Hamit Kucuk

Predictive value of neutrophil/lymphocyte ratio in renal prognosis of patients with granulomatosis with polyangiitis

Abstract Introduction: Granulomatosis with polyangiitis (GPA) is a rare necrotizing vasculitis, which usually involves the upper and lower respiratory systems and kidneys and often have a relapsing course. Neutrophil/lymphocyte ratio (NLR) has been shown to be a useful marker predicting not only progressive disease, but also mortality in various inflammatory diseases. We aimed to investigate the roles of NLR in predicting the extend of clinical involvement and prognosis of patients with GPA. Materials and methods: Consecutive newly diagnosed GPA patients who had follow-up for at least 6 months between 2010 and 2016 at Gazi University Internal Medicine-Rheumatology clinic were retrospectively analyzed. Results: Fifty-three newly diagnosed GPA patients were studied. NLR was significantly higher in the GPA group compared with the control group (4.50 [min–max: 0.07–34.81] vs 1.77 [min–max: 1.04–2.90], respectively, p < .001). NLR significantly correlated with ESR and CRP levels (r = .40 and r = .48, respectively, p < .001 for both). Discussion: GPA is a vasculitis with a significant morbidity and mortality (REF). Renal involvement usually presents with crescentric glomerulonephritis, resulting in significant and permanent loss of renal functions and end-stage kidney disease. Higher NLR at baseline is associated with worse renal outcome. Our findings suggest that baseline NLR could have a predictive value for renal prognosis. We have also demonstrated a significant correlation between NLR and BVAS activity scores. Our data suggest that GPA patients with a significantly high NLR at baseline might need closer follow-up for persistent disease activity.

Anakinra for the treatment of familial Mediterranean fever-associated spondyloarthritis

aorta and its branches. TA may be complicated by life-threatening pulmonary arterial hypertension (PAH) (2). Treatment with glucocorticoids and disease-modified anti-rheumatic drugs (DMARDs) appears to be partially effective (3). Strong expression of IL-6 in the aorta and elevated serum IL-6 levels have been reported in patients with TA and correlated with disease activity (4). Accumulating evidence also shows, in animal models, that lung-specific overexpression of IL-6 resulted in increased pulmonary vascular resistance (PVR) and pathological lesions similar to that seen in patients with PAH, including distal arteriolar muscularization, plexogenic arteriopathy, and periarteriolar infiltration of T cells (5). Altogether, these findings seem to indicate that IL-6 directly or indirectly promotes proliferation of both smooth muscle cells and endothelial cells, and that the IL-6 blocking could represent an ideal therapeutic target in TA patients with PAH (5–8). The rapidity of effectiveness of tocilizumab appears surprising in this case and could be related to an initial effect on vascular inflammation, as indicated by the fast clinical and biological effects observed in our and other studies (9, 10).

Correlation between IL-17A/F, IL-23, IL-35 and IL-12/-23 (p40) levels in peripheral blood lymphocyte cultures and disease activity in Behcet’s patients

Behcet’s disease is a chronic multisystemic disease with remissions and relapses. Several studies have shown that immune mechanisms play an important role in the development of the disease. In order to assess the association of disease activity with IL-17A/F, IL-23, IL-12/23 (p40) and IL-35 expression, we aimed to investigate production of these cytokines in peripheral blood mononuclear cells (PBMCs) from Behcet’s patients and normal controls. Furthermore, we included Systemic Lupus Erythematosus (SLE) as disease control to evaluate the specificity of our data for immunopathogenesis of BD. Totally 15 active, 15 inactive Behcet’s patients, 12 active and 12 inactive SLE patients and 12 healthy volunteers were enrolled in the study. Peripheral blood mononuclear cells were separated, lymphocyte cultures were performed and IL-17A/F, IL-12/23 p(40), IL-23, IL-35 cytokine levels were measured by ELISA in culture supernatants in the presence or absence of phytohemagglutinin (PHA) on time-dependent manner. IL-17 A/F levels increased parallel to IL-23 levels in Behcet’s and SLE patients. Compared to healthy controls, IL-17 A/F levels were higher in active Behcet’s and SLE patients; on the contrary, levels of IL-35 were lower. IL-17A/F, IL-12/23 (p40) and IL-23 levels were detectable most frequently in active Behcet’s patients followed by active SLE patients. Our results indicate that IL-17 A/F, IL-23 and IL-12/23 (p40) may play role in the immunopathogenesis of BD so as Th17 and Th1 cell responses. Since IL-35 levels were lower in active Behcet’s patients compared to inactive patients and healthy controls, there may be a plasticity between Th17 and Treg cells according to the state of disease activity.

