Association of inflammatory biomarkers and disease activity with subclinical myocardial dysfunction in psoriatic arthritis.

We examined the role of adipokines and pro-inflammatory cytokines in psoriatic arthritis-associated subclinical myocardial dysfunction, and the relationship between these variables and psoriatic arthritis (PsA) disease activity. Fifty-five PsA patients without cardiovascular risk factors and 25 controls underwent standard and speckle tracking echocardiography with global longitudinal strain (GLS) calculated. Standard anthropometric data and Disease Activity in Psoriatic arthritis (DAPSA) scores were recorded, with low disease activity defined as DAPSA ≤ 14 and moderate and high disease activity DAPSA > 14. Standard biochemical tests, adiponectin, resistin, leptin, tumor necrosis factor (TNF) alfa, interleukin 17 A (IL-17A), B lymphocyte chemoattractant (BLC), and monokine induced by intereferon gamma (MIG) were analyzed. Median age was 53.0 (46.0-61.0), median PsA duration 6.0 (4.0-13.0) years and median DAPSA score 25.5 (13.0-41.5). Lower GLS, tricuspid annular plane systolic excursion (TAPSE) and left ventricular ejection fraction (LVEF) were found in moderate and high PsA disease activity compared to low PsA disease activity and controls. PsA patients with GLS < 20 had higher body mass index (BMI), DAPSA score and uric acid levels, and lower adiponectin levels. Although patients with GLS < 20 had higher IL-17A levels, it was not statistically significant (P = 0.056). However, when we included healthy controls and analyzed differences based on a GLS cut-off of 20% in the entire population, the difference in IL-17A became statistically significant, 0.17 pg/mL (0.06-0.32) vs. 0.43 pg/mL (0.23-0.65), P = 0.017. The association between DAPSA score and GLS and IL-17 remained significant in multivariate analysis. Moreover, the association between GLS and IL-17 and adiponectin was significant after adjustment for age and BMI. Patients with moderate and high PsA disease activity have reduced myocardial function, lower adiponectin, and higher IL-17A levels.

Delphi-Based Consensus on Interstitial Lung Disease Screening in Patients with Connective Tissue Diseases (Croatian National-Based Study).

The aim of this study was to develop a Croatian Delphi-based expert consensus for screening interstitial lung disease (ILD) associated with connective tissue disease (CTD). A systematic literature review was conducted on risk factors for the development of ILD, prevalence and incidence of ILD, diagnostic and screening methods for ILD, and prognosis of ILD in idiopathic inflammatory myopathy (IIM), mixed connective tissue disease (MCTD), primary Sjögren's syndrome (pSS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc) were performed. Based on the evidence found, experts developed questionnaires for screening and monitoring ILD in each CTD, which were provided via an online survey. Following the electronic survey, two screening algorithms were developed based on the consensus opinions. The detection strategy for ILD included high-resolution computed tomography (HRCT) in addition to pulmonary function testing for IIM, MCTD, and SSc. and pulmonary function testing for newly diagnosed pSS, RA and SLE. However, in patients with identified risk factors for ILD HRCT, these tests should also be performed. A screening strategy for early identification of patients with various CTD-ILD was first developed by a multidisciplinary team of rheumatologists, pulmonologists, and radiologists to identify early CTD patients at risk of ILD, a severe extra-articular manifestation of CTD.

Association of HLA-DRB1 alleles with rheumatoid arthritis in Split-Dalmatia County in southern Croatia.

