Natural Autoantibodies in Biologic-Treated Rheumatoid Arthritis and Ankylosing Spondylitis Patients: Associations with Vascular Pathophysiology.

Cardiovascular (CV) morbidity and mortality have been associated with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Natural autoantibodies (nAAb) are involved in innate immunity, as well as autoimmunity, inflammation, and atherosclerosis. There have not been any studies assessing the effects of biologics on nAAbs in RA and AS, also in relation to vascular pathophysiology. Fifty-three anti-TNF-treated RA and AS patients were included in a 12-month follow-up study. Anti-citrate synthase (CS) and anti-topoisomerase I fragment 4 (TOPO-F4) IgM and IgG levels were determined by ELISA. Ultrasonography was performed to assess brachial artery flow-mediated vasodilation (FMD), common carotid intima-media thickness (ccIMT), and arterial pulse-wave velocity (PWV). Other variables were also evaluated at baseline and 6 and 12 months after treatment initiation. Anti-TNF therapy improved FMD in RA and PWV in AS and stabilized ccIMT. TNF inhibition increased anti-CS IgM and IgG, and possibly also anti-TOPO-F4 IgG levels. Various correlation analyses revealed that nAAbs might be independently involved in autoimmunity as well as changes in inflammation and vascular pathology over time in biologic-treated patients (p < 0.05). We also found associations between anti-TOPO-F4 IgG and anti-Hsp60 IgG (p < 0.05). Baseline nAAb levels or nAAb level changes might determine changes in CRP, disease activity, FMD, PWV, and ccIMT over time (p < 0.05). The interplay between arthritis and inflammatory atherosclerosis, as well as the effects of anti-TNF biologics on these pathologies, might independently involve nAAbs.

Effects of 1-year tofacitinib therapy on angiogenic biomarkers in rheumatoid arthritis.

OBJECTIVES: Cardiovascular (CV) morbidity and mortality, and perpetuated synovial angiogenesis have been associated with RA. In our study we evaluated angiogenic factors in relation to vascular inflammation and function, and clinical markers in RA patients undergoing 1-year tofacitinib therapy. METHODS: Thirty RA patients treated with either 5 mg or 10 mg twice daily tofacitinib were included in a 12-month follow-up study. Eventually, 26 patients completed the study and were included in data analysis. Levels of various angiogenic cytokines (TNF-α, IL-6), growth factors [VEGF, basic fibroblast (bFGF), epidermal (EGF), placental (PlGF)], cathepsin K (CathK), CXC chemokine ligand 8 (CXCL8), galectin-3 (Gal-3) and N-terminal prohormone brain natriuretic peptide (NT-proBNP) were determined at baseline, and at 6 and 12 months after initiating tofacitinib treatment. In order to assess flow-mediated vasodilation, common carotid intima-media thickness (ccIMT) and carotid-femoral pulse-wave velocity, ultrasonography was performed. Synovial and aortic inflammation was also assessed by 18F-fluorodeoxyglucose-PET/CT. RESULTS: One-year tofacitinib therapy significantly decreased IL-6, VEGF, bFGF, EGF, PlGF and CathK, while it increased Gal-3 production (P < 0.05). bFGF, PlGF and NT-proBNP levels were higher, while platelet-endothelial cell adhesion molecule 1 (PECAM-1) levels were lower in RF-seropositive patients (P < 0.05). TNF-α, bFGF and PlGF correlated with post-treatment synovial inflammation, while aortic inflammation was rather dependent on IL-6 and PECAM-1 as determined by PET/CT (P < 0.05). In the correlation analyses, NT-proBNP, CXCL8 and Cath variables correlated with ccIMT (P < 0.05). CONCLUSIONS: Decreasing production of bFGF, PlGF or IL-6 by 1-year tofacitinib therapy potentially inhibits synovial and aortic inflammation. Although NT-proBNP, CXCL8 and CathK were associated with ccIMT, their role in RA-associated atherosclerosis needs to be further evaluated.

