Seza Ozen

A new set of criteria for the diagnosis of familial Mediterranean fever in childhood

OBJECTIVESnSeveral sets of criteria mainly for adults have been proposed for the diagnosis of FMF. The aim of the present study is to validate the most widely used diagnostic Tel Hashomer criteria in children and to establish a new set of criteria for use in childhood.nnnMETHODSnThe study group consisted of 170 recently diagnosed FMF patients who had mutations at both alleles. They were interviewed about the presence of 35 features and manifestations of FMF at the time of diagnosis. Controls were consecutive patients without FMF (n = 141) who had episodes of fever and clinical features mimicking that of FMF. The diagnostic performance of the candidate features was assessed by multiple logistic regression analysis.nnnRESULTSnThe sensitivity and specificity of Tel Hashomer criteria in our study group were 98.8 and 54.6%, respectively. The multiple logistic regression analysis showed that 5 (fever, abdominal pain, chest pain, arthritis and family history of FMF) of the 35 candidate criteria discriminate FMF from controls with a sensitivity and specificity of 88.8 and 92.2%, respectively. The presence of two or more of these five criteria diagnosed FMF with a sensitivity of 86.5% and a specificity of 93.6%.nnnCONCLUSIONnIt was demonstrated that although the Tel Hashomer criteria were successful in diagnosing the FMF patients in childhood, its specificity was definitely low in children. The new set of criteria has a high sensitivity and specificity for the diagnosis of FMF and is practical to use on an everyday basis.

Macrophage activation syndrome in juvenile systemic lupus erythematosus: A multinational multicenter study of thirty‐eight patients

OBJECTIVEnTo describe the clinical and laboratory features of macrophage activation syndrome as a complication of juvenile systemic lupus erythematosus (SLE).nnnMETHODSnCases of juvenile SLE-associated macrophage activation syndrome were provided by investigators belonging to 3 pediatric rheumatology networks or were found in the literature. Patients who had evidence of macrophage hemophagocytosis on bone marrow aspiration were considered to have definite macrophage activation syndrome, and those who did not have such evidence were considered to have probable macrophage activation syndrome. Clinical and laboratory findings in patients with macrophage activation syndrome were contrasted with those of 2 control groups composed of patients with active juvenile SLE without macrophage activation syndrome. The ability of each feature to discriminate macrophage activation syndrome from active disease was evaluated by calculating sensitivity, specificity, and area under the receiver operating characteristic curve.nnnRESULTSnThe study included 38 patients (20 with definite macrophage activation syndrome and 18 with probable macrophage activation syndrome). Patients with definite and probable macrophage activation syndrome were comparable with regard to all clinical and laboratory features of the syndrome, except for a greater frequency of lymphadenopathy, leukopenia, and thrombocytopenia in patients with definite macrophage activation syndrome. Overall, clinical features had better specificity than sensitivity, except for fever, which was highly sensitive but had low specificity. Among laboratory features, the best sensitivity and specificity was achieved using hyperferritinemia, followed by increased levels of lactate dehydrogenase, hypertriglyceridemia, and hypofibrinogenemia. Based on the results of statistical analysis, preliminary diagnostic guidelines for macrophage activation syndrome in juvenile SLE were developed.nnnCONCLUSIONnOur findings indicate that the occurrence of unexplained fever and cytopenia, when associated with hyperferritinemia, in a patient with juvenile SLE should raise the suspicion of macrophage activation syndrome. We propose preliminary guidelines for this syndrome in juvenile SLE to facilitate timely diagnosis and correct classification of patients.

Diagnostic criteria for polyarteritis nodosa in childhood

Clinical and laboratory features of 31 children with a diagnosis of polyarteritis nodosa were evaluated retrospectively. All the patients had musculoskeletal involvement, renal involvement, or both during the course of the disease. We have defined involvement of these two systems as the major diagnostic criteria in polyarteritis nodosa. Ten additional minor criteria were defined: (1) cutaneous findings, (2) gastrointestinal involvement, (3) peripheral neuropathy, (4) central nervous system involvement, (5) hypertension, (6) cardiac involvement, (7) lung involvement, (8) constitutional symptoms, (9) presence of acute-phase reactants, and (10) presence of hepatitis B surface antigen. We propose that the presence of five of these criteria, including at least one major criterion, is highly suggestive of polyarteritis nodosa; such a combination was present in 97% of our patients. Fourteen of the patients were treated with corticosteroids alone and 14 were treated with a combination of steroids plus cyclophosphamide or azathioprine. At the last follow-up examination six patients in the steroid group and nine in the combination group were considered to have complete remission of disease or inactive disease with persisting symptoms in an organ system. The overall mortality rate was 16%; renal involvement had the greatest adverse effect on outcome. We suggest that in patients with five of the 12 diagnostic criteria, especially those with renal involvement, therapy should be initiated promptly while diagnostic procedures are being carried out.

