обобщаващи показателите относителен дял, средна аритметична, медиана, мода. На изходно ниво пациентите на бБПАРЛП са имали значително по-висока средна стойност на DAS28 (5,03 ± 0,84 SD спрямо 4,35 ± 1,20 SD, p < 0,001), CDAI (25,06 ± 7,32 SD срещу 20,83 ± 10,53 SD, p < 0,001) и SDAI (28,27 ± 8,74 SD срещу 23,19 ± 11,89 SD, p < 0,001) в сравнение с тези на конвенционални синтетични БПАРЛП (ксБПАРЛП). На 6-ия месец и при двете групи (бБПАРЛП и ксБПАРЛП) установихме значително намаляване на средните стойности на DAS28 (p < 0.001, p < 0.001), въпреки че по този показател не се наблюдава сигнифи- кантна разлика в активността на заболяването между групите (3.75 ± 2.49 SD срещу 3,90 ± 1,10 SD, р = 0,566). Пациентите на биологично лечение са имали значително по-ниска активност на заболяването в сравнение с тези на ксБПАРЛП след 6-ия и 12-ия месец от началото на терапията, оценени чрез CDAI (13,43 ± 4,98 SD срещу 16,81 ± 9,94 SD, p = 0,001; 8,65 ± 4,53 SD срещу 15,86 ± 10,02 SD, p < 0,001) и SDAI (14,63 ± 5,42 SD срещу 18,38 ± 10,49 SD, р < 0,001; 9,39 ± 4,92 SD срещу 16,79 ± 10,5 SD, p < 0,001). За разлика от резултатитe за DAS28 CRP, които не показват промяна между 6-ия и 12-ия месец при пациенти, получаващи ксБПАРЛП (3,90 ± 1,10 SD, 3,82 ± 1,12 SD, p = 0,156), наблюдаваме статистически значима разлика на 0, 6-и, 12-и месец от периода на проследяване по отношение на CDAI и SDAI. След една година проспективно проследяване терапията с бБПАРЛП води до трайна супресия – минимална активност на заболяването, оценена от DAS28 CRP, CDAI и SDAI, в сравнение с терапията с ксБПАРЛП, при пациенти, които са имали умерена активност

ObjectiveTo evaluate the efficacy and safety of olokizumab (OKZ) in patients with active rheumatoid arthritis despite treatment with methotrexate (MTX).MethodsIn 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 ResultsA 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%) (pConclusionsTreatment 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 numberNCT02760368.

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.

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.

Background: Odanacatib, a cathepsin K inhibitor, reduces bone resorption while maintaining bone formation. Previous work has shown that odanacatib increases bone mineral density in postmenopausal women with low bone mass. We aimed to investigate the efficacy and safety of odanacatib to reduce fracture risk in postmenopausal women with osteoporosis. Methods: The Long-term Odanacatib Fracture Trial (LOFT) was a multicentre, randomised, double-blind, placebo-controlled, event-driven study at 388 outpatient clinics in 40 countries. Eligible participants were women aged at least 65 years who were postmenopausal for 5 years or more, with a femoral neck or total hip bone mineral density T-score between −2·5 and −4·0 if no previous radiographic vertebral fracture, or between −1·5 and −4·0 with a previous vertebral fracture. Women with a previous hip fracture, more than one vertebral fracture, or a T-score of less than −4·0 at the total hip or femoral neck were not eligible unless they were unable or unwilling to use approved osteoporosis treatment. Participants were randomly assigned (1:1) to either oral odanacatib (50 mg once per week) or matching placebo. Randomisation was done using an interactive voice recognition system after stratification for previous radiographic vertebral fracture, and treatment was masked to study participants, investigators and their staff, and sponsor personnel. If the study completed before 5 years of double-blind treatment, consenting participants could enrol in a double-blind extension study (LOFT Extension), continuing their original treatment assignment for up to 5 years from randomisation. Primary endpoints were incidence of vertebral fractures as assessed using radiographs collected at baseline, 6 and 12 months, yearly, and at final study visit in participants for whom evaluable radiograph images were available at baseline and at least one other timepoint, and hip and non-vertebral fractures adjudicated as being a result of osteoporosis as assessed by clinical history and radiograph. Safety was assessed in participants who received at least one dose of study drug. The adjudicated cardiovascular safety endpoints were a composite of cardiovascular death, myocardial infarction, or stroke, and new-onset atrial fibrillation or flutter. Individual cardiovascular endpoints and death were also assessed. LOFT and LOFT Extension are registered with ClinicalTrials.gov (number NCT00529373) and the European Clinical Trials Database (EudraCT number 2007-002693-66). Findings: Between Sept 14, 2007, and Nov 17, 2009, we randomly assigned 16 071 evaluable patients to treatment: 8043 to odanacatib and 8028 to placebo. After a median follow-up of 36·5 months (IQR 34·43–40·15) 4297 women assigned to odanacatib and 3960 assigned to placebo enrolled in LOFT Extension (total median follow-up 47·6 months, IQR 35·45–60·06). In LOFT, cumulative incidence of primary outcomes for odanacatib versus placebo were: radiographic vertebral fractures 3·7% (251/6770) versus 7·8% (542/6910), hazard ratio (HR) 0·46, 95% CI 0·40–0·53; hip fractures 0·8% (65/8043) versus 1·6% (125/8028), 0·53, 0·39–0·71; non-vertebral fractures 5·1% (412/8043) versus 6·7% (541/8028), 0·77, 0·68–0·87; all p