OBJECTIVE: The aim of this study was to investigate the distribution of HLA-DRB1 alleles in patients with rheumatoid arthritis (RA) in the Sinj Region (SR) and the rest of the Split-Dalmatia County (SDC) in Croatia and to determine their relationship with disease severity. METHODS: A total of 74 RA patients and 80 healthy controls from the SR, and 74 RA patients and 80 healthy controls from the rest of the SDC were genotyped using sequence-specific oligonucleotide primed PCR. High-resolution typing of HLA-DRB1*04 alleles was performed using the single specific primed polymerase chain reaction (PCR-SSP) method. Serum anti-CCP, rheumatoid factor, C­reactive protein, and erythrocyte sedimentation rate were measured in all RA patients, whereas disease activity was assessed by DAS-28 and functional status by the Health Assessment Questionnaire Disability Index. RESULTS: The HLA-DRB1*04 allele was more frequent in patients with RA from the SR than that in patients from the rest of the SDC (18.2% vs. 9.5%; P = 0.014), whereas the HLA-DRB1*15 allele was more frequent in patients with RA from the rest of the SDC than in patients from the SR (16.2% vs. 7.4%; P = 0.010). Shared epitope (SE) positive patients from the SR had significantly higher serum anti-CCP and RF antibody levels (P = 0.014 and P = 0.004, respectively), higher disease activity (P = 0.043), and worse functional status (P < 0.001), than SE-positive patients from the rest of the SDC. CONCLUSION: The observed higher incidence of more severe forms of RA in the SR in comparison to the rest of the SDC might be associated with the higher incidence of HLA-DRB1*04 allele in the SR.

The Levels of Serum Serotonin Can Be Related to Skin and Pulmonary Manifestations of Systemic Sclerosis.

Background and Objective: The most prominent feature of systemic sclerosis (SSc), besides vasculopathy and autoimmune disorders, is excessive fibrosis. Serotonin affects hemostasis and can induce vasoconstriction, which is presumed to be one of the pathophysiological patterns in SSc that leads to fibrosis. Our aim was to explore the possible association of serotonin with some of the clinical features of SSc in our cohort of patients. Materials and Methods: We measured serotonin levels in sera of 29 female SSc patients. Patients were 41-79 years old, their average disease duration was 9 years. Serotonin values were analyzed in correlation with clinical and laboratory parameters, such as modified Rodnan skin score (mRSS), digital ulcers (DU), and spirometry parameters-forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), and lung diffusion capacity of carbon monoxide (DLCO). Statistical analyses were performed using statistical software Statistica. Results: We found correlation of serotonin level with mRSS (r = 0.388, p = 0.038). The highest values of serotonin were documented in patients with refractory DU, but this was not statistically significant. We also found a negative correlation between serotonin and FVC (r = -0.397), although it did not reach the level of significance (p = 0.114). Conclusions: Our study suggests that levels of serum serotonin could affect the course of skin fibrosis and partially restrictive pulmonary dysfunction in patients with SSc. We assume that serotonin might have influence on several features of SSc, but more studies are needed to reveal those relations.

Haemoglobin A1c-based screening for prediabetes and diabetes mellitus: a multi-center study in Croatian adult population.

INTRODUCTION: Based on the hypothesis that there is a substantial rate of adults with prediabetes and undiagnosed diabetes mellitus (DM), our aim was to perform haemoglobin A1c (HbA1c)-based screening in a cohort of Croatian adults and estimate the prevalence of prediabetes and undiagnosed DM according to American Diabetes Association criteria. MATERIALS AND METHODS: This multi-center, cross-sectional study performed in six Croatian hospitals included 5527 patients aged 40 to 70 years admitted to the Emergency Department or undergoing a primary care check-up. Haemoglobin A1c was measured from leftover whole blood samples using the enzymatic method on either Alinity c or Architect c-series analyser (Abbott Laboratories, Chicago, USA). Haemoglobin A1c between 39-47 mmol/mol was classified as prediabetes, while ≥ 48 mmol/mol as undiagnosed DM. RESULTS: After exclusion of 435 patients with known DM, the final cohort included 5092 patients (median age 57; 56% males). A total of 882 (17.3%) patients had HbA1c values between 39 and 47 mmol/mol. There were 214 (4.2%) patients with HbA1c ≥ 48 mmol/mol. Prediabetes prevalence ranged from 14.2% to 20.5%, while undiagnosed DM from 3.3% to 7.3%, with statistically significant differences among settings (P < 0.001). Age-stratified analysis showed that prediabetes and undiagnosed DM prevalence increase with age (P < 0.001), being 25.4% and 5.8%, respectively, in patients aged 60 to 70 years. CONCLUSION: Underlying impairment of glucose metabolism was identified in about one in five adults, with significant number of patients with already overt DM. These results should serve as a starting point for further steps directed towards promotion of preventive measures for DM in Croatia.

