Ezgi Deniz Batu

Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease

Systemic autoinflammatory diseases are driven by abnormal activation of innate immunity. Herein we describe a new disease caused by high-penetrance heterozygous germline mutations in TNFAIP3, which encodes the NF-κB regulatory protein A20, in six unrelated families with early-onset systemic inflammation. The disorder resembles Behçets disease, which is typically considered a polygenic disorder with onset in early adulthood. A20 is a potent inhibitor of the NF-κB signaling pathway. Mutant, truncated A20 proteins are likely to act through haploinsufficiency because they do not exert a dominant-negative effect in overexpression experiments. Patient-derived cells show increased degradation of IκBα and nuclear translocation of the NF-κB p65 subunit together with increased expression of NF-κB–mediated proinflammatory cytokines. A20 restricts NF-κB signals via its deubiquitinase activity. In cells expressing mutant A20 protein, there is defective removal of Lys63-linked ubiquitin from TRAF6, NEMO and RIP1 after stimulation with tumor necrosis factor (TNF). NF-κB–dependent proinflammatory cytokines are potential therapeutic targets for the patients with this disease.

A Case Series of Adenosine Deaminase 2-deficient Patients Emphasizing Treatment and Genotype-phenotype Correlations.

To the Editor: Deficiency of adenosine deaminase 2 (DADA2) causes a vasculopathy with autoinflammatory features associated with mutations in CECR1 1. The phenotype of DADA2 varies from only cutaneous lesions to full-blown systemic disease with central nervous system (CNS) involvement and aneurysms in visceral arteries that may overlap with the spectrum of polyarteritis nodosa (PAN)1,2,3. The Chapel Hill Consensus Conference (CHCC) 2012 defines PAN as a necrotizing vasculitis of medium or small arteries without glomerulonephritis or vasculitis in arterioles, venules, or capillaries and not associated with antineutrophil cytoplasmic antibodies4. Now, with the discovery of DADA2, we know that monogenic disorders may cause a PAN-like vasculopathy. Thus, DADA2 should be classified under the group of “vasculitis with a probable cause” in CHCC 20124. We herein present the characteristics of 6 DADA2 patients and their response to various therapies. Three of our patients had been initially screened at the U.S. National Institutes of Health (NIH) because they had suggestive features for the CECR1 mutations. Subsequently, we screened 17 patients with suggestive features and identified 3 new cases. We have evaluated the course of these patients for a followup of median 8.5 years. All patients were Turkish and were followed in the departments of Rheumatology and Pediatric Rheumatology at Hacettepe University, Ankara, Turkey. Three (patients 2, 3, and 5) had been included in a previous paper2. Peripheral blood samples for DNA extraction were obtained. Sanger sequencing was performed to sequence 10 exons of CECR1 in NIH (n = 3) and Hacettepe University (n = 3). Primer sequences are available in the Appendix. PCR products were directly sequenced using ABI Prism 3130 Automated Sequencer (Applied Biosystems). We defined 6 DADA2 patients from 5 families. The characteristics and treatment of patients … Address correspondence to Dr. S. Ozen, Department of Pediatrics, Division of Rheumatology, Hacettepe University Faculty of Medicine, Ankara 06100, Turkey. E-mail: sezaozen{at}hacettepe.edu.tr

Familial Mediterranean fever: current perspectives

Familial Mediterranean fever (FMF) is the most frequent monogenic autoinflammatory disease, and it is characterized by recurrent attacks of fever and polyserositis. The disease is associated with mutations in the MEFV gene encoding pyrin, which causes exaggerated inflammatory response through uncontrolled production of interleukin 1. The major long-term complication of FMF is amyloidosis. Colchicine remains the principle therapy, and the aim of treatment is to prevent acute attacks and the consequences of chronic inflammation. With the evolution in the concepts about the etiopathogenesis and genetics of the disease, we have understood that FMF is more complicated than an ordinary autosomal recessive monogenic disorder. Recently, recommendation sets have been generated for interpretation of genetic testing and genetic diagnosis of FMF. Here, we have reviewed the current perspectives in FMF in light of recent recommendations.