COVID-19: autoimmunity, multisystemic inflammation and autoimmune rheumatic patients.

Coronavirus disease 2019 (COVID-19) is associated with autoimmunity and systemic inflammation. Patients with autoimmune rheumatic and musculoskeletal disease (RMD) may be at high risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In this review, based on evidence from the literature, as well as international scientific recommendations, we review the relationships between COVID-19, autoimmunity and patients with autoimmune RMDs, as well as the basics of a multisystemic inflammatory syndrome associated with COVID-19. We discuss the repurposing of pharmaceutics used to treat RMDs, the principles for the treatment of patients with autoimmune RMDs during the pandemic and the main aspects of vaccination against SARS-CoV-2 in autoimmune RMD patients.

Inorganic pyrophosphate is reduced in patients with systemic sclerosis.

OBJECTIVE: The pathogenesis of calcinosis cutis, a disabling complication of SSc, is poorly understood and effective treatments are lacking. Inorganic pyrophosphate (PPi) is a key regulator of ectopic mineralization, and its deficiency has been implicated in ectopic mineralization disorders. We therefore sought to test the hypothesis that SSc may be associated with reduced circulating PPi, which might play a pathogenic role in calcinosis cutis. METHODS: Subjects with SSc and age-matched controls without SSc were recruited from the outpatient rheumatology clinics at Rutgers and Northwestern Universities (US cohort), and from the Universities of Szeged and Debrecen (Hungarian cohort). Calcinosis cutis was confirmed by direct palpation, by imaging or both. Plasma PPi levels were determined in platelet-free plasma using ATP sulfurylase to convert PPi into ATP in the presence of excess adenosine 5' phosphosulfate. RESULTS: Eighty-one patients with SSc (40 diffuse cutaneous, and 41 limited cutaneous SSc) in the US cohort and 45 patients with SSc (19 diffuse cutaneous and 26 limited cutaneous SSc) in the Hungarian cohort were enrolled. Calcinosis was frequently detected (40% of US and 46% of the Hungarian cohort). Plasma PPi levels were significantly reduced in both SSc cohorts with and without calcinosis (US: P = 0.003; Hungarian: P < 0.001). CONCLUSIONS: Circulating PPi are significantly reduced in SSc patients with or without calcinosis. Reduced PPi may be important in the pathophysiology of calcinosis and contribute to tissue damage with chronic SSc. Administering PPi may be a therapeutic strategy and larger clinical studies are planned to confirm our findings.

Peripheral quantitative computed tomography in the assessment of bone mineral density in anti-TNF-treated rheumatoid arthritis and ankylosing spondylitis patients.

INTRODUCTION: Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are associated with osteoporosis. There have not been many peripheral quantitative computed tomography (QCT) studies in patients receiving biologics. We assessed volumetric and areal bone mineral density (BMD) by forearm QCT and dual-energy X-ray absorptiometry (DXA), respectively in addition to laboratory biomarkers in these arthritides. METHODS: Forty RA and AS patients treated with either etanercept (ETN) or certolizumab pegol (CZP) were undergoing follow-ups for one year. Volumetric and areal BMD, as well as parathyroid hormone (PTH), osteocalcin, RANKL, 25-hydroxyvitamin D (VITD), P1NP, CTX, sclerostin (SOST), Dickkopf 1 (DKK-1) and cathepsin K (CATHK) were determined. RESULTS: We did not observe any further bone loss during the 12-month treatment period. Volumetric and areal BMD showed significant correlations with each other (p<0.017 after Bonferroni's correction). Trabecular QCT BMD at baseline (p=0.015) and cortical QCT BMD after 12 months (p=0.005) were inversely determined by disease activity at baseline in the full cohort. Trabecular QCT BMD at baseline also correlated with CTX (p=0.011). In RA, CRP negatively (p=0.014), while SOST positively (p=0.013) correlated with different QCT parameters. In AS, RANKL at baseline (p=0.014) and after 12 months (p=0.007) correlated with cortical QCT BMD. In the full cohort, 12-month change in QTRABBMD was related to TNF inhibition together with elevated VITD-0 levels (p=0.031). Treatment and lower CATHK correlated with QCORTBMD changes (p=0.006). In RA, TNF inhibition together with VITD-0 (p<0.01) or CATHK-0 (p=0.002), while in AS, treatment and RANKL-0 (p<0.05) determined one-year changes in QCT BMD. CONCLUSIONS: BMD as determined by QCT did not change over one year of anti-TNF treatment. Disease activity, CATHK, RANKL and VITD may be associated with the effects of anti-TNF treatment on QCT BMD changes. RA and AS may differ in this respect.