Case of Acute Disseminated Encephalomyelitis Associated with Cytomegalovirus Reactivation in an Immunocompromised Systemic Lupus Erythematosus Patient.

We present a case of an immunocompromised systemic lupus erythematosus female patient admitted to our hospital for general impairment, monoparesis, and temporary cognitive disability. The case represented a significant diagnostic and therapeutic challenge primarily because of a wide range of differential diagnosis options (CNS lupus, ischemic cerebrovascular disease, viral meningoencephalitis, progressive multifocal leukoencephalopathy, limbic encephalitis, and acute disseminated encephalomyelitis-ADEM). Brain MRI findings were compatible with ADEM, and microbiological tests showed a cytomegalovirus infection (CMV) which is rarely associated with ADEM despite the increasing number of immunocompromised patients prone to symptomatic CMV reactivation. Our patient was treated with intravenous methylprednisolone, immunoglobulin (IVIG), along with antiviral therapy resulting in a favorable therapeutic effect. In conclusion, only a few described ADEM cases have been associated with CMV, and none of them, to the best of our knowledge, in an immunocompromised patient. In this case, a multidisciplinary approach and broad diagnostic considerations were decisive for successful treatment and outcome.

Compassionate mesenchymal stem cell treatment in a severe COVID-19 patient: a case report.

COVID-19 presentations range from cold-like symptoms to severe symptoms with the development of acute respiratory distress syndrome (ARDS). We report on a severe COVID-19 patient who was mechanically ventilated and who developed ARDS and bacterial infection. Because of rapid clinical deterioration and the exhaustion of other treatment options, the family and attending physicians requested a compassionate use of adult allogeneic bone marrow-derived mesenchymal stem cells (MSC) in addition to commonly used immunosuppressive, antiviral, and supportive therapy. The clinical course is discussed thoroughly, with a special emphasis on the safety and effect of MSC therapy. Compassionate MSC treatment, given in three rounds, affected ARDS regression. The patient was discharged from the intensive care unit after 31 days and from hospital after 49 days in a good general condition. MSC treatment was not associated with any side effects and was well tolerated in a three-week period; therefore, it should be studied in larger trials and considered for compassionate use.

Ultrasound-Verified Peripheral Arthritis in Patients with HLA-B*35 Positive Spondyloarthritis.

BACKGROUND: We aimed to investigate possible association between the HLA-B*35 allele and peripheral arthritis, tenosynovitis and enthesitis. METHODS: Ultrasound of peripheral joints and tendons was performed in 72 HLA-B*35 positive patients with preliminary diagnosis of undifferentiated axial form of spondyloarthitis and joint and tendon pain. Patients with other known types of axial and peripheral spondyloarthritis were excluded as well as patients with other known types of arthritis. RESULTS: Pathological changes were found in the joints of 33 (46%) patients and on the tendons in 13 (18%) patients. The most common ultrasound findings were joint effusion and synovial proliferation with positive power Doppler signal grade 1. The most common ultrasound finding in patients with painful tendons was tenosynovitis. A higher disease activity and an increased incidence of elevated CRP (≥5 mg/L) were more often observed in the group with positive ultrasound findings. CONCLUSION: In this study, we showed that the HLA-B*35 allele could be a potential risk factor for developing peripheral arthritis, but not for tenosynovits and enthesitis in patients with the undifferentiated axial form of spondyloarthritis. This result may influence the follow up of these patients, especially since it gives us an opportunity to consider the use of different types of DMARDs in the treatment of these patients.

Low dose intravenous immunoglobulin in addition to cyclophosphamide in systemic sclerosis : Single centre experience.

