Achille Marino

Successful treatment with canakinumab of a paediatric patient with resistant Behçet’s disease

SIR, Behçet’s disease (BD) is a systemic vasculitis characterized by a wide clinical spectrum including recurrent oral and genital ulceration, uveitis, vascular, neurological, articular, renal and gastrointestinal manifestations [1]. Treatment of BD depends on the clinical manifestation and organ involvement. Although colchicine, NSAIDs and topical steroids are often sufficient for mucocutaneous and joint involvement, a more aggressive approach with immunosuppressive drugs is necessary for severe manifestations such as posterior uveitis, retinal vasculitis, recurrent fevers, vascular, neurological and gastrointestinal involvement. However, some patients still have refractory disease, flares or irreversible organ damage. Recent advances in the study of pathogenic mechanisms have enabled the identification of new potential targets and future biologic therapies for BD. In contrast to current non-specific immunosuppressive agents, often used empirically, the emergence of biotherapies provides the possibility of interfering with specific pathogenic pathways and appears to promise treatments for patients with refractory or relapsing BD [1]. We describe a child with juvenile BD with recurrent fevers, oral and genital ulceration, skin lesions, arthralgia and abdominal pain, who was unsuccessfully treated with a range of immunosuppressive drugs and biotherapies. He achieved clinical remission only with canakinumab, a fully human anti-IL-1 b antibody. A 9-year-old Caucasian boy was diagnosed as having BD at the age of 5 years, based on typical clinical manifestations. When he was 2 years old, he had started to complain of constipation, abdominal pain and encopresis, associated with recurrent oral ulceration, skin lesions (papulopustolar with ulcers, especially on the face) and photophobia. Two years later he presented with recurrent fevers, genital ulceration and headaches. Laboratory tests showed mild anaemia (haemoglobin 11.7 g/dl), normal ESR and CRP level, and positivity for HLA-B51. Coeliac disease screening, ANA, ANCA, anti-Saccharomyces cerevisiae antibodies, aCL, anti-b2-glycoprotein antibodies and faecal calprotectin were all negative. A barium enema showed dolichocolon and diffuse hypokynesia of the large bowel. Gastrointestinal endoscopy and brain MRI were normal. A pathergy test was also performed and resulted positive after 48 h. Uveitis was excluded by ophthalmological examination. A diagnosis of BD was made in October 2010 and treatment with colchicine (initially at the dosage of 0.25 mg/ day, after 4 months increased to 0.5 mg/day) and prednisone 15 mg/day was commenced. After a few months, due to persistent oral and skin ulceration, associated with constipation, abdominal pain, arthralgia, recurrent fever and headache, the colchicine was interrupted and thalidomide 50 mg/day was added to the prednisone (0.5 mg/kg/day). Three months later, clinical symptoms were still present, so MMF 250 mg twice a day was substituted for the thalidomide. However, clinical improvement was still not reached after another 4 months; therefore, biotherapy with adalimumab (24 mg/m every 2 weeks) was started in association with the MMF. Quite quickly, the fever, headache, abdominal pain and oral ulceration disappeared, but after a few months all systemic clinical features reappeared. So, adalimumab and MMF were stopped and anakinra (2 mg/kg) was introduced, initially at the dosage of 2 mg/kg/day, increased to 4 mg/kg/day, with only partial benefit. Oral and skin ulceration, recurrent fever, arthralgia, headaches and abdominal pain were in fact still present, associated with a persistent increase in inflammatory markers and mild anaemia. Thus, after 19 months of treatment with anakinra we switched to canakinumab, at a dose of 4 mg/kg every 28 days. After 4 months of this therapy, complete clinical and laboratory remission was obtained. Of note, steroid treatment was gradually reduced to 5 mg/day. At the last follow-up (6 months after the first dose) the boy was completely asymptomatic. BD is often difficult to treat, and requires biologic treatment in cases with severe systemic involvement. Initially, TNF inhibitor was used successfully, but resistant cases exist and hence other biologics have been tried. Canakinumab is a human mAb targeted at IL-1b that has been shown to be effective in various autoinflammatory syndromes such as cryopyrin-associated periodic syndrome and systemic JIA [2, 3]. Anakinra, a recombinant, non-glycosylated human IL-1 receptor antagonist, has been used in patients with BD refractory to conventional treatments [4]; and gevokizumab, a recombinant humanized anti-IL-1b antibody, was used in seven BD patients with resistant uveitis and retinal vasculitis [5]. Interestingly, our patient did not respond to anakinra, but benefited from canakinumab. Both agents are IL-1 blockers, but anakinra blocks IL-1a and IL-1b and has a short half-life (4 6 h), while canakinumab specifically targets IL-1b and has a longer half-life. To our knowledge, there are only a few published reports of BD patients treated with canakinumab: three adults [6, 7] and a 16-year-old girl [8]. To our knowledge our case is, therefore, the youngest reported so far. Although more studies are necessary to confirm the efficacy and safety of canakinumab in paediatric patients with persistent systemic