Correction to: A prospective, longitudinal monocentric study on laser Doppler imaging of microcirculation: comparison with macrovascular pathophysiology and effect of adalimumab treatment in early rheumatoid arthritis.

In the Original article, the legend of Figures 3 and 4 are interchanged and line number 387 is incomplete.

A prospective, longitudinal monocentric study on laser Doppler imaging of microcirculation: comparison with macrovascular pathophysiology and effect of adalimumab treatment in early rheumatoid arthritis.

Increased cardiovascular (CV) morbidity and mortality have been found in rheumatoid arthritis (RA). Tumour necrosis factor α (TNF-α) inhibitors may improve vascular function. In the first part of this study, we determined microcirculation during postoocclusive reactive hyperemia (PORH) representing endothelial function. In a nonselected population (n = 46) we measured flow-mediated vasodilation (FMD) of the brachial artery and laser Doppler flow (LDF) by ultrasound. Among LDF parameters, we determined TH1 (time to half before hyperemia), TH2 (time to half after hyperemia), Tmax (time to maximum) and total hyperemic area (AH). We measured von Willebrand antigen (vWF:Ag) by ELISA. In the second part of the study, we assessed the effects of adalimumab treatment on microcirculatory parameters in 8 early RA patients at 0, 2, 4, 8 and 12 weeks. We found significant positive correlations between FMD and LDF Tmax (R = 0.456, p = 0.002), FMD and TH2 (R = 0.435, p = 0.004), and negative correlation between vWF:Ag and Tmax (R = - 0.4, p = 0.009) and between vWF:Ag and TH2 (R = - 0.446, p = 0.003). Upon adalimumab therapy in early RA, TH2 times improved in comparison to baseline (TH2baseline = 26.9 s vs. TH24weeks = 34.7 s, p = 0,032), and this effect prolonged until the end of treatment (TH28weeks = 40.5, p = 0.026; TH212weeks = 32.1, p = 0.013). After 8 weeks of treatment, significant improvement was found in AHa (AHbaseline = 1599 Perfusion Units [PU] vs. AH8weeks = 2724 PU, p = 0.045). The PORH test carried out with LDF is a sensitive option to measure endothelial dysfunction. TH1 and TH2 may be acceptable and reproducible markers. In our pilot study, treatment with adalimumab exerted favorable effects on disease activity, endothelial dysfunction and microcirculation in early RA patients.

Effects of 1-year anti-TNF-α therapy on vascular function in rheumatoid arthritis and ankylosing spondylitis.

Accelerated atherosclerosis, increased cardiovascular morbidity and mortality have been associated with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Vascular function, clinical and laboratory markers and the effects of anti-TNF therapy were assessed in arthritides. Fifty-three 53 patients including 36 RA patients treated with either etanercept (ETN) or certolizumab pegol and 17 AS patients treated with ETN were included in a 12-month follow-up study. Ultrasonography was performed to determine flow-mediated vasodilation (FMD), common carotid intima-media thickness (ccIMT) and arterial pulse-wave velocity (PWV) in all patients. All assessments were performed at baseline and 6 and 12 months after treatment initiation. A significant improvement of brachial artery FMD was observed after 6 months (p = 0.004). A tendency of FMD improvement was also observed after 12 months (p = 0.065). ccIMT did not change throughout the year. PWV significantly improved after 12 months (p = 0.034). Higher baseline ccIMT (p = 0.009) and PWV (p = 0.038) were associated with clinical non-response (cNR) versus response (cR) to biologics. Multiple analysis confirmed the association of baseline ccIMT with age (p = 0.003) and cNR (p = 0.009), as well as that of baseline PWV with age at diagnosis (p = 0.022) and current chest pain (p = 0.004). Treatment itself determined the 12-month changes in FMD (p = 0.020) and PWV (p = 0.007). In a mixed cohort of RA and AS patients, TNF inhibition improved or stabilized vascular pathophysiology. Inflammation may be associated with FMD, while, among others, cNR may influence vascular function.