AIM: Systemic sclerosis (SSc) is a rare chronic disease characterized by pathologic collagen deposits in the skin and internal organs. Although it is considered to be an autoimmune disease, immunosuppressants have a limited effect on severe SSc. Intravenous immunoglobulins (IVIG) have shown favorable effects in patients with SSc by suppressing the action of profibrotic cytokines, so they could have additional effect on standard treatment such as cyclophosphamide (CYC). This article presents the immunomodulatory effect of low-dose IVIG in addition to CYC in the treatment of severe SSc in this center during the last 9 years. METHODS: This retrospective observational study analyzed the medical documentation of nine patients with SSc treated with low-dose IVIG (0.4 g/kg and month) together with intravenous CYC (600 mg/m2 and month). The therapeutic effect on lung and skin manifestations was assessed. RESULTS: Of the patients one had interstitial lung diseases (ILD), two had progressive skin diseases, and six had a combination of skin and lung involvement. The best results were achieved in skin changes, where complete healing of digital ulcers (DU) was recorded in every reported case. A decrease in the modified Rodnan skin score (mRSS) was noted in three patients and increased diffusion capacity of the lungs for carbon monoxide in another three patients. CONCLUSION: The results of the study suggest that IVIG may be an additional treatment option together with CYC for patients for whom other therapies have failed, but further studies on the exact role of IVIG in the treatment of severe SSc are required.

Differences in the prevalence and characteristics of metabolic syndrome in rheumatoid arthritis and osteoarthritis: a multicentric study.

The purpose of the study was to examine whether rheumatoid arthritis (RA) patients have higher prevalence of metabolic syndrome (MetS) than osteoarthritis (OA) patients in association with a higher level of chronic systemic inflammation in rheumatoid arthritis. A total of 583 RA and 344 OA outpatients were analyzed in this multicentric study. Metabolic syndrome was defined using the National Cholesterol Education Program Adult Treatment Panel III criteria. A 1.6-fold higher prevalence of MetS was found in patients with OA compared with the RA patients. Among the parameters of MetS, patients with OA had significantly higher levels of waist circumference, systolic blood pressure, fasting blood glucose and triglycerides, whereas HDL cholesterol and diastolic blood pressure values were similar in both groups of patients. Higher values of inflammatory markers [C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)] in MetS than in non-MetS patients and higher prevalence of MetS in patients with CRP level ≥5 mg/L in both RA and OA patients were found. In multivariate logistic regression analysis, significant predictors of MetS were type of arthritis (OA vs. RA; OR 2.5 [95 % CI 1.82-3.43]), age (OR 1.04 [95 % CI 1.03-1.06]) and ESR (OR 1.01; [95 % CI 1.00-1.01]). The significant association between OA and MetS was maintained in the regression model that controlled for body mass index (OR 1.87 [95 % CI 1.34-2.61]). The present analysis suggests that OA is associated with an increased risk of MetS, which may be due to a common underlying pathogenic mechanism.

Fulminant diffuse systemic sclerosis following aortic valve replacement.

We present a case of fulminant diffuse systemic sclerosis (dSSc) developed after the aortic valve replacement followed by fatal congestive heart failure within the 6 months from the initial symptoms. A 61-year-old male developed rapidly progressive diffuse systemic sclerosis following aortic valve replacement due to stenosis of bicuspid aortic valve. He presented with diarrhoea, weight loss, mialgia and arthralgia after cardiac surgery. Heart failure, due to myocardial fibrosis, was noted as a cause of death. We hypothesize that artificial materials like the ones used in mechanical valves or silicon materials in breast implants may induce fulminant course of pre-existing systemic sclerosis or create a new onset in predisposed individual.

Does tocilizumab contribute to elevation of rheumatoid factor and induction of paradoxical syaloadenitis in rheumatoid arthritis patients?

