A real-life analysis of patients with rheumatologic diseases on biological treatments: Data from TURKBIO Registry.

OBJECTIVE: TURKBIO registry, established in 2011, is the first nationwide biological database in Turkey. This study aimed to provide an overview of TURKBIO data collected by June 2018. METHODS: The registry included adult patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS), nonradiographic axial spondyloarthritis (nr-AxSpA), and psoriatic arthritis (PsA). Demographic and clinical features, disease activity markers, and other follow-up parameters, current and previous treat- ments, and adverse events were registered electronically at each visit using open-source software. The registration of patient-reported outcome measures was carried out electronically by the patients using touch screens. RESULTS: TURKBIO registry included a total of 41,145 treatment series with biologicals. There were 2,588 patients with axSpA (2,459 AS and 129 nr-axSpA), 2,036 with RA, and 428 with PsA. The total number of patients, including those with other diagnoses, was 5,718. In the follow-up period, the number of patients and also visits steadily increased by years. The yearly mean number of visits per patient was found to be 2.3. Significant improvements in disease activity and health assessment parameters were observed following the biological treatments. Biologics were often given in combination with a con- ventional synthetic disease-modifying antirheumatic drug in patients with RA. Infections were the most commonly seen adverse events, followed by allergic reactions. Tuberculosis was observed in 12 patients, malignancy in 18, and treatment-related mortality in 31. CONCLUSION: TURKBIO provided a valuable real-life experience with the use of biologics in rheumatic diseases in Turkey.

The impact of anti-TNF treatment on Wnt signaling, noggin, and cytokine levels in axial spondyloarthritis.

INTRODUCTION: Anti-tumor necrosis factor (anti-TNF) agents are commonly used in treatment of axial spondyloarthritis (axSpA), but clinical and radiological improvement is not achieved in all patients. We aimed to investigate the impact of anti-TNFs on inflammatory and noninflammatory parameters in patients with axSpA. METHODS: In this longitudinal study, 30 biologic naïve axSpA patients with high disease activity and 30 healthy controls were enrolled. All patients were treated with anti-TNF agents for 6 months. ASDAS-CRP, BASDAI, BASFI, BASMI, patient and physician global assessments were evaluated. C-reactive protein, COX2, TNF-α IL-6, IL-17, IL-22, IL-23, IL-33, sclerostin, dickkopf-1, and noggin levels were evaluated at baseline and at 6 months of anti-TNF treatment. RESULTS: At baseline, axSpA patients had significantly higher median (IQR) TNF-α levels, 34.4 (31.4-37.03) vs. 18.1 (12.1-28.4) pg/ml (p < 0.001), and lower DKK1, 446.7 (356.9-529.3) vs. 1088.7 (951.7-1244.4) pg/ml, and sclerostin, 312.4 (140.8-412.7) vs. 412.3 (295.4-512.8) pg/ml, compared to healthy controls (all p < 0.001). The median (IQR) serum levels of IL-17, IL-22, and IL-33 increased significantly after 6 months of anti-TNF treatment, from 93.3 (85.1-104.8) to 102.1 (86.6-114.6) pg/ml (p = 0.026), 159.2 (151.9-178.4) to 183.5 (156.3-304.6) pg/ml (p = 0.033), and 127.8 (106.6-186.1) to 147.06 (128.5-213.4) pg/ml (p = 0.016), respectively. Sclerostin and DKK-1 levels increased significantly after anti-TNF treatment from 312.4 (140.8-412.7) to 405.1 (276.3-452.5) pg/ml (p = 0.018) and 446.7 (356.9-529.3) to 881.3 (663.1-972.2) pg/ml (p < 0.001), while there was no significant change in noggin level. CONCLUSIONS: Many inflammatory cytokines increase after anti-TNF treatment and noggin is not affected by anti-TNF treatment in AxSpA. Noggin might be a therapeutic target in patients with axSpA. KEY POINTS: • Anti-TNF therapy is not sufficient for complete blockage of the inflammatory process in axial spondyloarthritis. • The increase in IL-17, IL-22, and IL-33 may decrease the efficiency of anti-TNF therapy. • Noggin might be a therapeutic target as a complementary or alternative approach to anti-TNF therapy in axial spondyloarthritis.

Serum levels of fetuin-A as a novel biomarker for disease activity in patients with Takayasu arteritis and granulomatous polyangiitis.

