Impact of disease activity on impaired glucose metabolism in patients with rheumatoid arthritis.

OBJECTIVE: To explore glucose metabolism in rheumatoid arthritis (RA) and its association with insulin resistance (IR) risk factors and disease activity indicators, including matrix metalloproteinase-3 (MMP3). METHODS: This single-center study included 127 non-diabetic subjects: 90 RA patients and 37 matched controls. IR-related risk factors, disease activity (DAS28-ESR/CRP), concentrations of inflammation markers, MMP3, glucose, specific insulin, and C-peptide (a marker of ß-cell secretion) were determined. Homeostasis Model Assessment was used to establish insulin resistance (HOMA2-IR) and sensitivity (HOMA2-%S). Associations of HOMA2 indices with IR-related risk factors, inflammation markers, and RA activity were tested using multiple regression analyses. RESULTS: RA patients had significantly increased HOMA2-IR index than controls. In the RA group, multivariate analysis revealed DAS28-ESR, DAS28-CRP, tender joint counts, patient's global assessment, and MMP3 level as significant positive predictors for HOMA2-IR (ß = 0.206, P = 0.014; ß = 0.192, P = 0.009; ß = 0.121, P = 0.005; ß = 0.148, P = 0.007; ß = 0.075, P = 0.025, respectively), and reciprocal negative for HOMA2-%S index. According to the value of the coefficient of determination (R2), DAS28-ESR ≥ 5.1 has the largest proportion of variation in both HOMA2-IR indices. DAS28-ESR ≥ 5.1 and ESR were independent predictors for increased C-peptide concentration (ß = 0.090, P = 0.022; ß = 0.133, P = 0.022). Despite comparability regarding all IR-related risk factors, patients with DAS28-ESR ≥ 5.1 had higher HOMA2-IR than controls [1.7 (1.2-2.5) vs. 1.2 (0.8-1.4), P = 0.000]. There was no difference between patients with DAS28-ESR < 5.1 and controls [1.3 (0.9-1.9) vs. 1.2 (0.8-1.4), P = 0.375]. CONCLUSIONS: RA activity is an independent risk factor for impaired glucose metabolism. DAS28-ESR ≥ 5.1 was the main contributor to this metabolic disturbance, followed by MMP3 concentration, outweighing the impact of classic IR-related risk factors.

Subclinical Atherosclerosis in Patients with Rheumatoid Arthritis and Low Cardiovascular Risk: The Role of von Willebrand Factor Activity.

BACKGROUND: To evaluate association between von Willebrand factor (vWF) activity, inflammation markers, disease activity, and subclinical atherosclerosis in patients with rheumatoid arthritis (RA) and low cardiovascular risk. METHODS: Above mentioned parameters were determined in blood samples of 74 non-diabetic, normotensive, female subjects, with no dyslipidemia(42 patients, 32 matched healthy controls, age 45.3±10.0 vs. 45.2±9.8 years). Intima-media thickness (IMT) was measured bilaterally, at common carotid, bifurcation, and internal carotid arteries. Subclinical atherosclerosis was defined as IMT>IMTmean+2SD in controlsat each carotid level and atherosclerotic plaque as IMT>1.5 mm. Majority of RA patients were on methotrexate (83.3%), none on steroids >10 mg/day or biologic drugs. All findings were analysed in the entire study population and in RA group separately. RESULTS: RA patients with subclinical atherosclerosis had higher vWF activity than those without (133.5±69.3% vs. 95.3±36.8%, p<0.05). Predictive value of vWF activity for subclinical atherosclerosis was confirmed by logistic regression. vWF activity correlated significantly with erythrocyte sedimentation rate, fibrinogen, modified disease activity scores (mDAS28-ESR, mDAS28-CRP), modified Health Assessment Questionnaire (p<0.01 for all), duration of smoking, number of cigarettes/day, rheumatoid factor concentration (p<0.05 for all), and anti-CCP antibodies (p<0.01). In the entire study population, vWF activity was higher in participants with subclinical atherosclerosis (130±68% vs. 97±38%, p<0.05) or atherosclerotic plaques (123±57% vs. 99±45%, p<0.05) than in those without. Duration of smoking was significantly associated with vWF activity (ß 0.026, p = 0.039). CONCLUSIONS: We demonstrated association of vWF activity and subclinical atherosclerosis in low-risk RA patients as well as its correlation with inflammation markers, all parameters of disease activity, and seropositivity. Therefore, vWF might be a valuable marker of early atherosclerosis in RA patients.

Evaluation of diagnostic parameters from parotid and submandibular dynamic salivary glands scintigraphy and unstimulated sialometry in Sjögren's syndrome.

