Safety and efficacy of biologic immunosuppressive treatment in juvenile idiopathic arthritis associated with inborn errors of immunity.

Objectives: This study aims to describe clinical features, therapeutic outcomes, and safety profiles in patients affected by juvenile idiopathic arthritis (JIA) and inborn errors of immunity (IEI) treated with biological Disease-modifying antirheumatic drugs (DMARDs). Methods: We enrolled three patients who were followed in the Pediatric Rheumatology Unit at Meyer Children's Hospital in Florence; these patients were affected by JIA, according to ILAR criteria, and IEI, according to the IUIS Phenotypical Classification for Human Inborn Errors of Immunity. Among them, two patients had 22q11.2 deletion syndrome (22q11.2DS) and one patient had X-linked agammaglobulinemia (XLA). Results: Case 1: A 6-year and 2-month-old boy was affected by 22q11.2DS, associated with oligoarticular JIA, at the age of 2 years. He was treated with non-steroidal anti-inflammatory drugs (NSAIDs) and methotrexate, along with oral glucocorticoids but with no benefits. Treatment with etanercept allowed him to achieve remission after 10 months. Case 2: A 6-year and 2-month-old girl was affected by 22q11.2DS, associated with oligoarticular JIA, at the age of 3 years and 11 months. She was treated with NSAIDs, joint injections, and methotrexate but without clinical response. Treatment with Adalimumab allowed her to achieve remission after 6 months. Case 3: A 12-year and 2-month-old boy was affected by XLA, associated with polyarticular JIA, at the age of 9 years and 11 months. He was treated with NSAIDs, methotrexate, joint injections, and oral glucocorticoids with no benefits. He failed to respond to anti-TNF-alpha, tocilizumab, and abatacept. Currently, he is undergoing therapy with sirolimus plus abatacept, which allowed him to achieve remission after 4 months. Conclusions: Results suggest that the use of immunosuppressive biological therapies can control disease activity in these patients. No adverse drug-related reactions were observed during the follow-up.

The common NOD2/CARD15 variant P268S in patients with non-infectious uveitis: a cohort study.

BACKGROUND: The etiology of Autoimmune chronic uveitis (ACU) is still unknown; NOD2/CARD15 gene mutations are responsible for the Blau Syndrome and can induce uveitis in animal models. PRESENTATION OF THE HYPOTHESIS: Aim of our study was to assess if NOD2/CARD15 variants have a role in the etiology or in the clinical course of patients with ACU, either idiopathic or associated with other inflammatory diseases. TESTING THE HYPOTHESIS: We consecutively enrolled 25 patients (19 pediatric and 6 adults) affected with ACU. For each patient medical history was reviewed and clinical data were recorded. Allelic and genotypic frequencies of NOD2/CARD15 variations were calculated in patients and matched with those of 25 healthy controls. The statistical analysis was performed. Fifteen patients showed the polymorphism P268S/SNP5 (SNP rs2066842) as heterozygous carriers while two patients were homozygous for the same polymorphism; one patient carried also the variant c647 18-16 TCT on intron 3, not previously reported in the literature. Statistical analysis for NOD2/CARD15 genotyping showed significant differences between patients and controls for allelic frequencies (p = 0.04, OR: 4.03, 95 %; CI = 1.2-13.5) but not for genotypic frequencies. We could not identify a significant phenotype-genotype correlation. IMPLICATIONS OF THE HYPOTHESIS: In our cohort of Italian patients, the NOD2/CARD15 common variant P268S/SNP5 could potentially be significantly associated with ACU.

Sodium thiosulfate for the treatment of calcinosis secondary to juvenile dermatomyositis.

We report the successful use of sodium thiosulfate in a patient with juvenile dermatomyositis complicated by ulcerative skin disease and progressive calcinosis. This therapy may have a role in improving calcinosis, even if more studies are necessary to determine the safety and efficacy of this treatment in juvenile dermatomyositis-related calcinosis.

Serum leptin, resistin, visfatin and adiponectin levels in tumor necrosis factor receptor-associated periodic syndrome (TRAPS).