OBJECTIVE: The aim of the present study was to investigate serum fetuin-A (Fet-A) levels in patients with Takayasu arteritis (TA) and granulomatous polyangiitis (GPA) and to analyze the relationship between serum Fet-A levels and disease activity scores. METHOD: Thirty-two TA and 28 GPA patients presented to the rheumatology clinic at Gazi University and met the criteria of American College of Rheumatology 1990 and 2012 International Chapell Hill meeting, respectively, and 20 healthy control subjects were included in the present study. We collected data on serum C-reactive protein (CRP), albumin, calcium, and phosphate levels as well as erythrocyte sedimentation rates. Calcification risk index (CRI) was calculated for each patient. The Birmingham Vasculitis Activity Score (BVAS) and Indian Takayasu Clinical Activity Score (ITAS), were used to assess disease activity in GPA and TA patients respectively. RESULTS: Serum Fet-A levels were significantly lower in the overall vasculitis group compared to control group (p = 0.015). In subgroup analysis, Fet-A levels were significantly lower in those with active disease, compared to control group (p = 0.001, for active TA (n = 18) and GPA (n = 17), respectively). However, there was no significant difference in serum Fet-A levels in inactive cases versus control subjects (p = 0.061, for inactive TA (n = 14) and GPA (n = 11), respectively). Serum Fet-A levels negatively correlated with BVAS (r = - 0.675) and ITAS scores (r = - 0.385), as well as with CRP and CRI. CONCLUSION: Our results suggest that serum Fet-A level could be a novel biomarker for assessment of activity status in patients with GPA or TA. Key Points • Serum Fetuin-A is negative acute phase protein and systemic calcification inhibitor synthesized in hepatocytes and secreted by various inflammation. • Serum Fetuin-A was negatively correlated with CRP, BVAS, and ITAS scores and significantly decreased in vasculitis patients with high disease activity. • Serum Fetuin-A could be a promising and useful biomarker for the assessment of disease activity for vasculitis, also that it might also be a predictor of long-term cardiovascular progression.

Diagnostic utility of serum biomarkers in large vessel vasculitis and their correlation with positron emission tomography.

OBJECTIVES: To investigate the association between vascular inflammation, as detected by positron emission tomography (PET) imaging and interleukin-6 (IL-6), pentraxin3, and B-cell-activating factor (BAFF) in subjects with LVV. METHODS: The study included newly diagnosed giant cell arteritis (GCA, n = 27) or Takayasu arteritis (n = 9) patients and healthy control (HC, n = 31) subjects. PET scan and blood samples were obtained before the introduction of treatments. IL-6, PTX3, and BAFF levels were determined quantitatively by enzyme-linked immunosorbent assay kits. RESULTS: Thirty-six patients with LVV (20 females, 16 males; age 64.5 ± 16.6 years) and 31 HC (14 females, 17 males; age 37.1 ± 9.6 years) were included. Serum levels of IL-6, PTX3, and BAFF were increased in patients with newly diagnosed LVV compared with healthy control subjects. In receiver operating characteristics (ROC) analysis, serum IL-6 and BAFF provided excellent discrimination of newly diagnosed LVV patients from HC (area under the ROC curve of >0.90 and >0.80, respectively). None of the inflammatory markers correlated with vascular inflammatory activity determined by PET scanning. CONCLUSIONS: Our results suggest that IL-6 and BAFF may serve as markers of large vessel vasculitis, while PTX3 is not useful. None of the inflammatory markers correlated with PET assessed vasculitis activity.

Phenotypic characterization of Familial Mediterranean Fever patients harboring variants of uncertain significance

Background/aim: Familial Mediterranean Fever (FMF) is the prototype of hereditary autoinflammatory disorders and caused by mutations on the MEFV gene located on the short arm of chromosome 16. Although some MEFV variants are clearly associated with disease phenotype, there are numerous variants with unknown clinical association which are termed as variants of uncertain significance (VUS). Here, we present clinical correlations of VUS in a large cohort of adult FMF patients from three tertiary centers located in Central Anatolia. Materials and methods: All patients were recruited from FMF in Central Anatolia (FiCA) cohort. Demographic (sex, age at disease onset) and clinical features (disease characteristics, attack frequency, mean colchicine dose, colchicine nonresponsiveness, amyloidosis, and persistent inflammation) of patients with VUS were compared with those harboring pathogenic variants. Disease severity and damage were also evaluated using international severity score for FMF (ISSF) and autoinflammatory disease damage index (ADDI), respectively. Results: Among 971 participants included, MEFV gene analysis results were available for 814 patients. Twenty-six (3.2%) patients had single heterozygous VUS and 54 (6.6%) had pathogenic/VUS complex heterozygous variants. Patients with single heterozygous VUS had similar demographic/clinical features, ISSF and ADDI scores compared to those with single heterozygous pathogenic variant (p > 0.05 for all). No difference was observed in the demographic and clinical features of patients with single heterozygous pathogenic mutation and pathogenic/VUS complex heterozygous variant (p > 0.05 for all). ISSF and ADDI scores were lower in pathogenic/VUS complex heterozygous patients than those harboring single pathogenic mutation (p = 0.006 and 0.004, respectively). Conclusion: Our findings suggest that patients with single heterozygous VUS has mild FMF phenotype similar to those with single pathogenic mutation. Pathogenic/VUS complex heterozygosity does not lead to a more severe clinical phenotype than having a single pathogenic variant.