Vasculitis in children

Primary systemic vasculitides of the young are relatively rare diseases, but are associated with significant morbidity and mortality, particularly if there is diagnostic delay. We provide an overview of paediatric vasculitides with emphasis on key differences in vasculitis presentation and management between children and adults. Significant advances in the field of paediatric vasculitis research include the development of classification criteria and disease outcome tools for paediatric disease; inclusion of paediatric patients in international multicentre randomized controlled trials of therapies in vasculitis; and development of rare disease trial designs for therapeutic trials of paediatric vasculitis. The continuation of unmet needs as well as the exploration of potential therapeutic avenues and considerations in the design of future trials are also discussed.

The myths we believed in familial Mediterranean fever: what have we learned in the past years?

Familial Mediterranean fever is the most common monogenic periodic fever syndrome over the world especially in the eastern Mediterranean. It presents with recurrent and self-limited inflammatory attacks of fever and polyserositis along with high acute-phase reactants. The disease is associated with mutations in the MEFV gene that encodes pyrin, a component of inflammasome, which leads to exaggerated inflammatory response through uncontrolled production of interleukin 1. With the identification of the gene associated with the disease, we believed that everything was solved and that this was an ordinary monogenic disease with autosomal recessive inheritance. However, through the breathtaking progress in the basic research field as well as the clinical care of these patients, we have understood that the picture for this monogenic disorder was more complicated than we had anticipated. In this review, we have discussed the myths we believed in familial Mediterranean fever and how they have evolved during the past years.

Tocilizumab treatment in childhood Takayasu arteritis: Case series of four patients and systematic review of the literature

OBJECTIVE Our aim was to describe our experience with tocilizumab (interleukin 6 receptor antagonist) treatment in children with Takayasu arteritis and to review previous studies regarding tocilizumab use in Takayasu arteritis patients. PATIENTS AND METHODS We reviewed the charts of all pediatric Takayasu arteritis patients followed up between 2000 and 2015 in Department of Pediatric Rheumatology in Hacettepe University, Ankara, Turkey, and we present the patients who were treated with tocilizumab. We screened PubMed and MEDLINE for articles involving Takayasu arteritis patients treated with tocilizumab. RESULTS We have followed four pediatric Takayasu arteritis patients who received tocilizumab. The median duration of immunosuppressive treatment before tocilizumab onset was 16 (1-60) months. The median duration of tocilizumab treatment was 9.5 (7-13) months. One of our patients received tocilizumab as a first line immunosuppressive treatment directly after methylprednisolone. Others were resistant to their initial immunosuppressive treatment (cyclophosphamide, methotrexate, or azathioprine). All achieved complete response to tocilizumab at the third month of treatment. None of the patients reported any adverse events during the follow-up. In literature review, we identified 19 articles describing 75 Takayasu arteritis patients treated with tocilizumab. Eight of these received tocilizumab before the age of 18 years. Tocilizumab was the first line immunosuppressive treatment in six patients (five adults and one child). CONCLUSION Our small series suggests that tocilizumab may be a promising alternative for Takayasu arteritis treatment. Long-term controlled studies are warranted to provide better evidence for tocilizumab treatment in childhood Takayasu arteritis.

A20 haploinsufficiency (HA20): clinical phenotypes and disease course of patients with a newly recognised NF-kB-mediated autoinflammatory disease

Objectives The association between mutations in TNFAIP3, encoding the NF-kB regulatory protein A20, and a new autoinflammatory disease has recently been recognised. This study aims at describing the clinical phenotypes and disease course of patients with A20 haploinsufficiency (HA20). Methods Data for all cases from the initial publication, and additional cases identified through collaborations since, were collected using standardised data collection forms. Results A total of 16 patients (13 female) from seven families with a genetic diagnosis of HA20 were included. The disease commonly manifested in early childhood (range: first week of life to 29 years of age). The main clinical symptoms were recurrent oral, genital and/or gastrointestinal ulcers (16/16), musculoskeletal (9/16) and gastrointestinal complaints (9/16), cutaneous lesions (8/16), episodic fever (7/16), and recurrent infections (7/16). Clinical phenotypes varied considerably, even within families. Relapsing-remitting disease course was most common, and one patient died. Laboratory abnormalities included elevated acute-phase reactants and fluctuating presence of various autoantibodies such as antinuclear antibodies (4/10 patients tested) and anti-dsDNA (2/5). Tissue biopsy of different sites revealed non-specific chronic inflammation (6/12 patients tested), findings consistent with class V lupus nephritis in one patient, and pustules and normal results in two patients each. All patients were treated: 4/16 received colchicine and 12/16 various immunosuppressive agents. Cytokine inhibitors effectively suppressed systemic inflammation in 7/9 patients. Conclusions Early-onset recurrent oral, genital and/or gastrointestinal ulcers are the hallmark feature of HA20. Frequency and intensity of other clinical manifestations varied highly. Treatment regimens should be based on disease severity, and cytokine inhibitors are often required to control relapses.