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

The aim of this study was to evaluate the possible association of

Background: Emerging data have demonstrated that mesenchymal stem cells (MSC) are well endowed with a broad repertoire of immunosuppressive tools and they could modulate the immune response on several levels via production of a plethora of soluble factors and contact-dependent mechanisms. For these reasons, mesenchymal stem cells-based protocols were spotlighted as promising multiple-hit treatment candidates for therapeutic intervention in a multitude of autoimmune diseases and debilitating conditions such as rheumatoid arthritis (RA). Objectives: In line with aforementioned and taking in mind the current shift in Th1/Th2 paradigm suggesting a key role of Th17/Treg axis dysregulations in RA pathogenesis, we aimed to appraise the immunoregulatory effects of secretory factors produced by adipose-derived MSC (AT-MSC) on Th17 and Tregs subsets and also pro-inflammatory cytokines production in patients with RA. Methods: The study encompasses 17 patients matching the ACR/EULAR 2010 criteria for RA. AT-MSC were isolated and cultured according to well-established protocols. Peripheral blood mononuclear cells (PBMCs) isolated from RA patients’ samples were cultured in AT-MSC conditioned media and in control media. Flow cytometry was used for detection of Th17 and Treg markers (of CD3, CD4, CD161, CD196 and CD25 and intracellular expression of FoxP3). ELISA was performed for testing the cytokines produced by PBMC (TGF-β1, TNF-α, IL-17A, IL-21). Results: We found significant elevation in percentage of CD4+CD25+FoxP3+Treg cell in the pool of PBMC cultured with AT-MSC as opposed to control medium, 4.22 ± 2% (mean ± SD) vs. 6.04 ± 3.6% (p = 0.001). Paired sample analysis of Th17 cells percentage values from all CD4+ in PBMC cultured with control media (mean ± SD) 10.13 ± 3.88% in contrast to Th17 percentage in PBMC cultured with AT-MSC supernatants 8.98 ± 3.58% showed significant decrease in Th17 numbers (p = 0.02) under the influence of AT-MSC secretory factors. Cultivation of RA patient`s PBMCs with AT-MSC supernatants led to significant up-regulation of TGF-β1 levels, (median [IQR]) 8.318 ng/ml (6.327 – 11.686 ng/ml) vs. 6.227 ng/ml; (1.681 – 10.148 ng/ml) (p = 0.013) and decrease in levels of TNF-α, IL-17A, and IL-21 respectively: 5 pg/ml (1.75 – 11.65 pg/ml) vs. 1 pg/ml (0.7 – 1.9 pg/ml) (p = 0.001); 4.2 pg/ml (3.1 – 6.1pg/ml) vs. 2.3 pg/ml (0.75 – 5.42 pg/ml) (p = 0.017); 75.1 ± 35.95 pg/ml vs. 52.09 ± 30.8 pg/ml (p = 0.022). The reduction in IL-17 levels positively correlated with the decrease of TNF-α (r = 0.921, p = 0.001). Conclusion: Our study unambiguously demonstrated that secretory factors produced by AT-MSC exert an immunoregulatory effect on Th17 and Treg cells and also could inhibit major effector cytokine pathways: TNF-α, IL-17, IL-21 production in RA in vitro. The study of mechanisms of immunoregulation induced by MSCs provide us better insight into the pathogenesis of rheumatoid arthritis and could be a potential therapeutic approach. Disclosure of Interests: Georgi Vasilev: None declared, Mariana Ivanova Goycheva Speakers bureau: Abbvie, Pfizer, UCB, Novartis, Ekaterina Ivanova-Todorova: None declared, Kalina Tumangelova-Yuzeir: None declared, Ekaterina Kurteva: None declared, Rumen Stoilov Speakers bureau: Abbvie, Pfizer, Amgen, UCB, Novartis, Dobroslav Kyurkchiev: None declared

Background: Hyaluronic acid (HA) is a natural polysaccharide, which is an important structural component of synovial fluid and cartilage. There are different injectable forms of HA used for clinical application. Highly cross-linked/high-molecular-weight hyaluronans (HMWHA) provide additional stability and improve functionality [1], resulting in longer bioavailability in the knee joint and promoting viscoinduction [2]. A direct comparison between the two most common injection protocols of HMWHA in our routine practice is of great practical interest, since viscosupplementation is among the most commonly used treatment modalities for patients with knee osteoarthritis (KOA) in Bulgaria [3]. Objectives: Our aim was to compare the clinical effectiveness of two different regimens for injecting intra-articular HMWHA in KOA patients under ‘real-world’ conditions in routine clinical practice. Methods: This prospective, open-label, observational study included 50 patients with KOA who were followed for a period of 1 year. They were divided into two therapeutic arms according to their preselected treatment regimen: patients injected once with HMWHA (n = 25; group 1) at baseline and patients injected twice 6 months apart with HMWHA (n = 25; group 2). A 100-mm visual analogue scale (VAS) for pain, disease-specific (Western Ontario & McMaster Universities Osteoarthritis index [WOMAC]) and generic (health assessment questionnaire – disability index [HAQ-DI]) questionnaires were used to evaluate patients at baseline, three months, six months, and one year later. Standardized radiographs were obtained at baseline and after one year. The response to the treatment was determined using the OMERACT-OARSI set of responder criteria [4]. Results: A single injection of HMWHA resulted in a statistically significant improvement in pain even at 12 months (ΔVAS = 10.12 ± 14.5 mm, p 0.05). Physical function was statistically improved in both groups (p 0.05). In the end of the follow-up period HAQ-DI did only statistically improve among patients in group 2. Conclusion: If maximal symptomatic relief is our primary goal, it would be logical to choose a two-injection regimen. However, if we take into account the financial aspect, we may be satisfied with a single injection of highly cross-linked HA over a year. References [1] Bowman S, awad ME, Hamrick MW, Hunter M, Fulzele S. Recent advances in hyaluronic acid based therapy for osteoarthritis. Clinical and translational medicine. 2018Dec;7(1):6. doi: 10.1186/s40169-017-0180-3 [2] Divine JG, Zazulak BT, Hewett TE. Viscosupplementation for knee osteoarthritis: a systematic review. Clin Orthop Relat Res. 2007;455:113–122. [3] Georgiev T, Stoilov R. Bulgarian rheumatology: science and practice in a cost-constrained environment. Rheumatology international. 2018Nov9:1-3. doi: 10.1007/s00296-018-4202-2 [4] Pham T, van der Heijde DM, altman RD, anderson JJ, Bellamy N, Hochberg M, Simon L, Strand V, Woodworth T, Dougados M. OMERACT-OARSI initiative: Osteoarthritis Research Society international set of responder criteria for osteoarthritis clinical trials revisited. Osteoarthritis and Cartilage. 2004May1;12(5):389-99. Disclosure of interests: Tsvetoslav Georgiev: None declared, Rumen Stoilov Speakers bureau: abbvie, Pfizer, amgen, UCB, Novartis