Appendectomy history is associated with severe disease and colchicine resistance in adult familial Mediterranean fever patients

Background/aim: Peritonitis attacks of Familial Mediterranean Fever (FMF) usually requires emergency medical admissions and it's hard to distinguish a typical abdominal attack from surgical causes of acute abdomen. Therefore, history of abdominal surgery, particularly appendectomy, is very common in patients with FMF. However, history of appendectomy might also give some clues about the course of FMF in the adulthood. This study was to determine whether the history of appendectomy help to anticipate disease course of FMF in the adulthood. Materials and methods: All patients recruited from FMF in Central Anatolia (FiCA) cohort, comprising 971 adult subjects. All patients fulfilled the Tel Hashomer criteria. Demographic data, FMF disease characteristics, co-morbid conditions, past medical history, surgical history and disease complications were meticulously questioned and laboratory features and genotype data (if available) were recruited from patient files. Results: Appendectomy history was evident in 240 (24.7%) subjects. Disease onset was earlier and peritonitis is strikingly more prevalent (97.1% vs. 89.6%, p < 0.001) in appendectomized patients. These patients had reported almost two fold more frequent attacks in the last year compared to appendix intact patients (median 3.5 vs. 2 attacks, p = 0.001) without a difference in frequency of musculoskeletal and skin attacks. Severe disease was more common (10% vs. 5.9%, p = 0.038) due to involvement of more attack sites throughout the life and more frequent attacks. Appendectomy patients had used higher daily doses of colchicine to control disease (1.43 ± 0.6 mg vs. 1.27 ± 0.52 mg, p = 0.002) but colchicine resistance was also more common in these patients, 15% vs. 6.7% respectively, p < 0.001. Conclusion: Appendectomy history is common in FMF patients and associated with frequent serositis attacks in adulthood. These patients require higher colchicine doses with a lower rate of response and more need for Interleukin-1 antagonist therapies.

Diagnostic Role of 18F-Fluorodeoxyglucose Positron Emission Tomography for the Evaluation of Patients With Inflammation of Unknown Origin.

BACKGROUND: Sometimes, the underlying causes of inflammation cannot be established despite meticulous investigation, including medical history, physical examination, laboratory tests, and radiologic procedures. Rheumatologists are often faced with patients whose condition is known as inflammation of unknown origin (IUO). Differential diagnosis of IUO is diverse, and investigation of these cases is challenging and time-consuming. OBJECTIVE: The study aimed to assess the diagnostic role of positron emission tomography/computed tomography (PET/CT) in the evaluation of patients with IUO. METHODS: The study sample consisted of 97 adult patients with IUO who have not been previously diagnosed with an infectious, inflammatory, or malignant disease. The necessary data were collected from January 2015 to June 2018 with a 6-month follow-up period. The patients were screened using PET/CT after a specific diagnosis could not be established with detailed laboratory and radiologic evaluations. RESULTS: A final diagnosis was established at follow-up, and 47 (54%) of the 97 patients had inflammatory diseases, 30 (34.4%) had malignancies, and 10 (11.4%) had infections. Despite meticulous investigation, 10 patients were left undiagnosed in the follow-up. PET/CT aided diagnosis in 59 patients (60.8%), but it was not helpful in 38 patients (39.2%). PET/CT was positive in 30 (63%) of the 47 patients with inflammatory diseases, whose final diagnosis was inflammatory rheumatic disease, as follows: large-vessel vasculitis in 19 patients, polymyalgia rheumatica in 7 patients, and seronegative arthritis or other rare miscellaneous diseases in 4 patients. The sensitivity of PET/CT was 67% with a specificity and diagnostic accuracy of 100% and 71%, respectively. CONCLUSIONS: Investigation of the underlying etiology of IUO is time-consuming and challenging. PET/CT may help identify the final diagnosis more quickly by locating an obscure inflammatory site; thus, it may reduce the number of unnecessary biopsies, diagnostic time, anxiety, work loss, morbidity, and mortality.

