Characteristics of Patients with Sarcoidosis with Emphasis on Acute vs. Chronic Forms-A Single Center Experience.

Sarcoidosis is a granulomatous disease of unknown etiology that can affect almost any organ. Although the acute form can have spontaneous regression, a certain number of patients can have a chronic form, which leads to an increase in mortality and a decrease in the quality of life. Considering that the risk factors are still unknown, we wanted to compare the characteristics of patients with acute and chronic forms of sarcoidosis in Serbia in order to determine significant differences between them with hopes of contributing to everyday clinical practice. A total of 2380 patients treated in our clinic were enrolled in this study. They were separated into the following two groups: 1126 patients with acute form and 1254 patients with chronic form. They were further compared by gender, smoking status, radiological status, exposition, biomarkers for sarcoidosis, organ involvement, and other comorbidities; the distribution of patients according to regions of Serbia was also noted. Statistical significance was found in radiological findings (p < 0.001), biomarkers (calcium in 24 h urine p < 0.001; chitotriosidase p = 0.001), and the affliction of organs (p < 0.001). The differences noted in this paper could help improve our understanding of this disease.

King's Sarcoidosis Questionnaire (KSQ) - Validation study in Serbian speaking population of sarcoidosis patients.

INTRODUCTION: Sarcoidosis is a multiorgan, multisystem chronic disease of unknown etiology and unpredictable course. Health status is reduced in sarcoidosis and assessing it is a difficult multitask effort due to many faces this disease might have. Recently, a new questionnaire for assessing health status in sarcoidosis was developed by a group of authors from England-King's Sarcoidosis Questionnaire (KSQ). The benefit of KSQ is the ability to develop the best care plan for the patient, as well as to differentiate the efficacy of the administered treatment. OBJECTIVE: The aim of this study was to validate the KSQ in Serbian speaking population of sarcoidosis patients. The test itself is a modular, multi-organ health status measure for patients with sarcoidosis for use in clinic and the evaluation of therapies. The correlation of KSQ with different clinical course of sarcoidosis (acute vs chronic disease) and with the clinical outcome status (COS) in sarcoidosis was also investigated. METHODS: A total of 159 biopsy positive sarcoidosis patients participated in this study. The average age of the participants was 49.67, majority was female (67.3%) and majority had only pulmonary form of sarcoidosis (71.7%). KSQ - new disease-specific health status instrument, was compared with 5 other already existing instruments already used and validated in sarcoidosis (Saint George Respiratory Questionnaire- SGRQ, Daily Activity List -DAL, Fatigue Assessment Scale- FAS, Medical Research Council dyspnea scale-MRC, Borg Dyspnea Scale and 15D as general questionnaire. RESULTS: KSQ has significant correlation with other quality of life questionnaires already used in sarcoidosis. Translated version of KSQ shows significant internal reliability, similar to the original KSQ. Serbian version of KSQ has significant correlation with different clinical course of sarcoidosis and with COS as well. The translated version of KSQ is reliable sarcoidosis specific instrument for assessing health status in these patients.

Serum High-Mobility Group Box 1 and Heme Oxygenase-1 as Biomarkers in COVID-19 Patients at Hospital Admission.

The careful monitoring of patients with mild/moderate COVID-19 is of particular importance because of the rapid progression of complications associated with COVID-19. For prognostic reasons and for the economic management of health care resources, additional biomarkers need to be identified, and their monitoring can conceivably be performed in the early stages of the disease. In this retrospective cross-sectional study, we found that serum concentrations of high-mobility group box 1 (HMGB1) and heme oxygenase-1 (HO-1), at the time of hospital admission, could be useful biomarkers for COVID-19 management. The study included 160 randomly selected recovered patients with mild to moderate COVID-19 on admission. Compared with healthy controls, serum HMGB1 and HO-1 levels increased by 487.6 pg/mL versus 43.1 pg/mL and 1497.7 pg/mL versus 756.1 pg/mL, respectively. Serum HO-1 correlated significantly with serum HMGB1, oxidative stress parameters (malondialdehyde (MDA), the phosphatidylcholine/lysophosphatidylcholine ratio (PC/LPC), the ratio of reduced and oxidative glutathione (GSH/GSSG)), and anti-inflammatory acute phase proteins (ferritin, haptoglobin). Increased heme catabolism/hemolysis were not detected. We hypothesize that the increase in HO-1 in the early phase of COVID-19 disease is likely to have a survival benefit by providing protection against oxidative stress and inflammation, whereas the level of HMGB1 increase reflects the activity of the innate immune system and represents levels within which the disease can be kept under control.