Background Rheumatoid arthritis (RA) is the most common type of autoimmune arthritis in which genetic predisposition in close interaction with environmental triggers seems to be the major factor in the disease pathogenesis. Genetic analyses suggest a polygenic inheritance, as the largest genetic contribution to RA susceptibility remains the HLA–DRB1 gene, residing within the HLA gene complex. Since immune dysregulation plays a key role in immune-mediated inflammatory disorders, genetic variations within cytokine loci may contribute to variability in the immune response determining susceptibility or resistance to a certain autoimmune disease. Objectives We aimed to investigate whether IL12B polymorphisms are involved in causation of RA and in variations of circulating IL-23 and IL-12p40 levels in our Bulgarian population. Methods A total of 125 RA patients aged from 18 to 79 years in comparison to 239 age- and sex-matched healthy controls (HC) were genotyped for rs17860508 and rs3212227. Both IL12B polymorphisms were investigated by polymerase chain reaction (PCR) - based methods. Serum IL-12p40 and IL-23 concentrations measurement was done using ELISA test in 67 RA patients and 55 age-matched HC. Results An association between the rs17860508 polymorphism and RA development was established under the allelic model (allele 2 vs allele 1; OR = 1.68, 95%CI = 1.17–2.42, p = 0.0044), the co-dominant model (2.2 vs 1.1, OR = 2.83, 95%CI = 1.37–5.86; 1.2 vs 1.1 OR = 1.76, 95%CI = 0.91–3.41; p = 0.017), the dominant model (1.2 + 2.2 vs 1.1; OR = 2.12, 95%CI = 1.15–3.90, p = 0.014), and the recessive model (2.2 vs 1.1 +1.2; OR = 2.00, 95%CI = 1.10–3.62, p = 0.022). These results suppose that the homozygous 2.2 genotype could be predisposing, while 1.1genotype might be protective factor to RA susceptibility. No association between the rs3212227 and RA risk was revealed under the same genetic models. Also, a combined two loci model was designed with a referent group - the individuals with the IL12Bpro 1.1 + IL12B 3’ UTR AA genotype. We found that the combination of IL12Bpro 1.1 with IL12B 3’ UTR AA genotype is protective factor for RA susceptibility, whereas the carriage of IL12Bpro allele 2 despite hetero- or homozygosity simultaneous with IL12B 3’ UTR AC/CC genotypes increase the RA risk more than 3-fold. The highest risk for RA susceptibility was established in the carriers of IL12B 3′ UTR allele C in combination with IL12Bpro 2.2 genotype, which was estimated to be 12.6 (95%CI = 2.478–71.412; p Conclusion IL12Bpro (rs17860508) and 3’ UTR (rs17860508) polymorphisms does confer susceptibility to RA either as an individual or combinatorial effect and might influence the RA occurrence through regulating the expression of IL-12/IL-23 p40 and production of IL-23. Disclosure of Interests Mariana Ivanova Goycheva Speakers bureau: Abbvie, Pfizer, UCB, Novartis, Irena Manolova: None declared, Georgi Vasilev: None declared, Lyuba Miteva: None declared, Rumen Stoilov Speakers bureau: Abbvie, Pfizer, Amgen, UCB, Novartis, Spaska Stanilova: None declared

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.

Author(s): Deodhar, Atul; Gensler, Lianne S; Sieper, Joachim; Clark, Michael; Calderon, Cesar; Wang, Yuhua; Zhou, Yiying; Leu, Jocelyn H; Campbell, Kim; Sweet, Kristen; Harrison, Diane D; Hsia, Elizabeth C; van der Heijde, Desiree | Abstract: ObjectiveTo evaluate the efficacy and safety of ustekinumab in 3 randomized, placebo-controlled studies in patients with axial spondyloarthritis (SpA). Studies 1 and 2 included patients with radiographic axial SpA (anti-tumor necrosis factor [anti-TNF]-naive patients and patients with inadequate response or intolerance to anti-TNF, respectively); study 3 patients had nonradiographic axial SpA.MethodsIn all 3 studies, patients were randomly assigned (1:1:1) to receive subcutaneous ustekinumab at 45 mg or 90 mg or placebo up to 24 weeks, after which placebo-treated patients were rerandomized to receive ustekinumab at 45 mg or 90 mg. The primary end point in studies 1 and 2 was the proportion of patients who met the Assessment of SpondyloArthritis international Society criteria for 40% improvement in disease activity (achieved an ASAS40 response). The primary end point in study 3 was the proportion of patients who achieved an ASAS20 response. Other disease activity and safety measures were also evaluated. A week 24 analysis of study 1 was preplanned to determine continuation of studies 2 and 3.ResultsFor study 1, the primary and major secondary end points were not met, and the study was discontinued. As a result, studies 2 and 3 were prematurely discontinued before they were fully enrolled. For all 3 studies, neither ustekinumab dose group demonstrated clinically meaningful improvement over placebo on key efficacy end points. The proportion of patients experiencing adverse events in the ustekinumab groups was consistent with that in previous studies.ConclusionIn these 3 placebo-controlled trials, efficacy of ustekinumab in the treatment of axial SpA was not demonstrated. The safety profile was consistent with that of studies in other indications.