A 56-year-old woman, treated with tocilizumab (TCZ) for 8 months for severe rheumatoid arthritis (RA), was admitted to the hospital due to the swelling and tenderness of parotid glands. The patient was diagnosed with seropositive erosive RA in 1988, and treated with different disease modifying antirheumatic drugs (DMARDs) that were used together with a low dosage of glucocorticoides, followed by biologic therapy with infliximab and adalimumab which also proved to be inefficient. The patient had an excellent initial response on TCZ therapy. After 8 months, she was presented with an extreme enlargement of parotid glands. Bacterial, viral, and granulomatous diseases were excluded. A spectrum of autoantibodies including anti-Ro and anti-La showed normal values, expect for slightly elevated anti-cyclic citrullinated peptide (anti-CCP) and extreme elevation of the rheumatoid factor (RF) to 10,100 IU/ml. The biopsy of salivary glands was done and histological specimen showed limphoplasmocytic syaloadenitis. Tocilizumab therapy was stopped and the dosage of glucocorticoids and methotrexate (MTX) was raised. After 6 weeks, the patient was in better condition with slightly lower levels of RF (9,010 IU/ml). We hypothesise that in this patient, TCZ stimulated RF hyper production which can induce a paradoxical secondary syaloadenitis in RA.

[The proposal of the Croatian Society for Rheumatology for the treatment of adult rheumatoid arthritis patients with biologics, 2013]. / Prijedlog Hrvatskog reumatoloskog drustva HLZ-a za lijecenje reumatoidnog artritisa odraslih bolesnika bioloskim lijekovima, 2013.

Standardized approach to the patients with rheumatoid arthritis (RA) is one of the requirements of good clinical practice. Croatian Society for Rheumatology (HRD) of Croatian Medical Association (HLZ) updated the Proposed treatment of rheumatoid arthritis (RA) with biologic agents in line with recent findings in rheumatology for the last 3 years. By complying with the agreed standards of treatment we can avoid malpractice and irrational consumption, and to the most patients provide a greater chance for a favorable outcome.

[The proposal of Croatian Society for Rheumatology for anti-TNF-alpha therapy in adult patients with spondyloarthritides, 2013]. / Prijedlog hrvatskog reumatoloskog drustva HLZ-a za primjenu inhibitora TNF-alpha u odraslih bolesnika sa spondiloartritisima, 2013.

Croatian Society for Rheumatology of Croatian Medical Association updated the proposal for the application of TNF-alpha inhibitors in adult patients with spondyloartritides (SpA) in accordance with the new classification of SpA and european recommendations for the treatment of SpA with biologic agents. In this way a standardized method of diagnosis, targeted treatment, monitoring and evaluating outcomes are proposed.

Relationship between interleukin-6 and cardiac involvement in systemic sclerosis.

OBJECTIVES: To explore the relationship between IL-6 levels and echocardiographic abnormalities, and N-terminal probrain natriuretic peptide (NT-proBNP) levels in SSc patients and to correlate tested parameters with European Scleroderma Activity (EUSTAR) score. METHODS: This case-control study included 31 SSc patients with preserved left ventricular ejection fraction (LVEF) and 32 matched healthy controls. Serum IL-6 and NT-proBNP levels were measured and subjects were evaluated by conventional and pulsed-wave tissue Doppler echocardiography. RESULTS: The level of IL-6 was significantly increased in patients with SSc (3.2 vs 2.2 pg/ml, P < 0.001). SSc patients had significantly lower values of LV systolic (7.7 vs 9.25 cm/s, P < 0.001) and early diastolic (8.7 vs 10.3 cm/s, P = 0.014) myocardial velocities and higher E/e' (9.04 vs 7.37, P = 0.001) ratio, although there was no between-group difference according to LVEF (68% vs 65%, P = 0.248). On evaluating the right ventricle there was no significant between-group difference in systolic tricuspid annular velocity (13 vs 13.9 cm/s, P = 0.105), but the peak early diastolic velocity was significantly lower (11.7 vs 13.6, P = 0.044) and E/e' was significantly higher (4.3 vs 3.38, P = 0.008) in SSc patients. IL-6 level showed correlation with LV mean e' (r = -0.57, P = 0.001), E/e' (r = 0.55, P = 0.001) and NT-proBNP (r = 0.52, P = 0.003). EUSTAR score correlated with LV E/e' (r = 0.48, P = 0.006), mean e' (r = -0.67, P < 0.001), mean s' (r = -0.51, P = 0.004), NT-proBNP (r = 0.60, P < 0.001) and IL-6 (r = 0.79, P < 0.001). CONCLUSION: IL-6 level is increased in patients with SSc and significantly correlates with LV diastolic dysfunction, NT-proBNP and EUSTAR score. These results support the role of IL-6 in the development of cardiac disease in SSc patients.