Autoimmune and angiogenic biomarkers in autoimmune atherosclerosis.

Several inflammatory, proteolytic, angiogenic and bone-associated factors play a role in the development of autoimmune, accelerated atherosclerosis in rheumatic diseases. Some of these may serve as biomarkers of vascular pathology and may be useful in the follow-up of vascular damage and outcome. Multi-biomarker profiles rather than a single markers would likely be optimal in this respect.

The NLRP3 inflammasome - interleukin 1 pathway as a therapeutic target in gout.

The NLRP3 inflammasome is implicated in the processing of the pro-inflammatory cytokine interleukin 1ß. Inflammatory disorders associated with the activation of the NLRP3 inflammasome - IL-1 axis are termed autoinflammatory diseases. Gout is an autoinflammatory disease, which is triggered by the deposition of monosodium urate crystals of precipitated uric acid. It is characterized by recurrent attacks of inflammation due to the activation of phagocytic cells that try to clear the crystals. NLRP3 inflammasome-mediated IL-1ß production plays a key role in the manifestation of the disease. Currently, the best approach to treat gout is to reduce uric acid concentration by targeting xanthine oxidase or uric acid transporters, or to use non-steroidal anti-inflammatory drugs. Nevertheless, most of these treatments are not effective enough and may results in side effects. During the past decades, our knowledge has greatly improved about the molecular mechanisms of NLRP3 activation. This knowledge enables and urges scientists to discover or design drugs that target pathways of NLRP3 inflammasome activation, or more preferentially, NLRP3 inflammasome itself. In this review, we discuss the already available drugs and products, that target the diverse pathways of the NLRP3 - IL-1ß axis, and the future therapeutic perspectives.

[Recommendation for the substantial choice between various nonsteroidal antiinflammatory drugs based on their safety profile]. / A nemszteroid gyulladáscsökkento gyógyszerek kiválasztásának szempontjai a biztonságosság tükrében.

Nonsteroidal antiinflammatory drugs are the most commonly used painkillers. Both analgetic and antiinflammatory effects of these medications are important in the treatment of rheumatic diseases. Despite their well-recognized efficacy, professional societies recommend using nonsteroidal antiinflammatory drugs with caution, balancing the various potential gastrointestinal, cardiovascular and renal adverse events. Clinicians should consider advanced age and history of concomitant diseases even in younger patients when considering treatment choice. As our Hungarian society is aging, prescribers must be aware of the basic pharmacodynamics and pharmacokinetics of nonsteroidal antiinflammatory drugs as well as drug interactions and potential adverse effects should be taken into consideration when using them according to the latest professional guidelines. Orv Hetil. 2018; 159(44): 1783-1788.

[Recent advances in gout: pathogenesis, diagnosis, comorbidities, treatment]. / Újdonságok köszvényben: patogenezis, társbetegségek, diagnosztika és terápia.