Background:Olokizumab (OKZ) is a new humanized monoclonal antibody targeting IL-61, 2. Here we present the results of the first phase III study of OKZ in patients with Rheumatoid Arthritis (RA).Objectives:The primary objective was to evaluate the safety and efficacy of OKZ administered subcutaneously (SC) every 2 weeks (q2w) and 64mg SC every 4 weeks (q4w) vs placebo in the treatment moderate-to-severe RA.Methods:In this randomized, double-blind, placebo-controlled, multicenter study in patients with moderately to severely active RA despite methotrexate (MTX) (ClinicalTrials.gov IdentifierNCT02760368, CREDO-1) patients received SC injections of OKZ 64 mg q2w, OKZ 64 mg q4w and PBO q2w for 24 weeks. Starting at Week (Wk) 14, non-responders were rescued. After Wk 24, subjects were eligible for an open-label study extension.The primary endpoint was American College of Rheumatology 20% (ACR20) response at Wk 12.Secondary endpoints included: percentage of subjects with low disease activity, improvement of physical ability. Safety outcomes, including treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs) and laboratory abnormalities (via central lab) were assessed.Results:428 patients were randomized to OKZ 64mg q2w (n=143), OKZ 64mg q4w (n=142), and PBO (n=143). Baseline characteristics were comparable between treatment arms: mean (SD) age was 51.3 (12.0) years, 82.7% of patients were female, disease duration 8.14 (7.6) and all patients were on MTX. Mean (SD) baseline DAS28-CRP was 6.0 (0.76) and HAQ-DI was 1.72 (0.49).130 (90.9%) patients in q2w, 134 (94.4%) in q4w and 132 (92.3%) in PBO arms completed the study.Both regimens of OKZ were significantly better than PBO in all primary and secondary endpoints (Table 1).Table 1.Key efficacy results (intent-to-treat population) NRI1OKZ q2wOKZ q4wPBONumber of Subjects143142143ACR20 Response, n (%) Wk 12 (primary endpoint)91(63.6)***100(70.4)***37(25.9)DAS2848(33.6)***55(38.7)***5(3.5)HAQ-DI Wk 12 LSM (SE)-0.54(0.041)-0.56(0.042)-0.20(0.042)Treatment Comparison vs PBO LSM Difference (SE)-0.34***(0.059)-0.36***(0.059)97.5% CI for LSM Difference-0.47, -0.21-0.49, -0.23ACR50 Response, n (%) Wk 2461(42.7)***69(48.6)***11(7.7)CDAI ≤2.8 Response, n (%) Wk 2412(8.4)**11(7.7)**01– NRI, Non-Responder Imputation; LSM, Least Squares Mean; **p-value difference from PBO The key efficacy outcomes were maintained throughout the 24-week.Overall incidence of TEAEs was 58.0% in OKZ q2w arm; 57.0% in OKZ q4w arm and 43.7% in PBO, TEAEs leading to study treatment discontinuation were reported in 4.9%, 3.5% and 0.7% patients, respectively.At least one TESAE (subcutaneous abscess, pulmonary tuberculosis, staphylococcal sepsis, toxic shock syndrome, cervix carcinoma, obstructive pancreatitis, diabetic vascular disorder) was reported in 8 (5.6%) of OKZ groups, numerically higher than 4(2.8%) in PBO. There was one death due to septic shock in the OKZ q2w arm.Conclusion:Treatment with OKZ over a 24-week period was associated with significant improvements in the signs, symptoms and physical function of RA, with a safety profile consistent with Phase II data for OKZ and with the data for the agents with similar mechanism of action.There were no discernible differences between the two regimens of OKZ in efficacy or safety outcomes.References:[1]Genovese MC et al. Ann Rheum Dis. 2014 Sep; 73:1607; 2. Takeuchi T, et al. Mod Rheumatol. 2016; 26:1Acknowledgments:Investigators and patients of CREDO-1 study.Disclosure of Interests:Evgeny Nasonov Speakers bureau: Lilly, AbbVie, Pfizer, Biocad, R-Pharm, Rumen Stoilov Grant/research support from: R-Pharm, Tamara Tyabut: None declared, Mark C. Genovese Grant/research support from: Abbvie, Eli Lilly and Company, EMD Merck Serono, Galapagos, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, Pfizer Inc., RPharm, Sanofi Genzyme, Consultant of: Abbvie, Eli Lilly and Company, EMD Merck Serono, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, RPharm, Sanofi Genzyme