Predictors of persistent inflammation in familial Mediterranean fever and association with damage.

OBJECTIVE: Persistent inflammation is an insidious and less studied feature of FMF. We investigated clinical determinants of persistent inflammation and its associations with individual damage items. METHODS: This is a cross-sectional analysis of 917 FMF patients, who fulfilled the Tel Hashomer criteria and had at least 6 months' follow-up. Patients were stratified based on whether they had persistent inflammation. We used logistic regression analysis to investigate independent predictors of persistent inflammation and the associated individual damage items. RESULTS: One hundred and forty-two (15%) patients had persistent inflammation. Active FMF (54%) was the most prominent reason for the persistent inflammation. Spondylarthritis (16%), other inflammatory arthritis (8%) and IBD (2%) were other frequent reasons. Male gender, history of exertional leg pain, inflammatory comorbidities, M694V homozygosity, colchicine resistance, lower education levels and musculoskeletal attack dominance were found to be the independent predictors of persistent inflammation. Earlier disease onset led to a tendency towards persistent inflammation. Patients with persistent inflammation were more likely to suffer damage. There is an increased risk of developing proteinuria, amyloidosis and renal insufficiency. CONCLUSION: We identified, for the first time, the predictors of persistent inflammation in adult FMF patients and related individual damage items of the Autoinflammatory Disease Damage Index. Persistent inflammation is insidious and one of the chief causes of damage; therefore, especially patients with these predictors should be followed up more closely. If detected, underlying inflammatory comorbidities should be assessed meticulously as early detection and proper treatment strategies may favourably impact the natural history of the disease.

Serum defensin levels in patients with systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of skin and lung as well as involvement of kidney, gastrointestinal system and heart. Aetiology and exact mechanism of disease is poorly understood. The association between antimicrobial peptides (AMPs) and other diseases such as idiopathic pulmonary fibrosis, diffuse panbronchiolitis, pulmoner alveolar proteinosis and psoriasis have been reported. A small number of studies have examined the role of AMPs on autoimmune diseases which has not been studied in scleroderma yet. We aimed to investigate AMP serum levels and their association with disease characteristics of SSc. METHODS: Forty-two patients (40 female, mean age 42 years) and 38 healthy subjects (32 female, mean age 38 years) were enrolled. For SSc patients, the following data were recorded: disease subset (limited/diffuse), autoantibodies (antinuclear, anti-centromere (ACA), and anti-SCL-70), blood tests, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP), modified Rodnan skin score, presence and history of digital ulcers, kidney, gastrointestinal disease and lung involvement assessed by computed tomography and pulmonary function tests. Association between serum AMPs and disease characteristics were analysed. RESULTS: Twenty-nine of the patients had diffuse (69%) and 13 of the patients had limited (31%) systemic sclerosis. Average disease duration was 5.5 years. Pulmonary involvement was detected in 20 patients (47.6%). Serum concentration of alpha defensin was higher than healthy subjects (563 ± 415 vs 377 ± 269 ng/mL, p = 0.02). However, no difference was observed for beta-1 and beta-2 defensins in SSc patients and healthy controls. In sub-group analysis patients with interstitial lung disease had higher levels of alpha defensin than those without lung involvement (684 ± 473 vs 430 ± 299 ng/ml, p = 0.04). There was also correlation between alfa defensin serum concentrations and CRP (r = 0.34). CONCLUSIONS: Alpha defensin levels are increased in scleroderma patients and correlated with lung involvement indicating a role in the pathogenesis of disease. TRIAL REGISTRATION: This study is not a clinical trial study.

Factors associated with damage in patients with familial Mediterranean fever.

OBJECTIVES: Defining predictors of damage would improve patient care. We applied damage indexes to patients with familial Mediterranean fever (FMF) and identified the predictors of damage. METHODS: This is a cross-sectional analysis of 926 FMF patients, who fulfilled the Tel-Hashomer criteria and had at least six months of follow-up. Patients were stratified according to their damage status (damage vs. no damage) defined with autoinflammatory disease damage index (ADDI) and modified ADDI (excluding musculoskeletal pain). We used logistic regression analysis to investigate independent predictors of damage for both indexes. RESULTS: Mean disease duration was 21.6±11.9 years. 527 patients (57%) had damage according to ADDI. Median ADDI score was 1 (0-11). Most common FMF-related damages were observed in musculoskeletal, reproductive and kidney domains. Female gender, inflammatory comorbidity, colchicine resistance, colchicine nonadherence, musculoskeletal attack dominance, diagnostic delay, follow-up time, and smoking history remained independent predictors of damage according to ADDI score. The rate of patients with damage defined by modified ADDI was only to 23%. M694V/M694V homozygosity, female gender, musculoskeletal attack dominance, colchicine resistance, persistent inflammation, follow up time and family history of amyloidosis were found to be predictors of damage according to modified ADDI score. CONCLUSIONS: Our study is the first to apply comprehensive damage indexes to FMF patients and identified predictors of damage. Factors linked to a severe FMF phenotype, including M694V homozygosity and persistent inflammation, were associated with only modified ADDI. Our findings justify the concerns about musculoskeletal pain and might point to the need for re-evaluation of ADDI for FMF patients.