After a "silence" period for decades, a great body of new information has become available about the pathogenesis, diagnosis and treatment of gout. New data on purine metabolism and urate transporters have been published. It has become evident that gout is an autoinflammatory disease involving the inflammasome and interleukin-1. With respect to diagnosis, microscopic evaluation of the urate crystal is still the gold standard, however, sensitive imaging techniques (ultrasound, modern computed tomography methods) are able to visualize crystal deposition and tophus formation. Tophus size may also be monitored over time. We see a renaissance of non-pharmacological, lifestyle-related treatment modalities. Pharmacotherapy includes the resolution of attacks and urate-lowering maintenance therapy. In 2016, two recent series of recommendations have been published. Treat-to-target therapy aiming at urate levels ≤360 µmol/l is crucial. Urate-lowering therapy includes xanthine oxidase inhibitors (allopurinol, febuxostat). However, a number of novel compounds (urate transporter inhibitors, recombinant uricase, interleukin-1 inhibitors) are under development or before introduction to gout treatment. Comorbidites should be considered throughout the follow-up of gout patients. Orv Hetil. 2018; 159(40): 1625-1636.

[Vitamin D metabolism and osteoporosis in systemic sclerosis]. / D-vitamin-anyagcsere és osteoporosis szisztémás sclerosisban.

In the past few years more and more data have become available on the important role of vitamin D in immunological processes and inflammation. The role of vitamin D deficiency in the pathogenesis as well as in disease progression of different autoimmune and inflammatory conditions is suspected. Vitamin D deficiency is prevalent in several autoimmune diseases, including systemic sclerosis. Hypovitaminosis has been found to be associated with low bone mineral density and higher prevalence of osteoporosis in this group of patients. Determinants of low bone density in SSc are poorly understood. Studies have shown the importance of both traditional osteoporotic as well as disease-specific factors (extent of skin involvement, presence of internal organ manifestation, malabsorption, systemic sclerosis subtype, serological profile, medication) in the development of low bone mineral density. The relationship between low bone density in systemic sclerosis patients and the above mentioned risk factors may be more complex and the real role of each factor is unclear. Yet very few studies reported clinically relevant low bone mass outcomes such as fracture risk assessment and fracture associated mortality in scleroderma. This review aims to synthesize data about the essential role of vitamin D in immune homeostasis as well as the prevalence of hypovitaminosis, low bone density, changes in bone turnover markers and presence of osteoporosis in scleroderma patients. Orv Hetil. 2017; 158(32): 1252-1258.

[Application of immunomodulatory therapeutic antibodies - a new perspective in oncology]. / Immunmoduláló antitestek alkalmazása - az onkológia új fejezete.

In the past decade major advances in tumor immunology, a better understanding of antigen recognition by T-cells likewise discovering the regulatory inhibitory signals resulted in the development of new immunotherapies with promising durable responses in various solid tumor types and in hematologic malignancies. This review focuses on immunomodulatory antibodies, namely immune checkpoint inhibitor therapy. The prototype of this new class of immune stimulating agents was cytotoxic T-lymphocyte antigen-4 (CTLA-4) antagonists. After demonstrating enhanced survival, ipilimumab was approved first in the United States in 2011, further on in the European Union for second-line (2011) and for first-line therapy (2013) of metastatic melanoma. Additional T-cell intrinsic pathways were identified and targeted for clinical development. Antibodies blocking the PD-1 pathway also showed promising clinical activity and objective tumor response in several types of tumors, including metastatic melanoma, non-small- cell lung cancer. On the other hand antitumor activity is frequently accompanied by significant reversible immune-related adverse events. To explore potential new immune checkpoint targets bring forth several challanges. Future clinical development will involve identifying potential biomarkers anticipating responsiveness to pathway blockade and additional tumor types likely to respond to the therapy. Furthermore, combination strategies, immune checkpoint inhibitors combined with cancer vaccines, targeted inhibitors and traditional chemotherapies are being evaluated in pre-clinical studies. Orv. Hetil., 2016, 157(Suppl. 2), 9-16.

Can we define difficult-to-treat systemic sclerosis?

