Ilaria Pagnini

Clinical and transcriptional response to the long-acting interleukin-1 blocker canakinumab in Blau syndrome-related uveitis.

OBJECTIVE To report on the clinical response to canakinumab in a patient with sporadic nucleotide-binding oligomerization domain-containing protein 2 (NOD-2)-associated pediatric granulomatous arthritis (Blau syndrome) and severe resistant panuveitis, and to describe gene expression profile changes throughout such treatment. METHODS A 4-year-old boy was diagnosed as having Blau syndrome on the basis of typical clinical features, histologic evidence of noncaseating granulomas, and a NOD2 mutation. Ocular involvement was initially controlled by topical and oral corticosteroids, but over the years visual impairment and complications, such as macular edema and retinal detachment, progressed. Ocular disease remained persistently active despite treatment with multiple different immunosuppressants; therefore, canakinumab treatment was started. Before and during the first 6 months of treatment, the gene expression profile was determined each month. RESULTS Canakinumab treatment was well tolerated and led to rapid quiescence of uveitis, which had been continuously active before this treatment. Gene expression profiling analysis of the patients blood prior to initiation of interleukin-1 (IL-1) blockade revealed differential expression of 1,993 transcripts when compared to healthy controls, and among the up-regulated transcripts, pathway analysis showed that the predominant network consisted of innate immunity-related transcripts. The transcriptional signature of the patient overlapped with the transcriptional signature of patients with systemic-onset juvenile idiopathic arthritis, and canakinumab treatment led to the normalization of most of these transcriptional changes. CONCLUSION The pathogenesis of Blau syndrome may be mediated by IL-1, and canakinumab may be useful when this disorder is unresponsive to more conventional treatments.

Early Predictors of Juvenile Sacroiliitis in Enthesitis-related Arthritis

Objective. To identify early predictors of sacroiliac (SI) involvement in a cohort of patients with enthesitis-related arthritis (ERA). Methods. During a 7-year followup period, all consecutive patients fulfilling the ILAR classification criteria for ERA were enrolled. Data collected included demographic, clinical and laboratory variables at disease onset, at the onset of inflammatory back pain, and at the last available followup visit. Pelvis radiographs and dynamic magnetic resonance imaging (MRI) scans for SI joints were obtained simultaneously in all patients who developed inflammatory back pain. Results. Fifty-nine children with ERA were studied; 40 male, 19 female; median age at disease onset 9 years 4 months (range 6 yrs 6 mo – 13 yrs 3 mo). At a median interval after disease onset of 1 year 3 months, 21 children reported symptoms of inflammatory back pain. In all cases, radiographs of SI joints were negative, while dynamic MRI revealed acute sacroiliitis in 17 cases. Multivariate analysis showed that the early predictors of SI were the number of active joints (p < 0.03) and the number of active entheses (p < 0.001) at onset. Conclusion. In our cohort, roughly 30% of children with ERA/juvenile idiopathic arthritis develop clinical and MRI evidence of sacroiliitis, detectable with dynamic MRI as early as 1 year after disease onset. Additional data from larger case series are needed to assess the specificity and sensitivity of this technique in the early phase of the disease and to confirm the rate of SI involvement reported in this cohort.

Macrophage activation syndrome/hemophagocytic lymphohistiocytosis and Kawasaki disease