OBJECTIVES: The aims of our study were to evaluate serum leptin, resistin, visfatin and adiponectin levels in patients with tumour necrosis factor receptor-associated periodic syndrome (TRAPS), in comparison to healthy controls, and to correlate their levels to parameters of disease activity and/or severity. METHODS: Serum leptin, resistin, visfatin and adiponectin levels were obtained from 14 TRAPS patients carrying mutations involving cysteine residues, from 16 TRAPS patients carrying other mutations, and from 16 healthy controls. Demographic, clinical and laboratory parameters, including amyloidosis were entered for each patient. Comparisons between groups as well as reciprocal comparisons have been evaluated. RESULTS: Serum leptin, resistin, visfatin and adiponectin did not significantly differ among the 3 groups. Patients carrying cysteine residues mutations showed lower visfatin serum levels than patients carrying other mutations (p<0.02). Serum leptin significantly correlated with the number of attacks/year (multiple R=0.32, multiple adjusted R2= 0.19, p <0.03). Serum adiponectin levels significantly correlated with the presence of amyloidosis (multiple R=0.79, multiple adjusted R2=0.57, p<0.03). Adiponectin values were a significant predictor for amyloidosis (AUC 0.75, 95 CI: 0.56-0.94, p<0.03), with a predicting cut-off value set at 23.16 pg/ml, the predictive positive value was 53.8%. Visfatin serum levels resulted respectively related to leptin (rs=0.42, r2=0.18, p<0.02) and to resistin (rs=0.57, r2=0.32, p<0.01) serum levels; whilst leptin and resistin serum levels did not reciprocally correlate. CONCLUSIONS: Although a prospective design study and larger cohort are mandatory, adipokines serum levels and their correlations with parameters of disease activity and/or severity seem to show a baseline pattern in TRAPS patients.

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.

Increased percentages of tumor necrosis factor-alpha+/interferon-gamma+ T [corrected] lymphocytes and calprotectin+/tumor necrosis factor-alpha+ monocytes in patients with acute Kawasaki disease.

In vivo exposure to microorganisms resident in the oral cavity is considered as a possible cause of Kawasaki disease (KD), and some epitopes derived from streptococci display homology with Factor H of Complement. Additionally, calprotectin, a major calcium binding protein released by neutrophils and activated monocytes, could be directly involved in endothelial damage occurring in KD. The aim of our study is to evaluate the percentages of IFN-gamma+ and/or TNF-alpha+ lymphocytes and double positive calprotectin/TNF-alpha monocytes (CD14+) after in vitro stimulation with streptococcal- and/or Factor H-derived peptides, in patients with acute KD. Peripheral Blood Mononuclear Cells (PBMCs) obtained from KD patients and febrile controls were stimulated in vitro with peptides. After culture, cells were collected, stained with fluorochrome-labelled monoclonal antibodies against CD3, CD14, calprotectin, IFN-gamma and TNF-alpha, and cytofluorimetric analyses were performed. Our results showed increased percentages of TNF-alpha+/IFN-gamma+ lymphocytes in KD patients in respect to controls when PBMCs were stimulated with streptococcal or Factor H-derived epitopes. In addition, also calprotectin+/TNF-alpha+ monocytes from KD patients were activated after PBMC in vitro stimulation. These findings lead us to speculate that some peptides, derived from oral streptococci and cross-reactive with the human Factor H of Complement, could induce lymphocyte and monocyte activation potentially involved in the pathogenesis of KD. Our results should be confirmed by further studies enrolling more patients and controls than those analyzed in our study.

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.

Role of etanercept in the treatment of tumor necrosis factor receptor-associated periodic syndrome: personal experience and review of the literature.

Tumor necrosis factor-alpha receptor (TNFR1)-associated periodic syndrome (TRAPS) is the most common autosomal-dominant autoinflammatory condition and is caused by mutations in the TNFRSF1A gene. TRAPS is characterized by recurrent attacks of fever typically lasting from 1 to 3 weeks; in addition to fever, common clinical features include mainly periorbital oedema, conjunctivitis, a migratory erythematous plaque simulating erysipela with underlying myalgia, and arthritis or arthralgia; serosal membrane inflammation is also possible. The identification of TNFRSF1A mutations as the genetic cause of TRAPS coincided with the wider use of biological agents in medicine and raised the possibility that blocking TNF could potentially represent the primary therapeutic goal in TRAPS, thus disclosing new treatment choices for this complex disease. In the past few years, isolated reports and case-series have been published suggesting that inhibition of TNF-alpha might represent a promising therapeutic approach in TRAPS. We present here our experience with etanercept in the treatment of patients affected with TRAPS, and we also add a review of the literature.