Allelic variants in genes associated with hereditary periodic fever syndromes as susceptibility factors for reactive systemic AA amyloidosis.

We investigated the hypothesis that low-penetrance mutations in genes (TNFRSF1A, MEFV and NALP3/CIAS1) associated with hereditary periodic fever syndromes (HPFs) might be risk factors for AA amyloidosis among patients with chronic inflammatory disorders, including rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), Crohns disease, undiagnosed recurrent fevers and HPFs themselves. Four of 67 patients with RA plus amyloidosis had MEFV variants compared with none of 34 RA patients without amyloid (P value=0.03). The E148Q variant of MEFV was present in two of the three patients with TNF receptor-associated periodic syndrome (TRAPS) complicated by amyloid in two separate multiplex TRAPS families containing 5 and 16 affected members respectively, and the single patient with Muckle–Wells syndrome who had amyloidosis was homozygous for this variant. The R92Q variant of TNFRSF1A was present in two of 61 JIA patients with amyloidosis, and none of 31 nonamyloidotic JIA patients. No HPF gene mutations were found in 130 healthy control subjects. Although allelic variants in HPFs genes are not major susceptibility factors for AA amyloidosis in chronic inflammatory disease, low-penetrance variants of MEFV and TNFRSF1A may have clinically significant proinflammatory effects.

Validation of the Auto-Inflammatory Diseases Activity Index (AIDAI) for hereditary recurrent fever syndromes

Objectives To validate the Auto-Inflammatory Diseases Activity Index (AIDAI) in the four major hereditary recurrent fever syndromes (HRFs): familial Mediterranean fever (FMF), mevalonate kinase deficiency (MKD), tumour necrosis factor receptor-associated periodic syndrome (TRAPS) and cryopyrin-associated periodic syndromes (CAPS). Methods In 2010, an international collaboration established the content of a disease activity tool for HRFs. Patients completed a 1-month prospective diary with 12 yes/no items before a clinical appointment during which their physician assessed their disease activity by a questionnaire. Eight international experts in auto-inflammatory diseases evaluated the patients disease activity by a blinded web evaluation and a nominal group technique consensus conference, with their consensus judgement considered the gold standard. Sensitivity/specificity/accuracy measures and the ability of the score to discriminate active from inactive patients via the best cut-off score were calculated by a receiver operating characteristic analysis. Results Consensus was achieved for 98/106 (92%) cases (39 FMF, 35 CAPS, 14 TRAPS and 10 MKD), with 26 patients declared as having inactive disease and 72 as having active disease. The median total AIDAI score was 14 (range=0–175). An AIDAI cut-off score ≥9 discriminated active from inactive patients, with sensitivity/specificity/accuracy of 89%/92%/90%, respectively, and an area under the curve of 98% (95% CI 96% to 100%). Conclusions The AIDAI score is a valid and simple tool for assessing disease activity in FMF/MKD/TRAPS/CAPS. This tool is easy to use in clinical practice and has the potential to be used as the standard efficacy measure in future clinical trials.

FRI0488 A Phase Iii Pivotal Umbrella Trial of Canakinumab in Patients with Autoinflammatory Periodic Fever Syndromes (Colchicine Resistant FMF, HIDS/MKD and TRAPS)