Genes and metabolic pathway of sarcoidosis: identification of key players and risk modifiers.

INTRODUCTION: Sarcoidosis is a rare multisystem granulomatous disease with unknown etiology. The interplay of vitamin D deficiency and genetic polymorphisms in genes coding for the proteins relevant for metabolism of vitamin D is an important, but unexplored area. The aim of this study was to investigate the association between single nucleotide polymorphisms (SNPs) in CYP2R1 (rs10741657), CYP27B1 (rs10877012), DBP (rs7041; rs4588), and VDR (rs2228570) genes and sarcoidosis, as well as the association between these SNPs and 25(OH)D levels in sarcoidosis patients. MATERIAL AND METHODS: For that purpose we genotyped 86 sarcoidosis patients and 50 healthy controls using the PCR-RFLP method. RESULTS: Subjects carrying the CC genotype of CYP27B1 rs10877012 have 10 times lower odds of suffering from sarcoidosis. Moreover, DBP rs4588 AA genotype was shown to be a susceptibility factor, where carriers of this genotype had eight times higher odds for developing sarcoidosis. In addition, the A allele of the DBP gene (rs4588) was associated with lower levels of 25(OH)D in sarcoidosis patients. CONCLUSIONS: These results suggest that patients with vitamin D deficiency should be regularly tested for genetic modifiers that are related to sarcoidosis in order to prevent development of serious forms of sarcoidosis.

Phenotypes of organ involvement in sarcoidosis.

Sarcoidosis is a highly variable, systemic granulomatous disease of hitherto unknown aetiology. The GenPhenReSa (Genotype-Phenotype Relationship in Sarcoidosis) project represents a European multicentre study to investigate the influence of genotype on disease phenotypes in sarcoidosis.The baseline phenotype module of GenPhenReSa comprised 2163 Caucasian patients with sarcoidosis who were phenotyped at 31 study centres according to a standardised protocol.From this module, we found that patients with acute onset were mainly female, young and of Scadding type I or II. Female patients showed a significantly higher frequency of eye and skin involvement, and complained more of fatigue. Based on multidimensional correspondence analysis and subsequent cluster analysis, patients could be clearly stratified into five distinct, yet undescribed, subgroups according to predominant organ involvement: 1) abdominal organ involvement, 2) ocular-cardiac-cutaneous-central nervous system disease involvement, 3) musculoskeletal-cutaneous involvement, 4) pulmonary and intrathoracic lymph node involvement, and 5) extrapulmonary involvement.These five new clinical phenotypes will be useful to recruit homogenous cohorts in future biomedical studies.

Utility of angiotensin-converting enzyme activity in aqueous humor in the diagnosis of ocular sarcoidosis.

PURPOSE: Many studies include elevated activity of angiotensin-converting enzyme (ACE) in serum in sarcoidosis and in ocular sarcoidosis as well, but there are only a few analyzing ACE activities in aqueous humor. The aim of this study is to illuminate the diagnostic value of ACE in aqueous humor in patients with ocular sarcoidosis. METHODS: We analyzed twenty patients with ocular sarcoidosis and 18 patients with nonocular involvement. All patients have biopsy-positive sarcoidosis of the lungs and/or mediastinal lymph nodes. Blood samples for ACE serum levels were obtained from all patients. Aqueous humor samples were taken by paracentesis with a 25-gauge needle in local anesthesia. With appropriate statistical tests, we compared ACE activity in serum and aqueous humor in patients with and without ocular sarcoidosis. RESULTS: The majority of our patients with ocular sarcoidosis were female (12/20), also in the group with systemic sarcoidosis and without ocular involvement (12/6). Mean age of the whole analyzed group of sarcoidosis patients was 45 ± 6 years. There is no statistically significant difference in ACE activity in serum between two groups of patients (with and without ocular sarcoidosis). There is statistically significant difference in ACE activity in aqueous humor among patients with ocular and nonocular sarcoidosis. ACE activity in aqueous humor is significantly higher in patients with ocular sarcoidosis. CONCLUSION: Increased ACE activity in aqueous humor can point to a diagnosis of ocular sarcoidosis, without the need for ocular biopsy.

Clinical Features of Ocular Sarcoidosis in Patients with Biopsy-proven Pulmonary Sarcoidosis in Serbia.