Background:Assessment of disease activity and quality of life are one of the main indicators for determining the effectiveness of treatment with disease-modifying antirheumatic drugs. In recent years, a new group has entered the market - target synthetic DMARDS, which prove their effectiveness in treating RA comparable to that of biological products.Objectives:The aim of this study is to evaluate the disease activity and quality of life of patients with rheumatoid arthritis (RA) treated with biological agents in comparison with Tofacitinib (real life data from Bulgarian population) and determine whether or not the benefits of different therapies were sustained over a follow up period of 1 year.Methods:164 patients were selected with a mean age 55.34 ± 16SD 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, Infliximab (INF) 20, Tofacitinib (TOF) 20. Disease activity and quality of life was the primary concern. Independent joint assessor evaluated 28 joints on baseline, 6th and 12th month’s thereafter. 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. The quality of life was evaluated via EQ-5D.All of the patients were on stable therapy according to the inclusion criteria, and didn’t interrupt any of the medications including biological or target synthetic treatment.Results:Significant clinical improvement and statistically significant reduction in disease activity were observed in patients treated with bDMARDS and tsDMARDS within 6 months (p The mean values showing the change of the SDAI over the study period also outline comparable profiles. All of the treatment groups achieved a rapid reduction in disease activity that continued to decrease through the 6 and 12 months period, respectively, as supported by changes in SDAI.The quality of life evaluated with EQ-5D revealed significant improvement on the 6-th month of follow up as well as after 12th month (pConclusion:Real-life data show that patients on biological treatment as well as those on Tofacitinib therapy achieve a significant decrease in disease activity after one year of follow-up. This gives us reason to accept the importance of non-inferior effect of jak-inhibitors and their place in treatment of Rheumatoid arthritis.Disclosure of Interests:Vladimira Boyadzhieva: None declared, Nikolay Stoilov: None declared, Ekaterina Kurteva: None declared, Rumen Stoilov Grant/research support from: R-Pharm

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.

Background Rheumatoid arthritis (RA) is an autoimmune inflammatory disease, characterised by chronic synovitis, bone and cartilage destruction, as well as systemic manifestation. In accordance with the pivotal role of cytokines in autoimmunity and their impact as biomarkers, we analysed gene expression at both mRNA and protein levels of several cytokines in peripheral blood of RA patients. Objectives The aim of the present study was to investigate the gene expressions at mRNA and protein levels of main pro-inflammatory (TNF-α, IL18, IL-12p40; IL-23, IL-6) and immunosuppressive (TGF-β1 and IL10) cytokines and transcription factor Foxp3 in peripheral blood of RA patients. Methods Total RNA from peripheral blood was isolated from 32 patients matching the ACR/EULAR 2010 criteria for RA and 27 healthy controls. Quantitative real-time polymerase chain reaction was performed for the 8 genes of interests, using the TaqMan detection system. Relative quantitative evaluation of mRNAs was performed by the comparative ΔΔCt method and results were presented as n-fold mean difference (RQ-relative quantity) of target genes relative to calibrator (healthy controls) after normalisation to the reference genes (GAPDH and 18srRNA). Serum quantities of cytokines were measured by ELISA. Results From studied pro-inflammatory cytokine genes, we found down-regulation in the following order: IL6 >TNFA>IL12B; up regulation of IL23A and no change in IL18 gene expression in RA patients group compared to healthy controls. For anti-inflammatory genes we detected significantly increased quantity for IL10 mRNA and no change for TGFB1 mRNA. The most profound down-regulation (more than 7-fold) was observed for IL6 gene (p TGFB1 mRNA levels were approximately equal in patients and controls in contrast to IL-10, which was upregulated in both mRNA (RQ=1.6; p=0.034) and serum levels (over 6.6 fold; p Conclusions Our results demonstrated significant differences in the expression of mRNA encoded cytokines and their protein quantities at systemic level of RA patients, mostly on IL-23, IL-6 and TNF-alpha. Disclosure of Interest None declared

Background Ankylosing spondylitis (AS) is an immune-mediated rheumatic disease belonging to the spectrum of axial spondyloarthritides, characterised mainly by chronic inflammatory back pain and radiographic sacroiliitis. Since genetic factors have been shown to be major determinants of susceptibility to the disease and contribute to amplification of immune responses, polymorphic variability in immune response genes are of interest. The interleukin-12p40 gene (IL12B) encodes the p40 polypeptide chain, which, together with p19, composes IL-23, a member of the IL-12 superfamily. Objectives In this study, we examined functional association between two IL12B polymorphisms – IL12Bpro (rs17860508) and IL12B 3’ UTR A/C (rs3212227), and cytokine production of both pro-inflammatory cytokines IL-12p40 and IL-23 in AS patients. Methods A total of 69 AS patients with a mean age 43±16 years and 257 healthy individuals from Bulgarian population were genotyped. Genotyping for the rs3212227 was performed by restriction fragment length polymorphisms-PCR assay and for the rs17860508 by allele specific-PCR. Serum IL-12p40 and IL-23 concentrations measurement was done using ELISA test. Results We found significant differences in the genotype (p=0.029) and allele (p=0.006) frequencies of rs17860508 polymorphism between AS patients and controls. An association between AS and the rs17860508 polymorphism was established under the allelic model (allele 2 vs. allele 1; OR=1.698), the dominant model (1.2+2.2 vs. 1.1; OR=2.427), and the co-dominant model (2.2 vs. 1.1; OR=2.812; 1.2 vs. 1.1; OR=2.252). Genotype and allele frequencies of rs3212227 polymorphism of the IL12B were similar in cases and controls. The mean (±SEM) levels of IL-12p40 and IL-23 in AS patients (176.5±20.7 pg/ml; 26.98±3.4 pg/ml, respectively) was significantly higher than in controls (88.8±9.6 pg/ml; 12.1±1.5; respectively) (p Conclusions Allelic variants in the IL12B genes have the potential to alter the expression of both IL-12p40 and IL-23 cytokines in specific manner for AS patients. Carriage of the IL12Bpro variant 1-allele and of the 3′-UTR A-allele in the genotype regardless of homo- or heterozygosity could enhance systemic IL-12p40 and IL-23 levels. Disclosure of Interest None declared