Our aim was to validate eight scintigraphic salivary gland (SG) parameters, as diagnostic parameters in patients with Sjögren's syndrome (SS). We used the standardized stimulated dynamic salivary gland scintigraphy (DSGS) protocol and correlated this with the unstimulated whole sialometry (UWS) functions. The DSGS and UWS tests meeting the European and the USA diagnostic classification criteria for SS were applied in twenty patients and in ten normal controls. The DSGS tests were performed 60min after the intravenous (i.v.) injection of 370MBq of technetium-99m-pertechnetate ((99m)TcO(-)4) and after per os stimulation with a 0.5g tablet of ascorbic acid administered 40min after the injection. Using time-activity curves, eight different parameters were calculated for each parotid gland (PG) and each submandibular salivary gland (SMG): a) time at maximum counts (Tmax), b) time at minimum counts (Tmin), c) maximum accumulation (MA), d) accumulation velocity (AV), e) maximum secretion (MS), f) maximum stimulated secretion (MSS), g) stimulated secretion velocity (SSV), and h) uptake ratio (UR). Values of UWS below 2.5mL/15min, were considered abnormal. All these parameters, as for the PG, showed significant abnormality in SS patients (P<0.001), especially of the secretion function. All SMG parameters also showed a significant abnormality (P<0.001), but especially of the accumulation function. There was a greater impairment of the above parameters in SMG than in PG in the SS patients. Sensitivity of the standardized DSGS was 100%, specificity 80%, negative prognostic value 100%, and positive prognostic value 91%. Sensitivity of UWS was 75%. In conclusion, this paper suggested that the best diagnostic parameters for the SS patients were those of: a) the maximum secretion, b) the maximum stimulated secretion for both the parotid and the submandibular glands, c) maximum accumulation and d) accumulation velocity of submandibular glands. The times at maximum and at minimum counts were non diagnostic.

Small cell neuroendocrine tumor of the larynx--a small case series.

Neuroendocrine tumors are the most common nonsquamous types of laryngeal neoplasms. They are classified as typical carcinoids, atypical carcinoids, small-cell neuroendocrine carcinomas, and paragangliomas. The aim of the paper is to present four patients with small-cell neuroendocrine tumor arising in larynx. There were one woman and three men whose ages were 47-77 years; all of them had metastases when first seen. The clinical presentation and management of such type of tumor are discussed. Small-cell neuroendocrine carcinomas are very aggressive neoplasms. Patients could benefit from surgery, but radiotherapy and chemotherapy remain the treatment of choice. Examination of a large series is required to define the most useful diagnostic methods and the most successful treatment modalities.

Rheumatoid arthritis is an independent risk factor for increased carotid intima-media thickness: impact of anti-inflammatory treatment.

OBJECTIVES: To evaluate the extent of subclinical atherosclerosis in patients with RA and low cardiovascular risk by measuring intima-media thickness (IMT) of the carotid arteries and to determine factors associated with increased IMT. METHODS: IMT was measured by ultrasonography in 42 non-diabetic, normotensive, female RA patients and 32 matched healthy controls [age 45.3 (10.0) vs 45.2 (9.8) years] at common carotid arteries (CCAs), carotid bifurcation (BF) and internal carotid arteries (ICAs), bilaterally. Mean and maximal (max) IMTs were calculated from three measurements at each site. Clinical work-up included laboratory analyses, determination of the disease activity and evaluation of treatment. RESULTS: RA patients had increased IMT (mm) in comparison with controls [CCA(max): 0.764 (0.148) vs 0.703 (0.100); CCA(mean): 0.671 (0.119) vs 0.621 (0.085); BF(max): 1.055 (0.184) vs 0.941 (0.161); BF(mean): 0.889 (0.168) vs 0.804 (0.124); ICA(max): 0.683 (0.108) vs 0.613 (0.093); ICA(mean): 0.577 (0.101) vs 0.535 (0.076)]. Parameters associated with IMT in RA patients were (correlation at x/6 measurement sites): age (6/6), BMI (2/6), smoking (2/6), RF concentration (2/6), sedimentation rate (1/6) and duration of MTX + chloroquine therapy (4/6; inverse correlation). Multivariate regression analysis revealed that RA is an independent risk factor for increased IMT. Factors correlating with IMT in the controls were: age (6/6), BMI (3/6), total cholesterol (5/6), low-density lipoprotein cholesterol (3/6), total/high-density lipoprotein cholesterol (2/6), triglycerides (1/6) and glycaemia (4/6). CONCLUSION: Despite a favourable risk profile, our female RA patients had significantly enlarged carotid IMT than controls. RA itself was an independent risk factor for increased IMT. Impact of chronic inflammation on atherosclerosis was confirmed by negative correlation of IMT and duration of anti-inflammatory treatment.

[Recommendations for tuberculosis screening before and during treatment with tumour necrosis factor inhibitors].