Assessment of the HScore for reactive haemophagocytic syndrome in patients with rheumatic diseases

Objectives: Reactive haemophagocytic syndrome (RHS) is a hyperinflammatory disorder often occurring in the background of several disorders such as infections, malignancies, and rheumatic diseases. Recently, a score known as the HScore was developed for the diagnosis of RHS. In the original study, most of the patients had underlying haematological malignancy or infection and the best cut-off value for the HScore was 169 (sensitivity 93%; specificity 86%). In this study we aimed to analyse the performance of the HScore in rheumatic disease-related RHS. Method: The patients with rheumatic disorders evaluated in the Departments of Rheumatology and Paediatric Rheumatology at Hacettepe University, Ankara, Turkey between 2002 and 2014 were reviewed retrospectively. The first group (n = 30) consisted of patients with RHS; the control group (n = 64) included patients with active rheumatic diseases without RHS. Results: In the RHS group, 14 (46.7%) had adult-onset Still’s disease (AOSD), 10 (33.3%) systemic juvenile idiopathic arthritis (SJIA), and six (20%) systemic lupus erythematosus (SLE). The control group (n = 64) consisted of 32 (50%) AOSD, 13 (20.3%) SJIA, and 19 (29.7%) SLE patients. Applying the HScore to the RHS patients, the best cut-off value was 190.5 with a sensitivity of 96.7% and specificity of 98.4%. When we excluded the patients from the control group who had not had bone marrow aspiration (n = 23), the same cut-off (190.5) performed best (sensitivity 96.7%; specificity 97.6%). Applying the 2004 haemophagocytic lymphohistiocytosis (HLH-2004) criteria gave a sensitivity of 56.6% and a specificity of 100% in the whole study group. Conclusions: In our study, a cut-off value for the HScore different from the original study performed better. Further studies are warranted to determine optimum cut-off values in different studies.

Familial Mediterranean Fever: Recent Developments in Pathogenesis and New Recommendations for Management

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease (AID) affecting mainly the ethnic groups originating from Mediterranean basin. The disease is characterized by self-limited inflammatory attacks of fever and polyserositis along with elevated acute phase reactants. FMF is inherited autosomal recessively; however, a significant proportion of heterozygotes also express the phenotype. FMF is caused by mutations in the MEFV gene coding for pyrin, which is a component of inflammasome functioning in inflammatory response and production of interleukin-1β (IL-1β). Recent studies have shown that pyrin recognizes bacterial modifications in Rho GTPases, which results in inflammasome activation and increase in IL-1β. Pyrin does not directly recognize Rho modification but probably affected by Rho effector kinase, which is a downstream event in the actin cytoskeleton pathway. Recently, an international group of experts has published the recommendations for the management of FMF. Colchicine is the mainstay of FMF treatment, and its regular use prevents attacks and controls subclinical inflammation in the majority of patients. Furthermore, it decreases the long-term risk of amyloidosis. However, a minority of FMF patients fail to response or tolerate colchicine treatment. Anti-interleukin-1 drugs could be considered in these patients. One should keep in mind the possibility of non-compliance in colchicine-non-responders. Although FMF is a relatively well-described AID and almost 20 years has passed since the discovery of the MEFV gene, there are still a number of unsolved problems about it such as the exact mechanism of the disease, symptomatic heterozygotes and their treatment, and the optimal management of colchicine resistance.

Periodic Fever, Aphthosis, Pharyngitis, and Adenitis Syndrome: Analysis of Patients From Two Geographic Areas.

Periodic fever, aphthosis, pharyngitis, and adenitis (PFAPA) syndrome is a periodic fever syndrome of childhood with an unknown etiology. Our aim was to compare the features between PFAPA syndrome patients from Turkey and those from the US, and patients with and without MEFV variants, and to test the performance of the Eurofever criteria in excluding other autoinflammatory disorders.