Development and preliminary validation of a diagnostic score for identifying patients affected with adult-onset autoinflammatory disorders.

To date, the rate of detection of autoinflammatory gene mutations in patients suspected of having an autoinflammatory disorder is very low. However, most of these data refer to pediatric populations. 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. Our aim was to develop and validate a set of variables for predicting the risk that a given adult patient presenting with recurrent fever episodes carries mutations in the MEFV or TNFRSF1A genes, in order to increase the probability of obtaining positive results on genetic testing. One hundred and ten consecutive patients with a clinical history of periodic fever attacks were screened for mutations in the TNFRSF1A and the MEFV genes. The mean age at disease onset was 27.85 years. Detailed information about each patient?s family history, personal history, and clinical manifestations were retrospectively collected. A diagnostic score was constructed based on univariate and multivariate analysis in a randomly-selected dataset (training set; n=40). The score was validated on an independent set of the remaining patients (validation set; n=70). Age at onset (odds ratio 0.958, P =0.050), positive family history of recurrent fever episodes (OR 5.738, P = 0.006 ), thoracic pain (OR 7.390, P = 0.002), abdominal pain (OR 2.853, P = 0.038) and skin involvement (OR 8.241, P = 0.003) were independently correlated with a positive genetic test result. A diagnostic score was calculated using the linear combination of the estimated coefficients of the logistic model (cut off equal to 0.24) revealing high sensitivity (0.94), high specificity (0.94) and high accuracy (0.94). We have identified variables that appear to be strongly related to the probability of detecting gene mutations in MEF and TNFRSF1A in adults, thus improving the evaluation of patients with suspected autoinflammatory disorders.

[Tuberculosis risk assessment in Italian healthcare centres]. / La valutazione del rischio tubercolosi nelle strutture sanitarie.

BACKGROUND: Tuberculosis transmission is a significant hazard in healthcare settings. METHODS: Risk factors suggested by CDC guidelines in 1994, which were adopted by the Italian Ministry of Health, were assessed in 29 centres via questionnaires in 2005. RESULTS: Few centers were equipped with negative pressure, respiratory isolation rooms. Half of the centres had high or ongoing risk. CONCLUSIONS: The hazard is underestimated mostly because of a high number of initially undiagnosed TB patients.

Macrophage migration inhibitory factor -173 polymorphism and risk of coronary alterations in children with Kawasaki disease.

OBJECTIVE: To investigate the possible relationship between MIF -173 polymorphism and susceptibility to, and severity of, Kawasaki disease (KD) in a cohort of Italian patients. METHODS: Sixty-nine patients (43 F, 26 M, median age 29 months, range 3-135 months) with KD and 60 sex-matched healthy caucasian children were genotyped for MIF-173. Typing of the MIF gene -173 G/C was performed by PCR and restriction fragment length polymorphism. RESULTS: Eight out of 69 (12%) KD children were non-responders: 7 required an additional IVIG infusion, while 1 received 2 IVIG infusions and then steroid administration. 9/69 (13%) KD children developed coronary artery abnormalities (CAA) during the second to fourth week of disease, and 4 of them required an additional IVIG infusion. MIF genotyping did not show significant differences between patients and controls. KD patients carrying a MIF -173*C allele developed CAA more frequently than those without MIF- (7/9 77.8% vs. 16/60 26.7%, OR 9.6, 95% CI 1.80-21.2, p<0.005). Non-responders to a single IVIG infusion carried the MIF -173*C allele more frequently than responders (6/8 = 75% vs. 17/61 = 28%, OR 5.1, 95% CI 1.42-22.31 p<0.014). In multiple regression analysis, KD patients carrying a MIF -173*C allele were found to have an increased risk of coronary involvement (OR 7.7, 95% CI 1.36-16.1, p=0.021). CONCLUSIONS: We showed that children carrying the MIF polymorphism -173*C had a higher percentage of CAA. A potential relationship between a MIF polymorphism and risk of CAA in KD might be considered.

Preliminary evidence that etanercept may reduce radiographic progression in juvenile idiopathic arthritis.