Cutaneous neonatal lupus: a case report and review of the literature

At the age of two months, a Caucasian male infant was referred to our Dermatology Unit at Meyer Pediatric Hospital because of a 3-week history of cutaneous erythematous annular lesions increasing in size and involving the left cheek, scalp, retroauricular areas, and abdominal skin (Figs. 1–3). The mother referred two previous spontaneous abortions. After an uncomplicated 39-week gestation period, an elective Cesarean section was performed. Weight at birth was 2.325 kg, and Apgar score was 9. Both mother and father were apparently healthy. At physical examination, cutaneous lesions were confirmed in the absence of other systemic manifestations. Laboratory findings did not show signs of inflammation. We diagnosed neonatal lupus erythematosus (NLE) and, therefore, cardiologic examination with ECG and echocardiography were performed but did not show abnormalities. The mother had a positive autoantibody profile for ANA (1 : 2560), anti-SSA/Ro 52, anti-SSB/La, and anti-U1RNP. She was only on hydroxychloroquine therapy. The results of the autoantibody profile of the infant confirmed positivity for ANA, ENA SSA-Ro 52, SSB-La, and U1RNP. After two months, cutaneous lesions had disappeared. At the age of six months, the boy was still asymptomatic, ECG was normal, and autoantibody profile had normalized.

What Do Cytokine Profiles Tell Us About Subsets of Juvenile Idiopathic Arthritis

Classification of juvenile idiopathic arthritis is an ongoing process and up to now has been predominantly based on clinical manifestations—mainly number of joints at onset of disease. In the meantime, basic studies have advanced our knowledge regarding the disease pathogenesis. Unfortunately, studies of cytokines and cytokine polymorphisms have not followed the predominantly clinical International League of Associations for Rheumatology classification in that no significant biological differences among the different disease categories have been demonstrated with robust associations. Only systemic-onset disease seems to be quite different from other disease categories with regard to biologic mechanisms; indeed, it now seems closer to autoinflammatory than to classic autoimmune diseases. New players in the immunologic basis of juvenile idiopathic arthritis (eg, interleukin-17 and regulatory T cells) are also discussed in this review.

How I treat juvenile idiopathic arthritis: A state of the art review

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children and an important cause of short and long-term disability. JIA encompasses several disease categories, each of which has distinct presentation, clinical manifestations, and, presumably, genetic background and etiopathogenesis. Correct choice and timely use of available medications to achieve early and sustained remission with as few side effects as possible remain challenges for the treating physician. This review aims to provide daily practical advice for the treatment of JIA patients on the basis of both our experience and existing recommendations.

Elbow monoarthritis: an atypical onset of juvenile idiopathic arthritis.

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic condition in childhood and an important cause of short and long term disability. Oligoarthritis is defined as an arthritis that affects four o fewer joints during the first 6 months of disease. The large majority of patients within this category belongs to a quite well defined disease which is not observed in adults. It is characterized by an early onset (before 6 years of age), an asymmetric arthritis involving mainly large joints, a female predilection, a high frequency of positive antinuclear antibodies (ANA), a high risk for developing chronic iridocyclitis and consistent HLA associations. We describe 3 clinical cases who presented monoarthritis of the elbow as early sign of oligoarticular JIA. All patients showed inflammatory markers elevation and 2/3 were ANA positive. MRI showed the presence of synovial inflammation without bone involvement. Intraarticular triamcinolone hexacetonide, led to remission in one case, while in the other two there was a re-activation of the disease treated with NSAIDs and/or MTX. The reported cases represent 0.6% of 490 patients with JIA followed by our unit in the last 10 years. Cases of exclusive involvement of the elbow at onset of JIA in literature are rare. Therefore, we report 3 cases of monoarthritis of the elbow as initial sign of oligoarticular JIA, a very atypical onset of this disease.