Background Periodic fever syndromes (PFS) are a group of rare auto-inflammatory conditions, which includes, among others, cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), hyper-IgD syndrome/mevalonate kinase deficiency (HIDS/MKD), TNF-receptor associated periodic syndrome (TRAPS). Canakinumab (CAN), a fully human, highly specific anti-IL-1β neutralising monoclonal antibody, is effective in CAPS.1 IL-1β has been shown to be involved in the pathogenesis of FMF, HIDS/MKD and TRAPS, for whom no approved treatment exists. A series of small open label studies suggested efficacy of CAN in colchicine resistant/intolerant FMF (crFMF), HIDS/MKD and TRAPS.2,3 We report the efficacy and safety of CAN from the randomised treatment epoch of a phase III trial in patients (pts) with crFMF, HIDS/MKD or TRAPS. Objectives Primary objective of this phase III pivotal trial was to demonstrate that CAN 150 mg (or 2 mg/kg for pts ≤40 kg) sc q4w is superior to placebo (PBO) in achieving a clinically meaningful response defined as resolution of the index flare at Day 15 and no new disease flares over 16 wks of treatment. Secondary objectives were: % pts who achieved a physician global assessment of disease activity (PGA) <2 (minimal/none); % pts with C-reactive protein (CRP) ≤10 mg/L; serum amyloid A level (SAA) ≤10 mg/L at Wk 16. Methods The trial (NCT02059291) consists of 3 disease cohorts (crFMF, HIDS/MKD and TRAPS) and 4 study epochs (E1–4): a screening epoch (E1) of up to 12 wks, a randomised treatment epoch (E2) of 16 wks, a randomised withdrawal epoch (E3) of 24 wks and an open-label treatment epoch (E4) of 72 wks. Pts (age ≥2 years) with crFMF, HIDS/MKD or TRAPS with a flare during E1 were randomised (1:1) in E2 to receive CAN or PBO. Safety assessments included adverse events (AEs). Results Of 181 pts (crFMF, n=63; HIDS/MKD, n=72; TRAPS, n=46) randomised in E2, 6 pts discontinued (5 PBO; 1 CAN). In all 3 disease cohorts, the proportion of pts who were responders for the primary outcome at Wk 16 was significantly higher with CAN vs PBO (Table). At Wk 16, a significantly higher proportion of pts achieved PGA score <2, CRP ≤10 mg/L and SAA ≤10 mg/L in the CAN group vs PBO in all 3 cohorts (Table). No new safety findings were reported in the CAN-treated pts through E2 (Table). Conclusions These results demonstrated superior efficacy of canakinumab at dose level of 150 mg q4w after a 16 weeks treatment period compared to placebo. The overall safety profile was not distinct from previous controlled studies and expectations in an auto-inflammatory patient population. Disclosure of Interest F. De Benedetti Grant/research support from: Pfizer, Abbvie, Roche, Novartis, Novimmune, BMS, J. Anton Grant/research support from: Novartis, Pfizer, Abbvie, Roche, SOBI, Consultant for: Novartis, M. Gattorno Grant/research support from: Novartis, SOBI, Consultant for: Novartis, SOBI, Speakers bureau: Novartis, SOBI, H. Lachmann Consultant for: Novartis, SOBI, Takeda, GSK, Speakers bureau: Novartis, SOBI, I. Kone-Paut Grant/research support from: SOBI, Roche, Novartis, Consultant for: Novartis, SOBI, Pfizer, Abbvie, Chugai, S. Ozen Consultant for: Novartis, Speakers bureau: SOBI, J. Frenkel Grant/research support from: Novartis, SOBI, A. Simon Grant/research support from: CSL Behring, Novartis, Xoma/Servier, A. Zeft: None declared, E. Ben-Chetrit Consultant for: Novartis, H. Hoffman Grant/research support from: BMS, Consultant for: Novartis, SOBI, Regeneron, Speakers bureau: Novartis, Y. Joubert Employee of: Novartis, K. Lheritier Shareholder of: Novartis, Employee of: Novartis, A. Speziale Employee of: Novartis, G. Junge Employee of: Novartis

Studying IFN-gamma, IL-17 and FOXP3 in pediatric lupus nephritis

BackgroundWe studied the cytokines secreted by the inflammatory T cell subgroups (IFN-γ and IL-17) and FOXP3 expression in lupus nephritis (LN) and analyzed associations with clinical and histopathological parameters.MethodsRenal tissue samples of 39 LN patients were studied. Immunohistochemical staining was carried out with antibodies against IFN-γ, IL-17, and FOXP3.ResultsBoth IFN-γ (+) and IL-17+ cells were statistically higher in LN tissues when compared with controls (pu2009<u20090.01). The cells in the tubulointerstitium were CD3u2009+u2009CD4+ displaying a Th1 and Th17 phenotype, whereas the less intense population in the glomeruli was CD3-CD4-. Interstitial CD3u2009+u2009CD4+ FOXP3+ cells were also significantly higher in LN biopsies than in control tissues (pu2009<u20090.01). IFN-γ (+) and IL-17+ cells were more intense among class IV LN as compared to class II, III LN (pu2009<u20090.01 and pu2009=u20090.001, respectively). Subsequently, when IL-17 and IFN-γ staining was compared between the proliferative LN classes, class III and IV patients had more intense staining compared to class II (all pu2009<u20090.05). IFN-γ immunostaining correlated positively with serum creatinine and negatively with albumin levels and glomerular filtration rate (GFR). IL-17 immunostaining correlated with proteinuria, requirement for pulse steroids, and SLEDAI renal score, and negatively with GFR. Furthermore, glomerular and interstitial IL-17 and IFN-γ stainings were significantly associated with various parameters of histological activity (pu2009<u20090.05).ConclusionWe suggest that IFN-gamma and IL-17 could have a role in the pathogenesis and progression of LN. The Th1 and Th17 cells may be imperative in the severity of LN. Recognizing the complexity of the immune pathways involved in lupus reminds us that targeting B cells only may not suffice to control the progression of the inflammation.