ACR/EULAR Sjögren classification criteria may not be adequate for extraglandular disease and necessitates defining ‘seronegative Sjögren's syndrome’

for the differentiation and expansion of IL-17Aand IL-22producing human Vg2Vd2 T cells. J Immunol 2010;184:7268–80. 7. Laggner U, Di Meglio P, Perera GK, Hundhausen C, Lacy KE, Ali N, et al. Identification of a novel proinflammatory human skin-homing Vg9Vd2 T cell subset with a potential role in psoriasis. J Immunol 2011;187:2783–93. 8. Kenna TJ, Davidson SI, Duan R, Bradbury LA, McFarlane J, Smith M, et al. Enrichment of circulating interleukin-17– secreting interleukin-23 receptor–positive g/d T cells in patients with active ankylosing spondylitis. Arthritis Rheum 2012;64: 1420–9. 9. Gaur P, Misra R, Aggarwal A. Natural killer cells and gd T cells alterations in enthesitis related arthritis category of juvenile idiopathic arthritis. Clin Immunol 2015;161:163–9. 10. Bowness P, Ridley A, Shaw J, Chan AT, Wong-Baeza I, Fleming M, et al. Th17 cells expressing KIR3DL21 and responsive to HLA-B27 homodimers are increased in ankylosing spondylitis. J Immunol 2011;186:2672–80. 11. Noordenbos T, Yeremenko N, Gofita I, van de Sande M, Tak PP, Canete JD, et al. Interleukin-17–positive mast cells contribute to synovial inflammation in spondylarthritis. Arthritis Rheum 2012;64:99–109. 12. Ciccia F, Guggino G, Rizzo A, Saieva L, Peralta S, Giardina A, et al. Type 3 innate lymphoid cells producing IL-17 and IL-22 are expanded in the gut, in the peripheral blood, synovial fluid and bone marrow of patients with ankylosing spondylitis. Ann Rheum Dis 2015;74:1739–47. 13. Appel H, Maier R, Wu P, Scheer R, Hempfing A, Kayser R, et al. Analysis of IL-17 cells in facet joints of patients with spondyloarthritis suggests that the innate immune pathway might be of greater relevance than the Th17-mediated adaptive immune response. Arthritis Res Ther 2011;13:R95. 14. Laloux L, Voisin MC, Allain J, Martin N, Kerboull L, Chevalier X, et al. Immunohistological study of entheses in spondyloarthropathies: comparison in rheumatoid arthritis and osteoarthritis. Ann Rheum Dis 2001;60:316–21. 15. McGonagle D, Marzo-Ortega H, O’Connor P, Gibbon W, Hawkey P, Henshaw K, et al. Histological assessment of the early enthesitis lesion in spondyloarthropathy. Ann Rheum Dis 2002; 61:534–7. 16. Bertotto A, Spinozzi F, Vagliasindi C, Vaccaro R. gd T cells in aqueous humour from untreated idiopathic uveitis patients. Br J Ophthalmol 1995;79:395. 17. Verjans GM, van Hagen PM, van der Kooi A, Osterhaus AD, Baarsma GS. Vg9Vd2 T cells recovered from eyes of patients with Behcet’s disease recognize non-peptide prenyl pyrophosphate antigens. J Neuroimmunol 2002;130:46–54. 18. Lo Presti E, Caccamo N, Orlando V, Dieli F, Meraviglia S. Activation and selective IL-17 response of human Vg9Vd2 T lymphocytes by TLR-activated plasmacytoid dendritic cells. Oncotarget 2016;7:60896–905.

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

Abstract 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

Abstract 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.

Magnetic resonance imaging features of Familial Mediterranean Fever associated spondyloarthritis

Methods Twenty-nine patients followed up in our clinic with FMF-SPA who fulfilled ASAS classification criteria for axial spondyloarthritis. To figure out only characteristics of FMF-SPA, we excluded those patients with psoriasis, Crohn disease/ulcerative colitis or positive HLA-B27 tests. Patient demographics, clinical features and MEFV mutation analyzes were recorded. All patients underwent sacroiliac and spinal contrast enhanced MR examination. T1, T2 weighted images (WI), STIR sequence and post-contrast fat saturated T1 WI were used to define MRI features.

Underlying causes of persistently elevated acute phase reactants in patiens with Familial Mediterranean Fever

Background Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are most commonly employed acute phase reactants in follow up of patients with Familial Mediterranean Fever (FMF). As a rule CRP increases during FMF attacks but it returns to normal values in attack free periods. Persistently elevated acute phase reactants in attack free periods can be occasionally observed in patients with FMF and is suggested to be a risk for the development of amyloidosis. Some authors suggested the use of IL-1 antagonists in such patients to prevent from amyloidosis. However there is no data regarding causes of elevated acute phase reactants in patients with FMF.