AB1024 A Rare Case of Neonatal Antiphospholipid Syndrome

Background Neonatal Antiphospholipid antibody syndrome (APS) is a rare clinical entity linked to the transplacental transfer of antiphospholipid antibodies (aPL). Additional risk factors such as asphyxia, sepsis, arterial or venous catheter, congenital thrombophylia are frequently associated, precipitating the thrombophylic action of aPL. Objectives We describe a case of neonatal thrombotic stroke associated with IgG (but not IgM) aPL. Methods A 6 month old Caucasian child presented to our clinic with a history of seizures, delayed psychomotor development, right hemiparesis and right homonymous hemianopsia. The family history was uncontributive. A placental abruption on the 3rd month of gestation and premature contractions in the second trimester were reported. The child was born at 38 weeks of gestational age with a natural childbirth, and a fetal APGAR index of 9/9. However the mother noticed a left facial hypotrophy since the first days of life, and described a progressively reduced use of his right arm. At 3 months of age the child developed a divergent strabismus, and recurrent partial seizures. Results Cerebral MRI at 6 months of age exhibited changes consistent with ischemic cerebral lesions in the left middle cerebral artery territory with a MR angiography showing a thinning caliber of this vessel. Heart ultrasound was unremarkable. Routine laboratory test including infectious serologies were normal or negative. Prothrombotic risk factors ie PT, APTT, fibrinogen, protein S, protein C, Lupus Anticoagulant, IgM Anticardiolipin antibodies and IgM β2 GP1 were negative or in normal range. IgG anticardiolipin were elevated at 17 U/ml (normal <10), and IgG β2 GP1 were also positive at 59 U/ml (normal <10). Molecular genetic testing demonstrated heterozygosity for G1691A factor V Leiden mutation. Subsequently, at the age of 9 months IgG anticardiolipin and β2 GP1 resulted negative. Testing for aPL was performed 6 months after the delivery in the mother and was negative. The child currently presents a refractory epilepsy and an abnormal neurological status with trunk hypotonia and global developmental delay. Conclusions aPL-related thrombosis is exceedingly rare In the neonatal period. The consequences depend on the type of organ and vessel involved, the vessel size and on the rapid or slow course of the thrombotic process. The most frequently described type of thrombotic events is deep venous thrombosis in the lower extremities, pulmonary embolism, and thrombotic complications in the central nervous system. aPL alone may not be sufficient to cause the ischemic damage, and others prothrombotic conditions are probably implicated. In our patient the heterozygosity for factor V Leiden mutation, placental abruption at the III month of pregnancy and premature contractions may have contributed to the thromboembolic disease in presence of maternal IgG aPL. Disclosure of Interest None declared

AB1025 Chronic Recurrent Multifocal Osteomyelitis (CRMO): The Importance of an Accurate Differential Diagnosis

Background CRMO is a rare auto-inflammatory disorder, characterized by pain related to the presence of multifocal sites of sterile bone inflammation. CRMO is a diagnosis of exclusion established by clinical presentation, imaging studies, and culture-negative bone biopsy. Objectives To compare 2 clinical cases with very similar clinical and radiological presentation but different diagnosis and outcome. Methods Case 1. MM is a 11-year-old boy presented with a 4-months history of progressive left-clavicle pain associated with fever and good response to non-steroidal anti-inflammatory drugs (NSAIDs). Clinical examination revealed right supra-clavicle lymphadenopathy, and functional limitation of left arm with pain elicited by left clavicle palpation. Laboratory tests showed increase of inflammatory markers but normal complete blood count and LDH levels. Chest X-ray and abdominal ultrasonography were negative. Left clavicle MRI was compatible with osteomyeltis and empiric antibiotic therapy was started with clinical improvement. Three months later the patient presented with pain at right shoulder and arm, fever and nocturnal awakenings associated with persistent lymphoadenopathy. Inflammatory markers were increased and infections were excluded. Elbow X-ray and ultrasonography resulted negative as well as bone marrow aspirate. Bone-scintigraphy showed multiple sites of uptake and whole-body MRI showed multiple bone lesions located on both scapulae, clavicles, upper limbs, vertebrae (D5-11), and sternum. A diagnosis of CRMO was hypothesized. Case 2. LP presented at the age of 15 y with lumbosacral pain worsened with back movements, load lifting, and running, and present also at night. NSAIDs therapy was started, with partial improvement. Laboratory tests revealed slight increase of inflammatory markers, while X-Ray of the pelvis and the lumbosacral spine was normal. As an infectious form was initially suspected, broad-spectrum intravenous antibiotic therapy was administered. Whole-body MRI showed multiple bone lesions of the left femur, right sacrum and spine (L4, D12), findings confirmed by bone PET. Bone marrow aspirate excluded the presence of blast cells and extrinsic infiltration. Results In order to obtain a definitive diagnosis bone biopsies were performed in both cases. In Case 1 bone histological examinations revealed lymphoid cells proliferation, and the diagnosis of B-cell lymphoblastic leukemia/lymphoma was confirmed by histological findings on lymph node biopsy. In Case 2 bone biopsy and histological examination showed lympho-histiocytic infiltrate without neoplastic cells. In the hypothesis of CRMO naproxen therapy was administered for 3 months, followed by clinical and radiological improvement. Conclusions In these two cases clinical and radiological (especially whole-body MRI findings) presentations were very similar, and the diagnosis was possible only with histology. Moreover, in Case 2 bone lesions detected with MRI had typical location and findings attributable to autoinflammatory-bone disorders and the patient had a good response to therapy with NSAIDs, unlike Case 1. These two cases point out the difficulties and the caution to correctly diagnose a rare autoinflammatory bone disease. Disclosure of Interest None declared

Localized scleroderma in a cohort of juvenile idiopathic arthritis children.

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in childhood. Localized scleroderma also known as morphea is an inflammatory, fibrosing skin disorder that leads to sclerosis of the dermis and eventually of the underlying tissues. The prevalence is estimated at around 1-9/100,000 with the onset before 10 years of age in 2% of patients.The association between different autoimmune diseases is well described, but few studies have been performed to investigate the relationship between JIA and other autoimmune diseases, in particular very little is written about the possible association between arthritis and morphea. In these cases articular involvement in terms of arthralgia, impaired joint mobility, or joint contracture, may be related to a mechanical etiology secondary to the contracture of the overlying skin.