To the Editor: We read with interest the two recent reports on Hemophagocytic Lymphohistiocytosis (HLH) associated with Kawasaki disease (KD) [1,2]. Both are inflammatory conditions and clinical features can overlap, to the point that in one of the two reported cases [1] the diagnosis was uncertain. In patients with rheumatologic disorders, particularly systemic onset Juvenile Idiopathic Arthritis, macrophage activation syndrome (MAS) is sometimes seen. MAS is a systemic inflammatory disorder caused by uncontrolled histiocytic proliferation, hemophagocytosis, activation of macrophages and inflammatory cytokine up-regulation. It can be secondary to several rheumatic diseases, including Kawasaki disease [3–5]. It is thought that reactive HLH and MAS may represent the same disorder [6–8]. We recently diagnosed with KD a patient who at the onset of disease also presented findings suggestive of MAS and would like to add our recent experience. A 20-month-old female presented with a history of fever for 6 days unresponsive to antibiotic treatment. Upon admission she was pale and restless; clinical evaluation showed bilateral conjunctivitis, a diffuse maculopapular rash, oral mucosal changes, and edema of the extremities. Laboratory investigations showed elevation of C-reactive protein (16.3 mg/L) but normal erythrocyte sedimentation rate, hemoglobin of 10.6 g/dl, platelet count 59,000/ l, hyponatremia (133 mEq/L), and elevated AST/ALT (185 and 64 UI/L, respectively). Infections were ruled out. Abdominal ultrasound showed splenomegaly, an abdominal effusion and hydrops of the gallbladder, while echocardiography showed abnormalities of all coronary arteries (with brightness of the left and dilatation of the anterior and right vessels) and a pericardial effusion. Diagnosis of KD was made and treatment with IVIG (2 g/kg) performed. Despite treatment she remained febrile and irritable. Laboratory tests showed further increase of C-reactive protein and liver function tests, hypoalbunimenia, persistent thrombocytopenia, as well as increased levels of d-dimers (2076 mg/dl, n.v. 50–250 ng/ml), lactate dehydrogenase, cholesterol, triglycerides, and ferritin. A second course of IVIG was then administered, with resolution of fever and reduction of laboratory abnormalities and coronary dilatations. The child was discharged 7 days after admission and was subsequently followed, up to complete recovery. Although bone marrow aspiration showing hemophagocytosis was not performed, even if she did not fulfill classical HLH criteria, on the basis of clinical and laboratory findings we diagnosed MAS [9]. Apart from nomenclature issues, we think that a practical point is represented by treatment decisions, in that MAS is usually treated with high steroids +/− cyclosporine only, while HLH is initially treated with more potent medications including etoposide [1]. At least some secondary (reactive) cases appear not to need chemotherapy but can be treated with standard high-dose immunosuppression only [10]. In conclusion, KD can present with criteria that are not included in the official definition, and therefore, can be atypical and/or incomplete; among those non-classic criteria, MAS/HLH can be seen [5].

Clinical Features and Outcome of Cogan Syndrome

OBJECTIVE To review the clinical features of Cogan syndrome, a rare vasculitis characterized by systemic, ocular, and audiovestibular symptoms. STUDY DESIGN Clinical records of patients with Cogan syndrome followed at 2 pediatric rheumatology institutions and those from a database search were reviewed. Data included clinical features at onset and during the disease course, treatments, and outcomes. RESULTS Twenty-three children with Cogan syndrome (15 males; mean age, 11.4 years [range, 4-18 years]) were included in the analysis. Eleven patients (47.8%) exhibited systemic features at disease onset, including fever, arthralgias-arthritis or myalgias, headache, and weight loss. Twenty-one patients (91.3%) had ocular symptoms, due mainly to interstitial keratitis, uveitis, or conjunctivitis/episcleritis. Vestibular symptoms (39.1%) included vertigo, vomiting, and dizziness. Auditory involvement (65.2%) consisted of sensorineural hearing loss, tinnitus, and deafness. Four patients had cardiac valve involvement, and 3 had skin manifestations. After a median 2 years of follow-up, 30.4% of the patients were in clinical remission, but all others had irreversible complications (deafness, 21.7%; sensorineural hearing loss, 13.0%; vestibular dysfunction, 4.3%; ocular complications, 13.0%; cardiac valve damage, 17.4%). CONCLUSION Audiovestibular and ocular involvement have a major impact on prognosis in children with Cogan syndrome.

Treatment strategies for childhood noninfectious chronic uveitis: an update

Background: Uveitis is an inflammatory disorder involving inflammation of the uveal tract. It is classified as anterior, intermediate, posterior or panuveitis, depending on the part of eye affected by the inflammatory process. In children, noninfectious, chronic uveitis is a relatively uncommon but serious disease, with the potential for significant long-term complications and possible blindness. Although frequently associated with an underlying systemic disease, for example, juvenile idiopathic arthritis, a significant number of cases in children show no associated signs or symptoms and are labeled as idiopathic. Results: We reviewed the available literature. Taking into account this evidence, an anti-inflammatory therapy based on an immunomodulatory approach seems a reasonable strategy for noninfectious chronic uveitis, in children as well as in adults. Due to a lack of controlled studies regarding uveitis in children, immunosuppressive strategy is supported only at evidence level III. Our aim is to review the currently available medical strategies for the treatment of childhood sight-threatening chronic uveitis. Conclusion: Uveitis in children can be severe. Methotrexate is the drug of choice for recalcitrant cases, and biologic therapies can be useful in selected situations.