INTRODUCTION: Systemic sclerosis (SSc) is a chronic autoimmune rheumatic disease characterized by microvascular alterations, immunopathology, and widespread fibrosis involving various organs. It is considered difficult to treat due to several reasons: complex pathogenesis, heterogeneity, late diagnosis, limited treatment options for certain organ manifestations, lack of personalized medicine. AREAS COVERED: This review presents the heterogeneity, survival and organ manifestations with their risk factors of systemic sclerosis and their current treatment options, while drawing attention to difficult-to-treat forms of the disease, based on literature indexed in PubMed. EXPERT OPINION: Despite recent advances in the management of SSc over the last decades, the disease presents significant morbidity and mortality. Although available treatment protocols brought significant advancements in terms of survival in SSc-associated interstitial lung disease and pulmonary arterial hypertension, less success has been achieved in the treatment of Raynaud's phenomenon and digital ulcers and the results are modest in case of heart, gastrointestinal, and renal manifestations. There are patients who do not respond to treatment and deteriorate even with adequate therapy. They can be considered difficult-to treat (D2T) cases. We have created a possible score system based on the individual organ manifestations and highlighted treatment options for the D2T SSc category.

Granulomatosis with polyangiitis or its mimic? A case report.

Differentiation between granulomatosis with polyangiitis (GPA) limited to the upper airways and cocaine-induced midline destructive lesion (CIMDL) may be particularly difficult because of their common histopathologic features and antineutrophil cytoplasmic antibody (ANCA) profiles. We herein present a case involving a young woman with an initial diagnosis of GPA based on upper and lower airway manifestations and constitutional symptoms, histopathologic evidence of granulomas, a positive cytoplasmic ANCA indirect immunofluorescent test result, and proteinase 3 positivity by enzyme-linked immunosorbent assay (ELISA). CIMDL was confirmed based on the appearance of a hard palate perforation, positivity for methylecgonine on urine toxicology, a positive perinuclear ANCA indirect immunofluorescent test result, and subsequent human neutrophil elastase (HNE) ANCA positivity by ELISA. Finally, based on the coexistence of CIMDL, constitutional symptoms, and lower airway manifestations, the diagnosis was modified to cocaine-induced GPA mimic. Urine toxicology for cocaine and HNE ELISA are indicated in young patients with GPA who develop limited airway disease to check for the presence of CIMDL and cocaine-/levamisole-induced ANCA-associated vasculitis. Continued abstinence from cocaine is the first-choice therapy for both CIMDL and cocaine-induced GPA mimic.

Effectiveness and waning of protection with the BNT162b2 vaccine against the SARS-CoV-2 Delta variant in immunocompromised individuals.

Introduction: In Hungary, the HUN-VE 3 study determined the comparative effectiveness of various primary and booster vaccination strategies during the Delta COVID-19 wave. That study included more than 8 million 18-100-year-old individuals from the beginning of the pandemic. Immunocompromised (IC) individuals have increased risk for COVID-19 and disease course might be more severe in them. In this study, we wished to estimate the risk of SARS-CoV-2 infection and COVID-19 related death in IC individuals compared to healthy ones and the effectiveness of the BNT162b2 vaccine by reassessing HUN-VE 3 data. Patients and methods: Among the 8,087,988 individuals undergoing follow-up from the onset of the pandemic in the HUN-VE 3 cohort, we selected all the 263,116 patients with a diagnosis corresponding with IC and 6,128,518 controls from the second wave, before vaccinations started. The IC state was defined as two occurrences of corresponding ICD-10 codes in outpatient or inpatient claims data since 1 January, 2013. The control group included patients without chronic diseases. The data about vaccination, SARS-CoV-2 infection and COVID-19 related death were obtained from the National Public Health Center (NPHC) during the Delta wave. Cases of SARS-CoV-2 infection were reported on a daily basis using a centralized system via the National Public Health Center (NPHC). Results: Out of the 263,116 IC patients 12,055 patients (4.58%) and out of the 6,128,518 healthy controls 202,163 (3.30%) acquired SARS-CoV-2 infection. Altogether 436 IC patients and 2141 healthy controls died in relation to COVID-19. The crude incidence rate ratio (IRR) of SARS-CoV-2 infection was 1.40 (95%CI: 1.37-1.42) comparing IC patients to healthy controls. The crude mortality rate ratio was 4.75 (95%CI: 4.28-5.27). With respect to SARS-CoV-2 infection, interestingly, the BNT162b2 vaccine was more effective in IC patients compared to controls. Primary vaccine effectiveness (VE) was higher in IC patients compared to controls and the booster restored VE after waning. VE regarding COVID-19 related death was less in IC patients compared to healthy individuals. Booster vaccination increased VE against COVID-19-related death in both IC patients and healthy controls. Conclusion: There is increased risk of SARS-CoV-2 infection and COVID-19 related mortality in IC patient. Moreover, booster vaccination using BNT162b2 might restore impaired VE in these individuals.