Inter-rater reliability of modified hand mobility in scleroderma test.

AIM: Systemic sclerosis (SSc) is a chronic autoimmune disease of unknown etiology characterized by excessive collagen production, endothelial cell injury, microvascular obliteration, cutaneous fibrosis and progressive visceral disease. The hands are frequently involved during the progression of the disease, with symmetrical skin thickening as a prominent feature. Modified hand mobility in scleroderma (mHAMIS) test is a measurement method to assess hand mobility in patients with SSc. Knowing the inter-rater reliability of the instrument is important in order for the results from different examiners to be accurately interpreted. The aim of this study was to test inter-rater reliability of the mHAMIS test. METHOD: Hand mobility for both hands was assessed in 25 female patients with SSc by 2 physiotherapists who have different years of experience. Patients who had flexion contracture in at least 1 finger and undergone hand surgery in the last year due to any injuries, were excluded from the study since hand mobility was prevented. Inter-rater reliability was determined using intra-class correlation coefficients (ICCs). RESULT: The ICCs were excellent between raters for dominant and non-dominant hands. The values were 0.92 and 0.93, respectively. CONCLUSION: The inter-rater reliability of the mHAMIS was found to be excellent. This research contributes to the literature by proving that the test can be used without causing bias in clinical trials.

Effectiveness of Canakinumab in Colchicine- and Anakinra-Resistant or -Intolerant Adult Familial Mediterranean Fever Patients: A Single-Center Real-Life Study.

OBJECTIVE: We aimed to present our single-center real-life experience of canakinumab use in adult patients with familial Mediterranean fever (FMF). METHODS: Data were derived from the Gazi FMF cohort, which was established in 2010. From that year, all patients with FMF were registered. The impact of FMF on their lives was tracked by either an FMF diary or mobile phone application (FMF-AIDD, free to download in App Store and Google Play). The records of patients who were treated with canakinumab were reviewed. RESULTS: Twenty-three adult patients with FMF (65% female) were enrolled in this study. The median age was 32 years (min-max, 24-58 years), and the disease duration was 26 years (14-59 years). A total of 86% of patients harbored homozygous or compound heterozygous exon 10 MEFV mutations. Indications for interleukin 1 inhibitor use were colchicine resistance (n = 12) or intolerance (n = 2), amyloidosis (n = 7), and chronic manifestations of the disease (n = 2). All patients used anakinra before. The median duration of canakinumab use was 7 months (min-max, 1-44 months). Pre- and post-canakinumab periods were compared. Attack severity, duration, frequency, C-reactive protein level, and erythrocyte sedimentation rate were significantly improved (p ≤ 0.01), whereas serum creatinine and alanine aminotransferase levels remained the same (p = 0.27 and p = 0.74, respectively). Canakinumab achieved complete disease remission in 14 patients (60%). Canakinumab was discontinued in 7 patients. The reasons for discontinuation were pregnancy (n = 2), dominance of axial spondyloarthropathy (n = 2), inflammatory bowel disease, patient's refusal, and weight gain. CONCLUSIONS: Canakinumab is effective in the prevention of FMF bouts without severe adverse effects. Treatment with canakinumab in an individualized dose and interval may be a reasonable choice for colchicine- and anakinra-resistant or -intolerant adult patients with FMF and those with chronic manifestations of disease.