Background Extrusion of the medial meniscus is a consequence of the complex interactions among joint structures and altered tissue mechanics involved in the osteoarthritis (OA) process.1 Potential contributing factors are cartilage loss, meniscal tears, obesity and knee malalignment2–4 – features strongly associated with knee OA. Ultrasound (US) measurement of medial meniscus radial displacement (MRD) is an easy to implement procedure that may serve as a starting point for assessment of the cartilage loss in patients with knee osteoarthritis. Objectives The aim of the study was to investigate the correlation between ultrasound-measured MRD and magnetic resonance imaging(MRI)-detected cartilage damage, as a referent method, in patients with medial femorotibial knee OA Methods 60 osteoarthritic knees of 48 patients (83% female) aged 40 to 80 years, meeting the ACR criteria for knee osteoarthritis, were included in the study. Patients with severe malalignment (varus or valgus deformity ≥20 degrees) were excluded. Radiographic stage was assessed according to the Kellgren-Lawrence (KL) grading system, as only KL I-III knees were included. MRD was measured in millimetres using diagnostic US with patients in the supine (non-weight-bearing) position. Magnetic resonance images were acquired by using 1.5 T MRI and were evaluated by a trained radiologist using Whole-Organ Magnetic Resonance Imaging Score (WORMS) for cartilage abnormalities of the medial femorotibial joint (MFTJ) and medial meniscal tears. Results There was a significant difference in values of MRD among studied radiographic groups (p Conclusions Joint space narrowing (KL >2) on radiography is associated with higher level of meniscal extrusion. Higher values of measured MRD by ultrasound may be indicative of greater cartilage damage of MFTJ. References [1] Crema, Michel D., et al. ”Factors associated with meniscal extrusion in knees with or at risk for osteoarthritis: the Multicenter Osteoarthritis study.”Radiology264.2 (2012): 494–503. [2] Hunter, D. J., et al. “The association of meniscal pathologic changes with cartilage loss in symptomatic knee osteoarthritis.” Arthritis & Rheumatology54.3 (2006): 795–801. [3] Lerer, D. B., et al. ”The role of meniscal root pathology and radial meniscal tear in medial meniscal extrusion.”Skeletal radiology33.10 (2004): 569–574. [4] Sharma, Leena, et al. “Relationship of meniscal damage, meniscal extrusion, malalignment, and joint laxity to subsequent cartilage loss in osteoarthritic knees.” Arthritis & Rheumatology58.6 (2008): 1716–1726. Disclosure of Interest None declared

Background Health-related quality of life (HRQoL) is a multi-dimensional concept that includes domains related to physical, mental, emotional, and social functioning. It goes beyond direct measures of patients’ health, and focuses on the impact health status has on quality of life. Objectives To measure the QoL (EuroQol – 5D) of patients with RA and analyse their change after one year treatment with csDMARDs and biologic DMARDs (bDMARDs). Methods For the purpose of the study were selected 220 patients: 29 males (13%) and 86 women (87%) meet the classification criteria for RA by ACR 1987 Patient’s age is between 18–85 years (mean age for DMARDs – 54.8, biologic DMARDs – 55.3 years). The duration of the disease is between 0.5–44 years. In our study 96 patients are treated with DMARDs and 124 with bDMARDs. Patients with significant comorbidity, infectious diseases, congestive heart failure (NYHA class III or IV), malignant hypertension, psychiatric illness, a history of lymphoproliferative disease or neoplasia were excluded from the study. All of the patients completed the questionnaire EuroQol-5D on baseline, 6th and 12th month of treatment. The results were calculated via licensed calculator Results On Baseline, first part of EQ-5D mean values in patients with biologic therapy were significantly lower than those in the csDMARDs group (p=0.001). During the follow-up period patients on biologic DMARDs experienced significant improvement in this indicator in both time intervals (6th month – 63.24±16.52 SD, 12th month – 76.38±14.85). After 6 months of treatment the group on bDMARDS have higher mean values for EQ-5D than the patients on csDMARDs (57.64±20.2 SD), which shows significantly higher Quality of life (p=0.0025). During the following period from 6th to 12th month the patients on csDMARDs didn’t have significant improvement in QoL (58.65±22.41 SD) (p=0.214). On the 12th month of the treatment the patients on bDMARDs have significantly higher QoL than the group on csDMARDs (p=0.000). Analysing the data from the second part of the questionnaire, we found similar results with the data obtained from the first. Patients on biological therapy experienced a significant improvement in quality of life during the entire follow-up period. In contrast, patients on csDMARDS had significant improvement in the mean values of the EQ-5D – 0.51±0.2 3SD to 6th month, after which there was a non-significant reduction of EQ-5D=0.49±0.23 SD to 12th month (p=0.266). Conclusions The patients on biologic DMARDs have significantly higher QoL than the patients on csDMARDs on the 6th and 12th month of treatment period. Disclosure of Interest None declared

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.

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.Genotyping for -1082A/G IL10 (rs1800896) and -308G/A TNFA (rs1800629) polymorphisms was performed for 154 SLE patients and 224 healthy controls.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).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.