Hand functions in systemic lupus erythematosus: a comparative study with rheumatoid arthritis patients and healthy subjects

Background/aim Systemic lupus erythematosus (SLE) frequently affects the small joints of the hand and may result in difficulty in activities of daily living. There are very few studies evaluating the problems encountered in the hands in patients with SLE. The aim of this study is to evaluate hand functions in patients with SLE and compare them with rheumatoid arthritis (RA) patients and healthy subjects. Materials and methods A total 46 female patients meeting the SLE classification criteria were recruited. Similarly, 51 female RA patients and 46 healthy female subjects served as the control groups. To assess the upper extremity disability level, the Disability Arm Shoulder and Hand Questionnaire (DASH) was used. Some functional performances such as hand grip and pinch strength were evaluated using a dynamometer and the Nine Hole Peg Test (NHPT), respectively. Results Hand functions were found to be impaired in both SLE and RA patients when compared to healthy controls. In addition, patients with SLE showed better performance in the NHPT, hand grip, and pinch strength than RA patients (P < 0.05). However, the patient-reported disability level was similar in both patient groups (P > 0.05). Conclusion Similar to patients with RA, hand functions are significantly impaired in patients with SLE in daily activities.

SAT0611 Canakinumab use in adult familial mediterranean fever patients: a large single centre experience

Background IL-1 blocking agents have been shown to be effective in the prevention of attacks in colchicine resistant FMF (crFMF) patients. Canakinumab is FDA approved long acting recombinant IL-1 receptor antagonist for use in crFMF patients which is available for off label use in Turkey. Herein, we aimed to share our real life single centre experience for use of canakinumab in adult crFMF patients. Methods Data was derived from Gazi FMF cohort which was established in year 2010. From that date patients with FMF who were diagnosed according to the Tel Hashomer criteria were registered. Co-morbidities, detailed attack characteristics, type, duration, severity, treatments, laboratory parameters and impact of FMF on their life in terms of quality of life and work productivity were recorded either by FMF diary or a mobile phone application (FMF AIDD free to download from AppStore and android market). A retrospective cohort analysis was made from records of patients who were treated with canakinumab. Results Eighteen adult crFMF patients (%61 female) treated with canakinumab were enrolled in this study. The median age was 3124–58 years and the median disease duration was 2816–40 years. All patients harbour homozygous or compound heretozygos exon 10 MEFV mutations. Treatment reasons for canakinumab were colchicine resistance (n=14) and amyloidosis (n=4). In three patients canakinumab was initiated directly, while in 15 it was switched from anakinra (seven was allergic to anakinra, one patient had significant leukopenia, in six fail to control attacks). The median duration of canakinumab use was 8 (min 1- max 22) months. In two patients canakinumab was used as 300 mg/monthly, and in remaining as 150 mg/monthly. Pre- and post-canakinumab periods of patients were compared (Table). Patient reported attack severity (p≤0.01), duration (p≤0.01), frequency (p≤0.01), C-reactive protein (CRP) (p≤0.01) and erythrocyte sedimentation rates (p≤0.01) were significantly improved while serum creatinine and alanine aminotransferase (ALT) levels remained same (p=0.2, p=0.35, respectively). Canakinumab achieved complete disease remission in 5 patients. Side effects requiring discontinuation of canakinumab were observed in none of patients. Table. Comparison of attack characteristics of 18 Adult crFMF patients before and after canakinumab Colchisine Colchicine+canakinumab P Attack severity, VAS 8,5 (5–10) 3,5 (0–10) <0,01 Attack duration, hours 108 (48–144) 24 (0–96) <0,01 Attack frequency* 6 (1–10) 1 (0–3) <0,01 CRP, mg/L 35,8 (3,8–85,0) 4,2 (2,45–55) <0,01 ESR, mm/h 38 (11–67) 12 (3–44) <0,01 Serum creatinine 0,66 (0,40–3,00) 0,70 (0,43–3,00) 0,20 ALT 20 (10–55) 19 (9–70) 0,35 Treatment duration, months 204 (48–456) 8 (1–22) *Attack frequencies adjusted for 3 months intervals. VAS: visual analogue scale, CRP: C-reactive protein, ALT: alanine aminotranspherase, ESR: erythrocyte sedimentation rate Conclusions Canakinumab is effective in the prevention of attacks with a favourable safety profile. Disclosure of Interest None declared