Platelet/lymphocyte ratio and mean platelet volume in patients with granulomatosis with polyangiitis

Abstract Background: Granulomatosis with polyangiitis (GPA) is a granulomatous necrotizing vasculitis with high morbidity and mortality. Anti-neutrophil cytoplasmic antibody is a valuable diagnostic marker, however its titer lacks predictive value for the severity of organ involvement. Platelet to lymphocyte ratio (PLR) and mean platelet volume (MPV) has been regarded as a potential marker in assessing systemic inflammation. We aimed to explore the value of PLR and MPV in the assessment of disease activity and manifestations of disease in GPA. Methods: 56 newly diagnosed GPA patients and 53 age-sex matched healthy controls were included in this retrospective and cross-sectional study with comparative group. Complete blood count was performed with Backman Coulter automatic analyzer, erythrocyte sedimentation rate (ESR) with Westergen method and C-reactive protein (CRP) levels with nephelometry. The PLR was calculated as the ratio of platelet and lymphocyte counts. Result: Compared to control group, ESR, CRP and PLR were significantly higher and MPV significantly lower in GPA patients. In patients group, PLR was positively correlated with ESR and CRP (r = 0.39, p = 0.005 and r = 0.51, p < 0.001, respectively). MPV was negatively correlated with ESR and CRP (r = - 0.31, p = 0.028 and r = - 0.34 p = 0.014, respectively). Patients with renal involvement had significantly higher PLR than patients without renal involvement (median:265.98, IQR:208.79 vs median:180.34 IQR:129.37, p = 0.02). PLR was negatively correlated with glomerular filtration rate (r = - 0.27, p = 0.009). A cut-off level of 204 for PLR had 65.6% sensitivity and 62.5 specificity to predict renal involvement. Conclusion: PLR exhibit favorable diagnostic performance in predicting renal involvement in patients with GPA.(AU)

Serum defensin levels in patients with systemic sclerosis

Abstract Background: Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of skin and lung as well as involvement of kidney, gastrointestinal system and heart. Aetiology and exact mechanism of disease is poorly understood. The association between antimicrobial peptides (AMPs) and other diseases such as idiopathic pulmonary fibrosis, diffuse panbronchiolitis, pulmoner alveolar proteinosis and psoriasis have been reported. A small number of studies have examined the role of AMPs on autoimmune diseases which has not been studied in scleroderma yet. We aimed to investigate AMP serum levels and their association with disease characteristics of SSc. Methods: Forty-two patients (40 female, mean age 42 years) and 38 healthy subjects (32 female, mean age 38 years) were enrolled. For SSc patients, the following data were recorded: disease subset (limited/diffuse), autoantibodies (antinuclear, anti-centromere (ACA), and anti-SCL-70), blood tests, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP), modified Rodnan skin score, presence and history of digital ulcers, kidney, gastrointestinal disease and lung involvement assessed by computed tomography and pulmonary function tests. Association between serum AMPs and disease characteristics were analysed. Results: Twenty-nine of the patients had diffuse (69%) and 13 of the patients had limited (31%) systemic sclerosis. Average disease duration was 5.5 years. Pulmonary involvement was detected in 20 patients (47.6%). Serum concentration of alpha defensin was higher than healthy subjects (563 ± 415 vs 377 ± 269 ng/mL, p = 0.02). However, no difference was observed for beta-1 and beta-2 defensins in SSc patients and healthy controls. In sub-group analysis patients with interstitial lung disease had higher levels of alpha defensin than those without lung involvement (684 ± 473 vs 430 ± 299 ng/ml, p = 0.04). There was also correlation between alfa defensin serum concentrations and CRP (r = 0.34). Conclusions: Alpha defensin levels are increased in scleroderma patients and correlated with lung involvement indicating a role in the pathogenesis of disease. Trial registration: This study is not a clinical trial study.(AU)

Comparison of clinical courses and mortality of connective tissue disease-associated interstitial pneumonias and chronic fibrosing idiopathic interstitial pneumonias.

Interstitial lung disease (ILD) is a common pulmonary manifestation of connective tissue diseases (CTD). Prognostic effect of radiological usual interstitial pneumonia (UIP) pattern in CTD-associated interstitial lung disease (CTD-ILD) is unknown. This study aimed to investigate the disease progression and mortality of patients with CTD-ILD and idiopathic interstitial pneumonias (IIP) including idiopathic pulmonary fibrosis (IPF) and idiopathic nonspecific interstitial pneumonia and the prognostic impact of the radiological UIP pattern on both disease groups. The medical records of 91 patients (55 with CTD-ILD and 36 with IIP) diagnosed with ILD at pulmonary medicine department, Faculty of Medicine, Gazi University from 2004 to 2014 were retrospectively reviewed. Patients included whose baseline high-resolution computed tomography (HRCT) scans showed either a UIP or non-UIP pattern. While 67.3% (n = 37) of CTD-ILD patients possessed UIP pattern, 38.9% (n = 14) of IIP patients had UIP pattern in HRCT. Respiratory functions including the forced expiratory volume in the first second (FEV1 ), functional vital capacity (FVC), and transfer coefficient for carbon monoxide (diffusing capacity of the lung for carbon monoxide [DLCO]) of IIP group at the time of diagnosis were significantly lower than CTD-ILD group (P = .007, P = .002, and P = .019, respectively). There was no significant survival difference between CTD-ILD and IIP by using the log-rank test (P = .76). Multivariate analysis revealed that UIP pattern in HRCT (Hazard ratio: 1.85; 95% Confidence interval = 1.14-3; P = .013), annual FVC (Hazard ratio: 0.521; 95% Confidence interval = 0.32-0.84; P = .007), and annual DLCO declines (Hazard ratio: 0.943; 95% Confidence interval = 0.897-0.991; P = .02) were independent risk factors for mortality in both CTD-ILD and IIP groups. We found that UIP pattern in HRCT and annual losses in respiratory functions were the main determinants of prognosis of ILDs either idiopathic or CTD-associated.

