Teresa Giani

Validation of a diagnostic score for the diagnosis of autoinflammatory diseases in adults

Most autoinflammatory disorders typically come out in the pediatric population, although a limited number of patients may experience disease onset during adulthood. To date, a late disease onset has been described only in familial Mediterranean fever, caused by mutations in the MEFV gene, and in tumor necrosis factor receptor-associated periodic syndrome, caused by mutations in the TNFRSF1A gene. The relative rarity and lack of information on adult-onset autoinflammatory diseases make it likely that mutations will be found in an even smaller percentage of cases. With the aim of improving the genetic diagnosis in adults with suspected autoinflammatory disorders, we recently identified a set of variables related to the probability of detecting gene mutations in MEFV and TNFRSF1A and, in addition, we have also proposed a diagnostic score for identifying those patients at high risk of carrying mutations in these genes. In the present study we evaluated the preliminary score sensitivity and specificity on a wider number of patients in order to validate the goodness of fit of the model. Two hundred and nineteen consecutive patients with a clinical history of periodic fever attacks were screened for mutations in MEFV and TNFRSF1A genes; detailed information about family/personal history and clinical manifestations were also collected. For the validation of the score we considered data both from the 110 patients used to build the preliminary diagnostic score and from the additional 219 patients enrolled in the present study, for a total number of 329 patients. Early age at disease onset, positive family history for recurrent fever episodes, thoracic pain, abdominal pain and skin rash, which are the variables that had previously been shown to be significantly associated with a positive genetic test result (12), were used for validation. On univariate analysis the associations with a positive genetic test were: age at onset (odds ratio [OR] 0.43, p=0.003), positive family history for recurrent fever episodes (OR 5.81, p<0.001), thoracic pain (OR 3.17, p<0.001), abdominal pain (OR 3.80, p<0.001) and skin rash (OR 1.58, p=0.103). The diagnostic score was calculated using the linear combination of the estimated coefficients of the logistic multivariate model (cut-off equals to 0.24) revealing good sensitivity (0.778) and good specificity (0.718). In conclusion, our score may serve in the diagnostic evaluation of adult patients presenting with recurrent fever episodes suspected of having an autoinflammatory disorder, helping identify the few subjects among them who may be carriers of mutations in MEFV and TNFRSF1A genes.

Colchicine myopathy and neuromyopathy: two cases with different characteristics.

Colchicine, a long established anti-inflammatory agent now used in several rheumatologic conditions, acts by inhibiting microtubular polymerization, as it binds equimolarly to tubulin molecules. Cytoskeletal microtubules are crucial in processes of cell viability, such as mitosis and intracellular vesicle motility.Gastrointestinal side effects are quite common and often minor in nature or duration, whereas neuromuscular toxicity is rare. We report 2 cases of colchicine myopathy in the context of very different clinical settings.

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

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.

Serum Amyloid A Circulating Levels and Disease Activity in Patients with Juvenile Idiopathic Arthritis

The aim of our study was to evaluate the association between circulating levels of serum amyloid A protein (SAA) and disease activity in patients with juvenile idiopathic arthritis (JIA). Our study group included 41 JIA patients (9 male, 32 female), classified according to the International League of Associations for Rheumatology (ILAR) criteria (5); 16 had polyarticular onset disease and 25 had oligoarticular onset disease. Among 25 patients with oligoarticular disease, three had extended oligoarthritis. Serum amyloid A (SAA), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were measured in both patients and 26 healthy controls. SAA levels were higher in JIA patients versus healthy controls (p<0.001). Significant positive correlations were found between SAA and the presence of active joints (rho=0.363, p<0.05), the number of active joints (rho=0.418, p<0.05), ESR (R=0.702, p<0.05) and CRP (R=0.827, p<0.05). No significant correlations between ESR and the presence of active joints (rho=0.221, p=0.225) or between ESR and the number of active joints (rho=0.118, p=0.520) were demonstrated in JIA patients. No significant correlations were obtained between CRP and the presence of active joints (rho=0.034, p=0.855) or between CRP and the number of active joints (rho=0.033, p=0.859). We discovered a significant increase in SAA levels in JIA patients, compared to controls, and a strong positive correlation between SAA level and JIA disease activity. We also discerned SAA to be a more sensitive laboratory marker than ESR and CRP for evaluating the presence and number of active joints. We suggest that SAA can be used as an additional indicator of disease activity in JIA.