PURPOSE: To analyze clinical characteristics of ocular sarcoidosis in a group of biopsy-proven sarcoid patients treated at the single referral center for sarcoidosis in Serbia. METHODS: A prospective study carried out on 88 biopsy-proven sarcoid patients between January 2012 and December 2014. All patients underwent complete ophthalmological examination. RESULTS: Ocular sarcoidosis was present in 32 patients (36.4% of all) and included: eyelid skin lesions (2.3%); orbital inflammation (2.3%); conjunctival lesions (7.9%); anterior uveitis (2.3%); intermediate uveitis (1.1%); posterior uveitis (15.9%); panuveitis (5.7%), and neuro-ophthalmologic manifestations (9.1%). Complications included cataract (20.4%); glaucoma (5.7%); cystoid macular edema (3.4%); epiretinal membrane formation (4.5%); macular atrophy (2.3%); and choroidal neovascularization (1.1%). Binocular visual impairment was present in one patient (1.1%), due to complications of posterior uveitis (macular scars). CONCLUSIONS: Patients in Serbia demonstrated ocular sarcoidosis as the first most common site of extrapulmonary sarcoid manifestations, with more often neuro-ophthalmologic lesions than in other European populations.

Administering the Sarcoidosis Health Questionnaire to sarcoidosis patients in Serbia.

OBJECTIVE: The aim of this study was to use a Serbian-language version of the disease-specific, self-report Sarcoidosis Health Questionnaire (SHQ), which was designed and originally validated in the United States, to assess health status in sarcoidosis patients in Serbia, as well as validating the instrument for use in the country. METHODS: This was a cross-sectional study of 346 patients with biopsy-confirmed sarcoidosis. To evaluate the health status of the patients, we used the SHQ, which was translated into Serbian for the purposes of this study. We compared SHQ scores by patient gender and age, as well as by disease duration and treatment. Lower SHQ scores indicate poorer health status. RESULTS: The SHQ scores demonstrated differences in health status among subgroups of the sarcoidosis patients evaluated. Health status was found to be significantly poorer among female patients and older patients, as well as among those with chronic sarcoidosis or extrapulmonary manifestations of the disease. Monotherapy with methotrexate was found to be associated with better health status than was monotherapy with prednisone or combination therapy with prednisone and methotrexate. CONCLUSIONS: The SHQ is a reliable, disease-specific, self-report instrument. Although originally designed for use in the United States, the SHQ could be a useful tool for the assessment of health status in various non-English-speaking populations of sarcoidosis patients.

Verifying Sarcoidosis Activity: Chitotriosidase versus ACE in Sarcoidosis - a Case-control Study.

BACKGROUND: Until now, a proper biomarker(s) to evaluate sarcoidosis activity has not been recognized. The aims of this study were to evaluate the sensitivity and specificity of the two biomarkers of sarcoidosis activity already in use (serum angiotensin converting enzyme - ACE and serum chitotriosidase) in a population of 430 sarcoidosis patients. The activities of these markers were also analyzed in a group of 264 healthy controls. METHODS: Four hundred and thirty biopsy positive sarcoidosis patients were divided into groups with active and inactive disease, and groups with acute or chronic disease. In a subgroup of 55 sarcoidosis patients, activity was also assessed by F-18 fluorodeoxyglucose positron emission tomography (18F-FDG-PET) scanning. Both serum chitotriosidase and ACE levels showed non-normal distribution, so nonparametric tests were used in statistical analysis. RESULTS: Serum chitotriosidase activities were almost 6 times higher in patients with active sarcoidosis than in healthy controls and inactive disease. A serum chitotriosidase value of 100 nmol/mL/h had the sensitivity of .5% and specificity of 70.0%. A serum ACE activity cutoff value of 32.0 U/L had the sensitivity of 66.0% and the specificity of 54%. A statistically significant correlation was obtained between the focal granulomatous activity detected on 18F-FDG PET/CT and serum chitotriosidase levels, but no such correlation was found with ACE. The levels of serum chitotriosidase activity significantly correlated with the disease duration (P < 0.0001). Also, serum chitotriosidase significantly correlated with clinical outcome status (COS) categories (ρ =0.272, P =0.001). CONCLUSIONS: Serum chitotriosidase proved to be a reliable biomarker of sarcoidosis activity and disease chronicity.

Neurosarcoidosis: two case reports with multiple cranial nerve involvement and review of the literature.