Patients with an autoimmune disease, such as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn's disease, ulcerative colitis, uveitis or psoriasis, and treated with the anti-tumour necrosis factor (TNF) alpha inhibitors are at high risk of developing various infections including tuberculosis (TB). Serious infections are the result of the patients' immunocompromised status that is caused by the primary disease itself, as well as by previous immunosuppressive therapy. In order to decrease the risk of developing TB, prior to the introduction of the anti-TNF alpha therapy, all patients should undergo screening for TB. Experiences from the countries that have already implemented recommendations for TB screening show a significant decrease in TB occurrence in the anti-TNF alpha treated patients. The PPD skin test result is considered positive if in duration is of size > or =5 mm. The BCG vaccine applied at birth has no effect on interpretation of PPD test results in adults. The diagnosis of active TB is contraindicated for the introduction of the anti-TNF alpha therapy; first, such patients should receive the TB treatment; and 6 months after the completion of the TB treatment, the introduction of the anti-TNF alpha therapy may be considered. The patients with the diagnosis of the latent TB infection (LTBI) should not immediately start with the anti-TNF alpha therapy, but they should first receive the TB chemoprophylaxis; not earlier than a month upon the introduction of the TB chemoprophylaxis, the anti-TNF alpha therapy may be introduced. The first TB follow-up screening during the anti-TNF alpha therapy is recommended 6 months after the anti-TNF alpha therapy has been introduced and the next one should be scheduled after 12 months.

[Diagnostic validity of dynamic salivary gland scintigraphy with ascorbic acid stimulation in patients with Sjögren's syndrome: comparation with unstimulated whole sialometry].

BACKGROUND/AIM: Beside many actual groups of classification criteria, uniform classification criteria for Sjögren's syndrome (SS) are still missing. The ophtalmic component of SS is well defined. Criteria for classifying its oral component remain controversial. The fifth item of the European Union and the United States of America (EU-US) revised diagnostic classification criteria in 2002, is an objective evidence of xerostomia, diagnosed by one of the tests: unstimulated whole sialometry (UWS), parotid sialography, and dynamic salivary gland scintigraphy (DSGS). The aim of this study was to evaluate senstitivity, specificity, positive and negative predictive value and accuracy of DSGS with ascorbic acid stimulation in detecting xerostomia in SS patients and to compare DSGS findings with UWS values. METHODS: Tests DSGS and UWS were done in 20 patients with SS and in 10 of the control subjects. The findings of DSGS were graded from 1 to 4 scintigraphie (SCT) grade 1--normal finding; SCT grade 2--moderate function damage; SCT grade 3--serious function damage, SCT grade 4--very serious function damage. UWS measured 1.5 hour after the breakfast lasted 15 minutes. UWS bellow 2.5 ml/15min min. considered pathological. RESULTS: All SS patients had pathological SCT findings. Comparing SCT grade between the patients and the control group, high statistical significance was found (p < 0.001). The estimated sensitivity of DSGS was 100%, specificity 80%, positive predictive value 91%, negative predictive value 100% and accuracy 93%. The calculated sensitivity of UWS was 75%. Salivary function damage detected by scintigraphy was in positive correlation with UWS findings. CONCLUSION: DSGS is a diagnostic test with high sensitivity, specificity, accuracy and positive and negative predictive values in detecting salivary function damage in SS patients. DSGS and UWS are very sensitive diagnostic tests for objective evidence of xerostomia, and have to be ones of the earliest investigations which shoud be performed in subjects suspected of SS. Test DSGS is more sensitive, and seems to better reflect symptoms of dry mouth than UWS.

Low bone mineral density and high bone metabolism turnover in premenopausal women with unipolar depression.

INTRODUCTION AND HYPOTHESIS: The majority of studies reporting decreased bone mineral density (BMD) in patients with unipolar depression neglected sex and age differences and menopause as the most important risk factor for osteoporosis. We presumed that physically healthy premenopausal women with unipolar depression have decreased BMD and altered bone cell metabolism. METHODS: BMD at lumbar spine and femoral neck by dual X-ray absorptiometry, bone alkaline phosphatase sera activity, 5b-tartarate resistant acid phosphatase sera activity and urine N-terminal telopeptide were measured in 73 premenopausal women with unipolar depression and compared with 47 healthy, age- and osteoporosis risk factors-matched premenopausal women. The duration and severity of depression, hormonal status (cortisol, prolactin, parathormone, oestradiol), antidepressive treatment, and physical activity through whole and modified QUALEFFO-41 questionnaire were evaluated. The results were statistically elaborated by the chi-square test, Student's t-test for independent samples, one-way analysis of variance - ANOVA, one-sample Kolmogorov-Smirnov test. Correlations were assessed by means of Pearson's coefficient. RESULTS: Patients with unipolar depression had significantly lower BMD, the decrease of which correlated only with the duration of depression. High bone metabolism turnover was found with a predomination of osteoresorption which, but not osteosynthesis, correlated with the severity of depression, estimated through Hamilton depression scores. Despite higher but not significant levels of cortisol in women with unipolar depression, the BMD decrease and high bone turnover seem not to be the consequence of hormonal changes or medical treatment. The significant correlations between physical activity and osteoresorption markers were found indicating possible underlying mechanism. CONCLUSIONS: Premenopausal women with unipolar depression have significantly lower BMD because of stimulated bone cell metabolism with predomination of osteoresorption process, mostly due to decreased physical activity in depression. These women should be investigated for osteoporosis and the multidisciplinary team approach is advocated.