Effect of tofacitinib therapy on angiotensin converting enzyme activity in rheumatoid arthritis.

Introduction: The Renin-Angiotensin-Aldosterone system (RAAS) has been implicated in the regulation of the cardiovascular system and linked to rheumatoid arthritis (RA). Little information has become available on the effects of Janus kinase (JAK) inhibition on RAAS. Here we studied the effects of 12-month tofacitinib treatment on angiotensin converting enzyme (ACE), ACE2 production and ACE/ACE2 ratios in RA along with numerous other biomarkers. Patients and methods: Thirty RA patients were treated with tofacitinib in this prospective study. Serum ACE concentrations were assessed by ELISA. ACE2 activity was determined by a specific quenched fluorescent substrate. ACE/ACE2 ratios were calculated. We also determined common carotid intima-media thickness (ccIMT), brachial artery flow-mediated vasodilation (FMD) and carotid-femoral pulse-wave velocity (cfPWV) by ultrasound. C-reactive protein (CRP), rheumatoid factor (RF) and anti-citrullinated protein autoantibodies (ACPA) were also determined. All measurements were performed at baseline, as well as after 6 and 12 months of tofacitinib treatment. Results: After the dropout of 4 patients, 26 completed the study. Tofacitinib treatment increased ACE levels after 6 and 12 months, while ACE2 activity only transiently increased at 6 months. The ACE/ACE2 ratio increased after 1 year of therapy (p < 0.05). Logistic regression analyses identified correlations between ACE, ACE2 or ACE/ACE2 ratios and RF at various time points. Baseline disease duration also correlated with erythrocyte sedimentation rate (ESR) (p < 0.05). One-year changes of ACE or ACE2 were determined by tofacitinib treatment plus ACPA or RF, respectively (p < 0.05). Conclusion: JAK inhibition increases serum ACE and ACE/ACE2 ratio in RA. Baseline inflammation (ESR), disease duration and ACPA, as well as RF levels at various time points can be coupled to the regulation of ACE/ACE2 ratio. The effect of tofacitinib on RAAS provides a plausible explanation for the cardiovascular effects of JAK inhibition in RA.

[Diagnostic value of 18F-FDG PET/CT in fever of unknown origin]. / A 18F-FDG-PET/CT helye az ismeretlen eredetu láz diagnosztikai algoritmusában.

Fever of unknown origin is a common differential diagnostic problem in medicine. More than 60 years have passed since the first established definition of the disease, and despite constant development and improvement of diagnostic procedures, the differential diagnosis and choosing adequate therapy still remains a challenge in this patient population. The medical literature lists at least 200 diseases that may manifest with fever of unknown origin, and it encompasses a wide clinical spectrum. This symptom is present in approximately 1.5-3% of hospitalized patients. In recent decades, not only the concept of fever of unknown origin has changed several times, but the recommended differential diagnostic procedures as well. Positron emission tomography is one of the latest imaging procedures that also contributes to establishing the correct diagnosis. The purpose of this publication is to provide an overview of different diseases which might cause fever of unknown origin, and the most frequently used diagnostic algorithms, moreover to highlight the importance of positron emission tomography in the evaluation of the aetiology of fever of unknown origin. Orv Hetil. 2022; 163(49): 1935-1942.