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

This study aimed to evaluate the relationship between physical function, disease activity, spinal mobility and bone parameters in ankylosing spondylitis (AS) patients. Fifty patients (27 men and 23 women) were examined. The clinical assessment included Bath AS Disease Activity Index, AS Disease Activity Score, Bath AS Functional Index, Bath AS Metrology Index (BASMI). Lumbar spine and femoral neck bone mineral density (BMD), spinal trabecular bone score (TBS) and the TBS T-score were calculated by dual-energy X-ray absorptiometry. Prevalence rates for osteoporosis and osteopaenia were 14% and 36%, respectively and for partially and fully degraded microarchitecture – 34% and 16%, respectively. A similar inverse correlation was observed between BASMI and TBS, TBS T-score and femoral BMD bone parameters, which were significantly lower in patients ≥45 years of age. No significant correlations were detected between any bone parameter and indicators of disease activity and physical function. Patients with a dis...

Background Systemic lupus erythematosus (SLE) is a complex polygenic autoimmune disease, characterized by autoantibody production, inflammatory manifestation and imbalanced cytokine production. In accordance with the pivotal role of Th17 cell in autoimmunity and the altered Th17/Tregs balance in response to changes in the cytokine milieu we analyzed mRNA expression of several cytokines in peripheral blood of SLE patients. Quantification of mRNA expression in peripheral blood could be useful to assess the disease activity of SLE patients. Objectives The aim of the present study was to investigate the gene expressions at mRNA level of proinflammatory (TNFA, IL18, IL12B); Th17-related (IL23A); immunosuppressive (TGFB1 and IL10) cytokines and Treg-specific transcription factor Foxp3 in peripheral blood of women with SLE. Methods Total RNA from peripheral blood was isolated from 28 female patients with SLE and 17 healthy women. Quantitative real-time polymerase chain reaction was performed for 7 genes of interests, using the TaqMan detection system. Relative quantitative evaluation of mRNAs was performed by the comparative ΔΔCt method and results are presented as n-fold mean difference (RQ-relative quantity) of target genes relative to calibrator (healthy controls) after normalization to the reference gene-GAPDH. Disease activity in SLE was determined by SLEDAI and divided into three categories: mild (0–5), moderate (6–10) and high (>10). Results The results reveal considerable overexpression of IL23A in SLE patients compared to healthy controls (RQ=5.347; p 10 (RQ=8.54; p 10. A significant good correlation between IL18 and the SLEDAI score was found (r=0.5548; p=0.002). Higher IL18 expression was observed among patients with worsened SLE compared to those with mild (RQ=1.656; p=0.008) and moderate (RQ=1.474; p=0.034) disease activity. We further demonstrated positively correlation between the expression levels of IL23A and TGFB1 (r=0.7276; p Conclusions These results suggest that upregulation of IL23 and TGFB1 in addition to downregulated Foxp3 expression may contribute to skewing towards Th17 profile in SLE pathogenesis and this was the most markedly manifested at the highest level of disease activity. Our results support indirectly the idea for restoring Th17/Treg balance as a therapeutic target in SLE. Disclosure of Interest None declared

Background Rheumatoid arthritis is a chronic systemic disabling condition associated with pathology mainly of the peripheral joints. Quality of Life (QoL) encompasses the impact of the disease and its treatment on the ability of the patient to fulfill/satisfy his or her needs. Assessing QoL in RA is an attempt to ensure the concern of patients that this important aspect of their daily lives will be measured. Objectives To evaluate the change of QoL of Bulgarian patients with RA after 6 months to 1-year of treatment with csDMARDs and bDMARDs by using two generic questionnaires (HAQ-DI and SF-36) and a disease-specific measurement RAQoL. Methods A total of 220 patients with a mean age 55.05±10.63SD meeting the 1987 ACR classification criteria for RA were included in the study. The mean disease duration was 9.97±5.78SD. Patients were stratified according to treatment regimens into 2 age-matched treatment groups: 96 on csDMARDs and 124 on bDMARD therapy. Subjects with significant comorbidity, infectious disease, congestive heart failure (NYHA class III or IV), malignant hypertension, psychiatric illness, a history of lymphoproliferative disease or neoplasia were excluded from the study. All participants completed the HAQ-DI, SF-36v2TM and RAQoL at baseline, at months 6 and 12 thereafter. The scores of the three instruments were calculated via licensed calculator. Comparison was performed by analysis variance ANOVA. Results At baseline the mean scores of HAQ-DI and RAQoL did not differ greatly among patients on csDMARDs and bDMARDs (1.29±0.78SD vs 1.13±0.54SD, p=0.063; 16.31±8.26SD vs 15.03±7.13SD, p=0.219, respectively). However, the mean physical component summary score of SF-36 was significantly higher in bDMARDs compared with csDMARDs (32.98±5.97 vs 31.05±7.82, p=0.039), while in the mental component of this scoring system not such a difference was found (p=0.983). After 6 months subjects treated with bDMARD showed a significant decreasing of the means of the HAQ-DI and RAQoL, as opposed to the other treatment group (0.86±0.5SD vs 1.17±0.76SD, p Conclusions Patient treated with bDMARDs showed better results for QoL than those on therapy with csDMARDs within a period of 12 months of treatment. Current management strategies should focus on improving the symptoms of activity and maintaining physical function in order to increase QoL in patients with RA. Disclosure of Interest None declared