[Distal renal tubular acidosis as a cause of osteomalacia in a patient with primary Sjögren's syndrome].

BACKGROUND: One half of the patients with primary Sjögren's syndrome has extraglandular manifestations, including renal involvement. The most frequent renal lesion is tubulo-interstitial nephritis, which manifests clinically as distal tubular acidosis and may result in the development of osteomalacia. CASE REPORT: In a 29-year-old female patient, with bilateral nephrolithiasis, the diagnosis of primary Sjögren's syndrome, tubulo-interstitial nephritis, distal renal tubular acidosis, and hypokalemia were established. She was treated for hypokalemia. Two years later she developed bone pains and muscle weakness, she wasn't able to walk, her proximal muscles and pelvic bones were painful, with radiological signs of pelvic bones osteopenia and pubic bones fractures. The diagnosis of osteomalacia was established and the treatment started with Schol's solution, vitamin D and calcium. In the following two months, acidosis was corrected, and the patient started walking. CONCLUSION: In our patient with primary Sjögren's syndrome and interstitial nephritis, osteomalacia was a result of the long time decompensate acidosis, so the correction of acidosis, and the supplementation of vitamin D and calcium were the integral part of the therapy.

[Systemic lupus erythematosus and dermatomyositis--case report].

The association of systemic lupus erythematosus (SLE) with idiopathic polymyositis or dermatomyositis is reported to occur in the range of 4-16%. Myositis can occur before or after SLE, or sporadically both diseases can be present simultaneously. This case report concerns a 36-year-old female patient suffering from Raynaud's phenomenon, polyarthralgia in the small joints of the hands, and skin changes compatible with Gotron's indications. Symmetric proximal muscle weakness of the extremities, fever of up to 40 degrees C, heliotrope rashes with erythematous changes in the face, upper arms, and posterior shoulders occurred subsequently. Laboratory analyses revealed increased acute phase reactants, hypochromic anaemia, lymphopenia, and increased levels of all muscle enzymes. Immunoserology demonstrated positive ANA, anti-Sm, and anticardiolipin antibodies (aCL), while anti dsDNA, anti Ro, anti La, and anti Jo-1 antibodies proved negative. Hypocomplementaemia and elevated levels of immune complexes were also detected. Pathologic sediment and proteinuria were revealed via urine analyses, while a kidney biopsy confirmed lupus nephritis (type IVa according to the World Health Organisation classification). Biopsy of erythematous changes of the posterior shoulder demonstrated leukocytoclastic vasculitis. Electromyography of the lower extremities established myopathic changes. Inflammation of the muscles was confirmed via magnetic resonance imaging. The patient was categorised as having two separate coexistent diseases--SLE and dermatomyositis. Both the classification criteria of the American College of Rheumatology for SLE and the diagnostic criteria for dermatomyositis, proposed by Bohon and Peter, were fulfilled simultaneously. Treatment commenced with pulses of methylprednisolone and continued with oral therapy, including Resochin. Pulses of intravenous cyclophosphamide were also administered. After six weeks of therapy, biohumoral remission of both diseases was achieved, while complete recovery from muscle weakness was accomplished after four months.

[Allergic granulomatous angiitis]. / Alergijski angiitis i granulomatoza.

Allergic granulomatous angiitis (AGA)--Churg-Strauss syndrome, is a rare autoimmune disease characterized by three distinct clinical phases: prodromal, eosinophilic, and vasculitic, and most of respiratory symptoms and signs begin in the first two phases of the disease. Two female patients of different age, who fulfilled the diagnostic criteria for AGA, and were in different phases and with the different duration of the disease are presented. The first patient (24 years of age) was admitted to the hospital due to aggravation of asthma, heart failure, and polyneuropathy. The second one (45 years of age) was also hospitalized due to the worsening of asthma, polyneuropathy, and fever. Both were treated continuously with glucocorticoids. The older patient also received a total of six pulse doses of cyclophosphamide. Satisfactory response to such a treatment was achieved in both cases.