Autoinflammatory Diseases with Periodic Fevers.

Purpose of ReviewOne purpose of this review was to raise awareness for the new autoinflammatory syndromes. These diseases are increasingly recognized and are in the differential diagnosis of many disease states. We also aimed to review the latest recommendations for the diagnosis, management, and treatment of these patients.Recent FindingsFamilial Mediterranean fever (FMF), cryopyrin-associated periodic syndrome (CAPS), tumor necrosis factor receptor-associated periodic fever syndrome (TRAPS), and hyperimmunoglobulinemia D and periodic fever syndrome/mevalonate kinase deficiency (HIDS/MVKD) are the more common autoinflammatory diseases that are characterized by periodic fevers and attacks of inflammation. Recently much collaborative work has been done to understand the characteristics of these patients and to develop recommendations to guide the physicians in the care of these patients. These recent recommendations will be summarized for all four diseases.SummaryFMF is the most common periodic fever disease. We need to further understand the pathogenesis and the role of single mutations in the disease. Recently, the management and treatment of the disease have been nicely reviewed. CAPS is another interesting disease associated with severe complications. Anti-interleukin-1 (anti-IL-1) treatment provides cure for these patients. TRAPS is characterized by the longest delay in diagnosis; thus, both pediatricians and internists should be aware of the characteristic features and the follow-up of these patients. HIDS/MVKD is another autoinflammatory diseases characterized with fever attacks. The spectrum of disease manifestation is rather large in this disease, and we need further research on biomarkers for the optimal management of these patients.

Therapeutic approaches for the treatment of renal disease in juvenile systemic lupus erythematosus: an international multicentre PRINTO study

Objectives To evaluate therapeutic approaches and response to therapy in juvenile systemic lupus erythematosus (SLE) with renal involvement in a large prospective international cohort from four geographic areas. Methods New onset and flared patients with active renal disease (proteinuria ≥0.5u2005g/24u2005h) were enrolled in 2001–2004. Therapeutic approaches and disease activity parameters were analysed at baseline, 6, 12 and 24u2005months. Response was assessed by the PRINTO/ACR criteria. Results 218/557 (79.8% female subjects, 117 new onset and 101 flared) patients with active renal disease were identified; 66 patients were lost to follow-up and 11 died. Mean age at disease onset for new onset group was higher than for flared group (13.1 vs 10.2u2005years, p<0.0001). At baseline, both groups had similar renal activity with similar median doses of corticosteroids (1.0–0.76u2005mg/kg/day). Cyclophosphamide (43.1%) and azathioprine (22%) were the most common immunosuppressive drugs. At baseline, South American patients received higher doses of corticosteroids than in other areas in new onset (median 1.16 vs 0.8–1 mg/kg/day) while cyclophosphamide use was similar in all four regions in the new onset group. There were no differences regarding the use of azathioprine or mycophenolate mofetil worldwide. PRINTO 70 response was reached in a greater percentage of new onset versus flared patients (74.8% vs 53.3%; p=0.005) at 6u2005months while at 24u2005months ACR 90 was reached by 69.9% and 56.1%, respectively. Conclusions New onset and flared juvenile SLE improved similarly over 24u2005months with minimal differences in therapeutic approaches worldwide.

Enalapril‐induced anemia in a renal transplant patient

Side‐effects of angiotensin converting enyzme (ACE) inhibitors, such as a slight decrease in hematocrit, are increasingly being reported. A 14‐year‐old renal transplant patient on enalapril therapy developed anemia with reticulocytosis. She was investigated for other causes of anemia and enalapril therapy was ceased. Her hemoglobin level increased and reticulocyte count decreased after cessation of therapy. No other cause of anemia was found. Although anemia in patients receiving ACE inhibitors such as enalapril has previously been reported, this is the first reported patient who developed anemia associated with mild reticulocytosis and macrocytosis.