Platelet/lymphocyte ratio and mean platelet volume in patients with granulomatosis with polyangiitis.

BACKGROUND: Granulomatosis with polyangiitis (GPA) is a granulomatous necrotizing vasculitis with high morbidity and mortality. Anti-neutrophil cytoplasmic antibody is a valuable diagnostic marker, however its titer lacks predictive value for the severity of organ involvement. Platelet to lymphocyte ratio (PLR) and mean platelet volume (MPV) has been regarded as a potential marker in assessing systemic inflammation. We aimed to explore the value of PLR and MPV in the assessment of disease activity and manifestations of disease in GPA. METHODS: 56 newly diagnosed GPA patients and 53 age-sex matched healthy controls were included in this retrospective and cross-sectional study with comparative group. Complete blood count was performed with Backman Coulter automatic analyzer, erythrocyte sedimentation rate (ESR) with Westergen method and C-reactive protein (CRP) levels with nephelometry. The PLR was calculated as the ratio of platelet and lymphocyte counts. RESULT: Compared to control group, ESR, CRP and PLR were significantly higher and MPV significantly lower in GPA patients. In patients group, PLR was positively correlated with ESR and CRP (r = 0.39, p = 0.005 and r = 0.51, p < 0.001, respectively). MPV was negatively correlated with ESR and CRP (r = - 0.31, p = 0.028 and r = - 0.34 p = 0.014, respectively). Patients with renal involvement had significantly higher PLR than patients without renal involvement (median:265.98, IQR:208.79 vs median:180.34 IQR:129.37, p = 0.02). PLR was negatively correlated with glomerular filtration rate (r = - 0.27, p = 0.009). A cut-off level of 204 for PLR had 65.6% sensitivity and 62.5 specificity to predict renal involvement. CONCLUSION: PLR exhibit favorable diagnostic performance in predicting renal involvement in patients with GPA.

Effect of interleukin-1 antagonists on the quality of life in familial Mediterranean fever patients.

BACKGROUND: Familial Mediterranean fever (FMF) patients suffer from chronic complications of disease such as AA amyloidosis, chronic arthritis, and spondylitis. Reduced quality of life (QoL) is a feature of chronic diseases but it is also impaired in patients with FMF. Despite the regular use of colchicine at a maximal dose, about 10% of patients do not respond well or resistant to colchicine (crFMF). IL-1 inhibitors have been shown to be effective in controlling attacks in crFMF patients. Herein, we aimed to investigate QoL changes of crFMF patients with IL-1 inhibitors. METHODS: All patients were prospectively monitored for the frequency, duration, severity of attacks, patient global assessments (Visual Analog Scale; VAS), and laboratory features. Either anakinra or canakinumab was used as IL-1 antagonist treatments. Demographic information, MEFV gene mutations, attack characteristics, and previous treatments were registered. Short form-36 (SF-36) quality of life scale was implemented by the interviewer for evaluating the QoL before and 3 months after the treatment. RESULTS: A total of 44 patients were included in this study. Striking improvements were detected in frequency, duration, and VAS severity of attacks (p < 0.001). In the comparison of pre- and post-treatment, SF-36 sub-components significant improvements were observed on physical function, role limitation due to physical difficulty, role limitation due to emotional problem, energy, emotional well-being, social function, pain, general health, and health change. CONCLUSIONS: In conclusion, IL-1 antagonists prevent attacks and improve QoL of crFMF.

Clinical characteristics of avascular necrosis in patients with Behçet disease: a case series and literature review.