BACKGROUND: Involvement of the central nervous system is registered in a relatively small number of patients with sarcoidosis. In this article we present two cases with various neurological symptoms that fulfill criteria for neurosarcoidosis (NS). In addition, we review the literature on NS with special attention to isolated cranial nerve involvement. METHODS AND RESULTS: First patient: Neurological examination identified multiple cranial neuropathy, moderate right-sided hemiparesis, polyradiculoneuritis of the lower limbs and positive meningeal signs. Laboratory tests showed serum and cerebrospinal fluid (CSF) inflammatory abnormalities, with increased values of the angiotensin-converting enzyme (ACE). CSF analysis also showed presence of 9 oligoclonal IgG bands. Brain and spine magnetic resonance imaging (MRI) revealed diffuse meningopathy, and focal granulomatous lesion in the body of the L5 vertebra. Lung sarcoidosis was confirmed by additional diagnostic procedures. The patient was treated with Methylprednisolone and a tapering course of oral Prednisone, which reduced the pain in the back and legs and improved the strength of the right leg. However, the other neurological deficiencies remained. After confirming lung sarcoidosis, the patient received Methotrexate in addition to Prednisone but during the following 2 years the patient's condition progressively worsened and ended in death. Second patient: Neurological findings showed weakness of the right n. oculomotorius and the right n. trochlearis, as well as the right-side face weakness. We found raised level of the ACE in serum and CSF. Thorax high-definition computed tomography (HDCTT) showed ribbon-like domains of discrete changes in the pulmonary parenchyma. MRI of the brain showed multiple white matter lesions. This patient also received Methylprednisolone followed by Prednisone, and after two months, ocular motility normalized. CONCLUSION: The diagnosis of NS is always a challenge. For this rerason definitive diagnosis requires the exclusion of other causes of neuropathy. Multiple cranial neuropathies should always arouse suspicion of NS.

Hormones of thyroid gland in sera of rats treated with different dose of concentrated potassium iodine solutions.

INTRODUCTION: Potassium iodine (KI) is used as a drug therapy for treating numerous diseases such as small-vessel vasculitis, erythema nodosum, vasculitis nodularis, Sweet's syndrome, tuberculosis and granulomatosis, and for iodized salt. At the same time, KI can be harmful. Iodine intake may increase the frequency of thyroiditis in humans, and may induce the occurrence of experimental thyroiditis (ET) in animals. Investigations on an experimental model for the examination of thyroiditis in Wistar rats have clearly showed morphological changes in the rat thyroid evoked by KI administration. OBJECTIVE: The purpose of this study was to compare the effects of low and high doses of KI on the thyroid gland of Wistar rats and determine the effect on hormone status (T4, T3 and TSH) in this rat strain. METHODS: Two groups of rats from the Wistar strain were treated with a low iodine dose (225 microg/g BW) and with a high iodine dose (675 microg/g BW) of KI solutions. Untreated nonimmunized animals served as controls. The solution was administrated daily intraperitoneally during the period of 26 consecutive days. RESULTS: Monitoring hormone status (TSH, T3 and T4) and morphological changes it was found that therapeutic doses of KI applied in treatment induced the occurrence of experimental thyroiditis (chronic destructive Hashimoto's thyroiditis in humans) and cell necrosis in animals not carrying a genetic susceptibility. Significant inflammatory changes were observed in rats treated with a high iodine dose. CONCLUSION: The early iodine induced cell necrosis and inflammation in the nonimmunized animals without genetic susceptibility is a new experimental model of thyroiditis.

Differences in symptom severity and health status impairment between patients with pulmonary and pulmonary plus extrapulmonary sarcoidosis.