Glucocorticoids in the management of systemic juvenile idiopathic arthritis

Glucocorticoids have been the mainstay of treatment for many years in systemic-onset juvenile idiopathic arthritis (sJIA), causing important side effects and some difficulties in the management of this disease. Until the introduction of biologic agents, oral glucocorticoids were used to control fever and other systemic features for several months or even years if systemic manifestations persisted. Nowadays, clinicians have valid alternatives that have revolutionized the natural history of sJIA. Biologic agents, such as the interleukin-1 inhibitors anakinra and the more recent canakinumab, or the interleukin-6 inhibitor tocilizumab, have improved the prognosis of this debilitating disease. Glucocorticoids still have to be considered at the onset of disease when a non-steroidal anti-inflammatory drug therapy fails or when there are life-threatening complications such as severe anemia or pericarditis, or macrophage activation syndrome. Local (intra-articular) triamcinolone hexacetonide is the treatment of choice for arthritis limited to one joint or a few joints in patients without systemic activity. To date, there is still great heterogeneity in the management of sJIA patients, but in recent years there have been attempts to design algorithms and treatment protocols for glucocorticoids, disease-modifying anti-rheumatic drugs, and biologic agents. This review provides an overview of the current knowledge of glucocorticoid therapy in sJIA, comments on recently published recommendations, and gives practical support to the clinician for management of this disease.

Pediatric Osteoporosis: Diagnosis and Treatment Considerations

Osteoporosis is now increasingly recognized in children due to the increased prevalence of disorders associated with bone loss. Fragility fractures represent the cardinal clinical features of pediatric osteoporosis and children presenting with fragility fractures deserve an accurate assessment to rule out a secondary cause. Indeed, in the pediatric population, a low bone mass is often a consequence of a chronic disease or its treatment; genetic bone disorders represent the cause of only a small fraction of cases. The position statement of the International Society for Clinical Densitometry guides physicians in interpreting densitometric data and making diagnoses of osteoporosis in children. Once a diagnosis of osteoporosis has been made, the aim is to identify children in whom bone status may deteriorate if left untreated. To date, bisphosphonates have represented the mainstay of treatment for pediatric osteoporosis. However, due to the peculiar pathophysiology of osteoporosis in this age group, a pharmacological agent with an anabolic effect on bone may provide clinicians with other therapeutic options in children. Multicenter studies are needed to optimize treatments and define optimal clinical response in treated children.

Flares after withdrawal of biologic therapies in juvenile idiopathic arthritis: Clinical and laboratory correlates of remission duration

To assess the time in remission after discontinuing biologic therapy in patients with juvenile idiopathic arthritis (JIA).

Immunosuppressive Activity of Abatacept on Circulating T Helper Lymphocytes from Juvenile Idiopathic Arthritis Patients

Background: Abatacept is used in the treatment of juvenile idiopathic arthritis (JIA) patients, but the activity of the drug on T helper cell function is not yet fully known. Methods: The ability of abatacept to affect cytokine production in vitro and the proliferative response to both recall antigens and polyclonal stimulation was firstly assessed in healthy donors. Then, 10 JIA patients who were due to start abatacept treatment were recruited and longitudinally evaluated during the first 90 days of therapy. Both their clinical response to the treatment and in vitro analysis aimed to assess the proliferative response to recall antigens and the proportions of circulating T helper subsets. Results: Abatacept reduced the proliferative response to recall antigens and the production of proinflammatory cytokines such as IFN-γ and TNF-α in healthy donors in vitro. It was also efficient in improving symptoms and reducing parameters of inflammation in JIA patients. Abatacept reduced the proliferative response to recall antigens, and this effect was significant soon after drug infusion (2 days). Regarding the proportions of circulating CD4+ T lymphocytes, only a reduction in the frequencies of circulating Treg cells was observed. Conclusions: Abatacept in vitro inhibits proliferation and cytokine production in healthy donors, and reduces parameters of inflammation in vivo in JIA patients. The reduction of the proliferative response to recall antigens induced by abatacept was evident only soon after drug administration, suggesting that its immunosuppressive activity is maintained only for a short time.