Is the prevalence of arterial hypertension in rheumatoid arthritis and osteoarthritis associated with disease?

In this study, we compare the prevalence of arterial hypertension (HT) in rheumatoid arthritis (RA) and osteoarthritis (OA) patients, exposed to high- and low-grade chronic inflammation, respectively, to assess the possible association between chronic inflammation and HT. A total of consecutive 627 RA and 352 OA patients were enrolled in this multicentric study. HT was defined as a systolic blood pressure (BP) ≥ 140 and/or diastolic BP ≥ 90 mmHg or current use of any antihypertensive drug. Overweight/obesity was defined as body mass index (BMI) ≥ 25, and patients ≥65 years were considered elderly. The prevalence of HT was higher in the OA group than in the RA group [73.3 % (95 % CI, 68.4, 77.7) and 59.5 % (95 % CI, 55.6, 68.4) P < 0.001, respectively]. When the results were adjusted for age and BMI, the HT prevalence was similar in both groups [RA 59 % (95 % CI, 55.1, 63.8) OA 60 % (95 % CI, 58.4, 65.0)]. In both groups, the prevalence of HT was higher in the elderly and those who were overweight than in the younger patients and those with a BMI < 25. Overweight (BMI ≥ 25) and age ≥65 were independent predictors of HT in multivariate logistic regression model, which showed no association between HT and the disease (RA or OA). The results indicate a robust association of age and BMI with HT prevalence in both RA and OA. The difference in HT prevalence between RA and OA is due rather to age and BMI than to the features of the disease, putting into question specific association of HT with RA.

Are the anti-cyclic citrullinated peptide antibodies independent predictors of myocardial involvement in patients with active rheumatoid arthritis?

OBJECTIVES: The anti-CCP antibodies are specific serological markers of RA, especially the aggressive course of joint disease. It has been postulated that the chronic inflammatory state is underlain by cardiovascular (CV) disease and that a higher level of anti-CCP antibodies is implicated in CV risk. The aim of the study was to assess: (i) the possible impact of anti-CCP antibodies on left ventricular diastolic dysfunction; and (ii) the possible differences in the effects of DASs on diastolic dysfunction. METHODS: The study included 80 RA patients (70 females and 10 males) with no clinically evident CV disease, or concomitant diseases, and 80 matched healthy controls. Upon clinical and laboratory evaluation, all subjects underwent M-mode, two-dimensional and colour Doppler echocardiographic examination. RESULTS: Isovolumetric relaxation time (IVRT) prolongation as the first sign of diastolic dysfunction was present in 36.25% of RA patients and in 15% of control subjects. IVRT was found to correlate with anti-CCP antibody titre (r = 0.382, P = 0.002) and modified DAS including CRP [DAS-28-CRP(4v)] (r = 0.204, P = 0.039). On multivariate linear regression analysis, anti-CCP antibody titre showed significant correlation with IVRT, while the ratio of early and late transmitral wave (E/A ratio) independently correlated with age and DAS-28-CRP(4v). CONCLUSIONS: Anti-CCP antibody is an important marker, independently associated with impaired left ventricular relaxation and the DAS-28-CRP(4v) is a more sensitive predictor of cardiac involvement in the RA than the DAS-28 variant including the ESR.