Development and retrospective validation of the juvenile spondyloarthritis disease activity index

To develop and validate the Juvenile Spondyloarthritis Disease Activity Index (JSpADA) for use in clinical practice and research.

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

Distal extremity pain as a presenting feature of Fabry's disease.

Fabrys disease (FD) is an X‐linked lysosomal storage disease. Distal extremity pain can be an early finding and renal, cardiac, and cerebrovascular complications may lead to complications and mortality. Treatment is now available for these patients, who may not be diagnosed correctly for years if the neuropathic nature of the pain is not recognized. The aim of our study was to describe early clinical features in a cohort of patients with FD and to emphasize the importance of distal extremity pain for early diagnosis.

Identification of autoantibodies against inner ear antigens in a cohort of children with idiopathic sensorineural hearing loss.

Abstract Immune-mediated pathogenesis has been suggested for idiopathic sensorineural hearing loss. Recent studies have investigated the relationship between idiopathic sensorineural hearing loss and autoantibodies against inner ear antigens. We conducted a prospective, observational study in a series of pediatric patients affected by idiopathic sensorineural hearing loss. Autoantibodies against inner ear (anti-Cogan peptide, anti-connexin 26, anti-DEP1/CD148 and anti-reovirus), previously described in the serum of patients with Cogan’s syndrome, were detected in our population. The characteristics of children whose results were positive were also evaluated to verify if clinical data, disease progression and response to treatment could confirm an immune-mediated pathogenesis. Eleven patients were enrolled and 9 of them were positive for inner ear antibodies. Non-organ specific autoantibodies were present in 5 children out of 9. An immune-mediated condition was diagnosed in 2 cases and minor immune manifestations were found in 2 additional patients. In 5 cases hearing loss remained stable without therapy, while 4 children developed progression. Two subjects were treated with corticosteroids and methotrexate, achieving hearing improvement. Another subject showed stabilization on methotrexate. Inner ear autoantibodies can be positive in children with autoimmune sensorineural hearing loss, and in conjunction with clinical data may assist the clinician in identifying a subset amenable for immune modulation therapy. Large prospective studies are needed to investigate usefulness, diagnostic and prognostic role of these autoantibodies.

Alteration of Fecal Microbiota Profiles in Juvenile Idiopathic Arthritis. Associations with HLA-B27 Allele and Disease Status.

Alteration of gut microbiota is involved in several chronic inflammatory and autoimmune diseases, including rheumatoid arthritis, and gut microbial “pro-arthritogenic” profiles have been hypothesized. Intestinal inflammation may be involved in spondyloarthropathies and in a subset of patients affected by Juvenile Idiopathic Arthritis (JIA), the most common chronic rheumatic disease of childhood. We compared the fecal microbiota composition of JIA patients with healthy subjects (HS), evaluating differences in microbial profiles between sub-categories of JIA, such as enthesitis-related arthritis (JIA-ERA), in which inflammation of entheses occurs, and polyarticular JIA, non-enthesitis related arthritis (JIA-nERA). Through taxon-level analysis, we discovered alteration of fecal microbiota components that could be involved in subclinical gut inflammation, and promotion of joint inflammation. We observed abundance in Ruminococcaceae in both JIA categories, reduction in Clostridiaceae and Peptostreptococcaceae in JIA-ERA, and increase in Veillonellaceae in JIA-nERA, respectively, compared with HS. Among the more relevant genera, we found an increase in Clostridium cluster XIVb, involved in colitis and arthritis, in JIA-ERA patients compared with HS, and a trend of decrease in Faecalibacterium, known for anti-inflammatory properties, in JIA-nERA compared with JIA-ERA and HS. Differential abundant taxa identified JIA patients for the HLA-B27 allele, including Bilophila, Clostridium cluster XIVb, Oscillibacter, and Parvimonas. Prediction analysis of metabolic functions showed that JIA-ERA metagenome was differentially enriched in bacterial functions related to cell motility and chemotaxis, suggesting selection of potential virulence traits. We also discovered differential microbial profiles and intra-group variability among active disease and remission, suggesting instability of microbial ecosystem in autoimmune diseases with respect to healthy status. Similarly to other chronic autoimmune and inflammatory diseases, different microbial profiles, as observed among different JIA subgroups compared to HS, and potential functional acquisition related to migration, could promote inflammation and contribute to the disease pathogenesis.