BACKGROUND: Although sarcoidosis most commonly affects the lungs, it is a multisystemic disease that often involves other organs. In this study, we compared fatigue, dyspnea, and the impact upon the activities of daily living and health status scores between patients with isolated pulmonary and pulmonary plus extrapulmonary sarcoidosis. METHODS: In this cross-sectional study, we investigated 81 biopsy proven sarcoidosis patients. Fatigue was assessed by the standardized Fatigue Scale (FS). Dyspnea was determined by the Baseline Dyspnea Index (BDI) and the Modified Medical Research Council (MRC) Dyspnea Scale. Activities of daily living were assessed with the List of Daily Activities (DAL). Health status was measured by two standardized questionnaires: a generic measure--fifteen-dimensional measure of health-related quality of life (15D), and a respiratory-specific measure--St George's Respiratory Questionnaire (SGRQ). Patients were excluded if they had an associated illness that could influence their health status. RESULTS: Statistically significant differences were demonstrated between the isolated pulmonary group and the pulmonary plus extrapulmonary group for fatigue (FS-total score: 2.4+/-0.64 vs. 2.8+/-0.62, p=0.007), dyspnea (BDI: 8.45+/-2.44 vs. 5.92+/-1.84, p<0.001; there was no statistically significant difference in MRC), activities of daily living (DAL: 4.33+/-2.93 vs. 5.87+/-2.40, p=0.014), and health status (SGRQ-total score: 33.07+/-22.81 vs. 43.69+/-21.55, p=0.04). CONCLUSION: There are significant and clinically relevant differences in the severity of symptoms, restrictions of activities of daily living and impairment of health status between the patients with isolated pulmonary and pulmonary plus extrapulmonary sarcoidosis. Patients with pulmonary plus extrapulmonary sarcoidosis are more impaired in all these categories.

Pulmonary sarcoidosis.

Sarcoidosis is an inflammatory granulomatous disease that is characterized by diverse organ system manifestations, a variable clinical course, and a predilection for affecting relatively young adults worldwide. Abnormalities on chest radiographs are detected in 85% to 95% of patients who have sarcoidosis. Approximately 20% to 50% of patients who have sarcoidosis present with respiratory symptoms, including dyspnea, cough, chest pain, and tightness of the chest. The clinical course and manifestations of pulmonary sarcoidosis are protean: spontaneous remission occurs in approximately two thirds of patients; up to 30% of patients have chronic course of the lung disease, resulting in progressive, (sometimes life-threatening) loss of lung function. Morbidity that correlates to sarcoidosis occurs in 1% to 4% of patients.

[Chronic sarcoidosis].

INTRODUCTION: According to available literature data, chronic pulmonary and extrapulmonary sarcoidosis occurs in 10-30% of all sarcoidosis patients. Unpredictable course of the disease is a great challenge for scientists and researchers. Clinical and biological parameters for evaluation and prediction of the course of the disease are still the topic of different scientific investigations all over the world. According to an American case control study on sarcoidosis, unique diagnostic criteria have been established in order to simplify the diagnosis of sarcoidosis. The aim of this study was to present the morbidity and the clinical course of sarcoidosis in our patients. MATERIALS AND METHODS: We analyzed 370 sarcoidosis patients and confirmed the diagnosis of sarcoidosis by biopsy of the suspected granuloma, and by excluding any other possible cause of granulomatous inflammation. In our analyzed patients with sarcoidosis, chronic form was diagnosed in about 30%. An extremly unpredictable, chronic form of the disease was established in patients with extrapulmonary localisations (heart, CNS, liver and bones). CONCLUSION: Follow-up criteria and control examinations of sarcoidosis patients are suggested as well.

[Application of measuring instruments--quality of life questionnaires in patients with chronic sarcoidosis].

INTRODUCTION: Health-related quality of life in interstitial lung diseases, especially in sarcoidosis, has hardly received appropriate attention in clinical studies due to lack of validated methods of measurement. Until now, in patients with sarcoidosis and interstitial lung diseases, several generic and respiratory specific quality-of-life instruments were used in order to discover the most valid and reliable quality-of-life instrument. Sarcoidosis is a multi-system disease that affects quality of life in many different ways. MATERIAL AND METHODS: In this study the Sarcoidosis Health Questionnaire was used to evaluate the quality of life in sarcoidosis patients. 89 biopsy positive sarcoidosis patients were analyzed (16 male, 73 female); their mean age 46.15 +/- 11.11 years. 34 (39%) patients presented with acute sarcoidosis, 53 (61%) with chronic sarcoidosis and 46 patients (51.7%) had extrapulmonary disease. In regard to treatment, 51 (57%) patients were treated with corticosteroids 18 (20%) with methotrexate and in 20 (23%) spontaneous remission was reported. All analyses were performed using the Statistical Package for Social Science Software: A probability value less than 0.01 considered being statistically significant. RESULTS: Statistically significant correlation was found between the sarcoidosis health questionnaire scores and chronic sarcoidosis. daily 0.001, emotional 0.014 and total 0.01. In regard to treatment, significant difference between groups was found in the domain of physical (sig 0.006) emotional (sign 0.005) and total (sign 0.001) scores. CONCLUSION: The first sarcoidosis specific questionnaire shows perfect correlation with the possible clinical course in patients with sarcoidosis.