In this study, we analyzed the putative association between the −308 G/A polymorphism in the promoter region of the tumor necrosis factor (TNF) α gene (rs1800629) and chronic inflammatory arthritis in the Bulgarian population. A case-control study was carried out on 58 patients with ankylosing spondylitis (AS), 108 rheumatoid arthritis (RA) patients and 177 healthy subjects. −308 G/A TNF-α genotypes of patients and controls were determined by restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR). No significant association between the rs1800629 polymorphism and RA risk in the study cohort was observed. However, there were significant differences in the genotype and allele frequencies of the −308 G/A TNF-α polymorphism between AS patients and the healthy subjects. In logistic regression analysis, the presence of the TNF-α −308A allele in the genotype (AA + AG vs. GG) was associated with a 3.298 times lower risk of developing AS. In addition, in AS, there were associations for age at disease onset ( 4; OR = 0.152) and response to anti-TNF treatment (OR = 2.25) under a dominant model (AA + AG vs. GG). In conclusion, our results suggested that the promoter polymorphism −308 G/A in the TNF-α gene had no significant effect on RA development, but could play a role in AS development and in determining the age of disease onset, disease severity and therapeutic outcome of AS in the Bulgarian patients who participated in our study.

The insulin-like growth factor (IGF) system plays a prominent role in the regulation of immunity and inflammation. Inappropriate balance of IGF-1 signaling has been reported in autoimmune disorders. This study was designed to compare +3179G/A IGF-1R genotype distribution in 148 systemic lupus erythematosus (SLE) patients with a group of 240 healthy donors. We also investigated serum IGF-1 levels in SLE patients and healthy controls in an association to genotype. IGF-1 serum levels were measured by enzyme-linked immunosorbent assay and genotyping for the +3179G/A polymorphism was performed by restriction fragment length polymorphisms (RFLP)-polymerase chain reaction (PCR) assay. The higher frequency of homozygous genotype AA (22% vs 17% with OR 1.319, 95% CI 0.71––2.44) and lower frequency of heterozygous genotype AG (42% vs 46% with OR 0.698, 95% CI 0.38–1.27) were seen in cases versus controls. Serum IGF-1 levels were comparable between SLE patients and age- and sex-matched healthy donors, even when the groups was stratified according to +3179G/A IGF-1R genotypes. However, when patients were sub grouped according to the disease activity index (SLEDAI score), serum IGF-1 levels were increased in patients with severe disease activity. These results indicated that systemic lupus erythematosus activity is affected by a modulation of the insulin-like growth factor-1 signal pathway and +3179G/A IGF-1R polymorphism.

Genetic polymorphisms in cytokine genes, which influence gene expression, may have an important impact on SLE susceptibility and severity. The aim of this study was to examine the possible influence of two functional polymorphisms in cis-regulatory regions of IL12B gene in the susceptibility and clinical symptoms of SLE in Bulgarian patients. Female SLE patients (n = 141) and 124 healthy women were included in the study. Genotyping for the IL12B A/C polymorphism in 3'UTR was performed by restriction fragment length polymorphisms PCR assay and for the IL12Bpro polymorphism by allele-specific PCR. Genotype-22 of IL12Bpro polymorphism was overrepresented among women with SLE (28 vs. 17%; OR = 1.875; 95% CI: 1.037 ÷ 3.390; P = 0.037). Respectively, a higher frequency of allele-2 was found in patients than in controls (51% vs. 40%; OR = 1.566; 95% CI: 1.110 ÷ 2.210; P = 0.011). Also, we found significantly elevated frequency of genotype-22 of IL12Bpro polymorphism among SLE patients who were simultaneously carrier of genotype-AA of SNP in 3'UTR. Women with both homozygous genotypes, genotype-AA of SNP in 3'UTR and genotype-22 of IL12Bpro polymorphism, had a 2.1-fold significantly elevated risk for SLE development. The carrying of genotype-11 of IL12Bpro polymorphism was positively associated with hematological and neuropsychiatric manifestations of SLE. We have provided evidence that the IL12Bpro polymorphism was associated with SLE development among Bulgarian women. Although a strong individual effect of SNP in 3'UTR of IL12B was not detected, we found that genotype-22 of IL12Bpro was predominantly combined with genotype-AA of SNP in 3'UTR among SLE patients and this combination elevates the risk of SLE.

ObjectivesTo determine the safety, tolerability and signs of efficacy of MOR103, a human monoclonal antibody to granulocyte–macrophage colony-stimulating factor (GM-CSF), in patients with rheumatoid arthritis (RA).MethodsPatients with active, moderate RA were enrolled in a randomised, multicentre, double-blind, placebo-controlled, dose-escalation trial of intravenous MOR103 (0.3, 1.0 or 1.5 mg/kg) once a week for 4 weeks, with follow-up to 16 weeks. The primary outcome was safety.ResultsOf the 96 randomised and treated subjects, 85 completed the trial (n=27, 24, 22 and 23 for pooled placebo and MOR103 0.3, 1.0 and 1.5 mg/kg, respectively). Treatment emergent adverse events (AEs) in the MOR103 groups were mild or moderate in intensity and generally reported at frequencies similar to those in the placebo group. The most common AE was nasopharyngitis. In two cases, AEs were classified as serious because of hospitalisation: paronychia in a placebo subject and pleurisy in a MOR103 0.3 mg/kg subject. Both patients recovered fully. In exploratory efficacy analyses, subjects in the MOR103 1.0 and 1.5 mg/kg groups showed significant improvements in Disease Activity Score-28 scores and joint counts and significantly higher European League Against Rheumatism response rates than subjects receiving placebo. MOR103 1.0 mg/kg was associated with the largest reductions in disease activity parameters.ConclusionsMOR103 was well tolerated and showed preliminary evidence of efficacy in patients with active RA. The data support further investigation of this monoclonal antibody to GM-CSF in RA patients and potentially in those with other immune-mediated inflammatory diseases.Trial registration numberNCT01023256