Avascular necrosis (AVN), also known as osteonecrosis, is characterized by death of the osteocytes due to inadequate blood supply caused by various mechanisms. The hip is the most common affected joint followed by knee. Incidence of AVN in rheumatic diseases is variable and high corticosteroid (CS) therapy is a known major risk factor for development of AVN. Data on the AVN in Behçet disease (BD) are limited. The purpose of this study is to examine the clinical and treatment characteristics of BD patients with diagnosis of AVN. Retrospective medical records of 337 BD patients were reviewed. Nine BD patients with AVN were detected. The clinical data of these patients with AVN have been reviewed. All patients had MRI of the symptomatic joints compatible with AVN. All of the nine patients who were diagnosed with AVN were male. Median duration of BD was 7 years. Median time between diagnosis of BD and detection of AVN was 3 years (1-16 years). Multiple joints were involved in seven patients. Six patients had bilateral knee AVN. Six patients had vascular BD. The median time interval between initial CS dose and AVN development was 24 months (range = 2-100). The median highest daily CS dose was 64 mg/day (range = 32-80) and median cumulative CS dose prior to AVN was 18 g. All of patients had intravenous pulse steroids. CS treatment, smoking and vascular involvement may predispose to AVN in patients with BD. According to this cohort, AVN in BD frequently tended to be in the knee joint and bilateral.

Efficacy and safety of interleukin-1 inhibitors in familial Mediterranean fever patients complicated with amyloidosis.

BACKGROUND: Colchicine is the mainstay of the treatment of familial Mediterranean fever (FMF). However, 10% of FMF patients do not respond well to colchicine. Efficacy of interleukin (IL)-1 inhibitors in reducing attacks have been demonstrated in colchicine-resistant FMF (crFMF) patients recently. Colchicine is still the only approved drug for the prevention of amyloidosis in FMF and utility of IL-1 inhibitors in crFMF cases who already has amyloidosis remain to be elucidated. Herein, we evaluated efficacy and safety of IL-1 inhibitors in patients with crFMF-associated AA amyloidosis in a relatively large single center study. METHODS: Medical records of FMF patients complicated with AA amyloidosis in our dedicated FMF center were retrospectively reviewed and those patients who ever treated with IL-1 inhibitors were enrolled into the study. Patient global, physician global assessments (on 0-10 cm visual analog scale), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), serum creatinine and 24-h urinary protein excretion values for each visit were recruited from computer-based hospital records. Treatment response of patients were assessed with clinical symptoms, serum albumin, CRP and ESR values. Renal outcome parameters were analyzed on those not receiving renal replacement therapy. RESULTS: Seventeen patients were identified with crFMF-amyloidosis that ever treated with IL-1 inhibitors. Background colchicine therapy was continued in all patients in maximal-tolerated dose along with IL-1 inhibitors. All patients benefit from IL-1 antagonists assessed by patient and physician global assessments. Inflammatory markers, CRP and ESR, were significantly reduced in all and normalized in 12 out of 17 patients. More importantly, the amount of proteinuria was remarkably improved following IL-1 inhibitor therapy (1606 mg/day to 519 mg/day, p = .008). Both anakinra and canakinumab were well-tolerated without severe side effects. All patients were initially treated with anakinra but switched to canakinumab in seven patients (one leukopenia, four injection site reaction, two inefficacy). CONCLUSION: We evaluated the clinical and laboratory responses to IL-1 inhibitors in crFMF-associated amyloidosis patients. We found significant decreases in CRP, ESR and proteinuria after IL-1 inhibitor therapy. This study confirmed that IL-1 inhibitors are effective for controlling attacks and inflammatory activity in FMF patients complicated with AA amyloidosis. Moreover, they reduce or stabilize amount of proteinuria and preserve renal function in short-term follow-up. Prolonged prospective clinical trials are warranted to assess their long-term efficacy in this particular patient group.

Serum ferritin as an activity marker for granulamotosis with polyangiitis.

BACKGROUND: Serum ferritin correlates well with the activities of systemic lupus erythematosus (SLE) and dermatomyositis, but it has not been previously studied in patients with vasculitis. METHODS: Medical records of granulomatosis with polyangiitis (GPA, Wegener's granulomatosis) patients with at least six months of regular follow-up were evaluated. The activity of GPA was assessed with Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG). Serum ferritin and other acute phase markers were measured at initial presentation. RESULTS: Serum ferritin levels were found to be the highest in GPA patients with alveolar hemorrhage, median (IQR) 1041 (1281) µg/L. Patients with renal disease also had high levels of ferritin and it was correlated with concurrent glomerular filtration rate (r = -0.65, p < .001). Serum ferritin is also correlated well with the BVAS/WG scores (r = 0.79, p < .001). CONCLUSIONS: Measurement of serum ferritin might help in assessing disease activity of GPA.