OBJECTIVE: To investigate the rate of radiographic progression, as measured with the carpo-metacarpal ratio (Poznanski score), during etanercept (ETN) therapy in children with polyarticular juvenile idiopathic arthritis (JIA). METHODS: Patients included in the Italian ETN registry who had a standard radiograph of both hands and wrists in the posteroanterior view made at start of treatment and after 1 year were included in the study. The clinical response was assessed by means of the ACR Pediatric definition of improvement. Radiographic progression was determined by calculating the change in the Poznanski score between the baseline and the 1-year radiographs. RESULTS: A total of 40 patients were studied. The frequency of ACR pediatric 30, 50, and 70 response at 1 year was 77%, 72%, and 50%, respectively. The median change in the Poznanski score between baseline and 1 year was + 0.3 units, meaning that, on average, patients experienced improvement in radiographic progression. CONCLUSION: Our pilot study provides evidence that ETN is potentially capable of reducing the progression of radiographic joint damage in JIA. This finding deserves confirmation in a controlled trial.

Loss of efficacy during long-term infliximab therapy for sight-threatening childhood uveitis.

OBJECTIVE: To describe efficacy and safety of infliximab in the treatment of childhood chronic uveitis during a long-term follow-up. METHODS: Fifteen patients (median age 12 yrs, range 5-21 yrs) with chronic uveitis were enrolled. Before infliximab treatment, children had presented active uveitis despite treatment with MTX and/or CSA. All were also receiving oral prednisone (1-2 mg/kg/day) for at least 1 month. Infliximab (5 mg/kg) was administered at weeks 0, 2, 6 and then every 6-8 weeks. Later on, in patients enrolled in Florence the administration interval was progressively increased up to 10 weeks if uveitis did not flare, whilst in children from Padua the scheduled infusion rate was maintained every 6 weeks. Absence or recurrence rate of uveitis up to the last visit was recorded. RESULTS: Median follow-up on treatment was 30 months (range 16-38 months), median number of infusions 22 (range 11-30). During the first year, 13/15 children achieved a complete remission over a median period of 10 weeks, but all relapsed thereafter. The probability of a first relapse was correlated to length of treatment, once remission was achieved (P < 0.03). The total number of relapses correlated with the duration of treatment (r(s) = 0.81; P < 0.002) and with the total number of infusions (r(s) = 0.83; P < 0.001). The total number of relapses on treatment at last follow-up was not significantly different between the two centres. CONCLUSIONS: Even if limited to a small group, infliximab appears to be an effective treatment for uveitis in children, but its efficacy seems to wane over time.

Clustered cases of pneumonia among healthcare workers over a 1-year period in three Italian hospitals: applying the WHO SARS alert.

BACKGROUND: The World Health Organization (WHO) has recommended that a severe acute respiratory syndrome (SARS) alert should be raised when two or more healthcare workers (HCW) in the same health care unit fulfil the SARS clinical criteria, with onset of illness in the same 10-day period. However, in a number of European countries (including Italy) data on reasons for sickness absence are not routinely collected within current HCW worker sickness reporting systems, because of concerns about privacy. To help plan for the implementation of the proposed alert system in Italy, we aimed to determine the minimum number of alert cases defining a cluster. PATIENTS AND METHODS: Sickness absences longer than 7 days in HCW employed in three hospitals in 2003, were identified by checking the hospitals' administrative databases. HCW with onset of illness in the same 10-day period were contacted and asked whether they have been diagnosed with pneumonia. RESULTS: Overall, 273 absences > 7 days were recorded and 36 clusters of at least two absences > 7 days were identified; a total of 94 HCW were involved in these clusters. Only two HCW involved in different clusters, reported pneumonia. CONCLUSION: The occurrence of clusters of two or more cases of pneumonia in HCW in the same hospital unit appears to be an uncommon event, and thus the alert system proposed is not likely to result in large numbers of false positive alerts. However, it may be difficult to implement this alert system in countries where clinical data on sickness absences are not routinely collected, and alternative mechanisms should be considered.

Juvenile psoriatic arthritis and acquired sensorineural hearing loss in a teenager: is there an association?

Autoimmune inner ear disease is a cause of sensorineural hearing loss, first described in 1979 by McCabe. The occurrence during rheumatic diseases is already documented in adults, but to our knowledge, this evidence is still lacking in children. A 13-yr-old girl affected by juvenile psoriatic arthritis, treated with etanercept, developed a bilateral and asymmetric sensorineural deafness. The patient significantly improved after steroid administration. Once ruled out the principal causes of sensorineural hearing loss, we also considered the hypothesis of an anti-TNF side effect. However, the clinical presentation, the efficacy on steroid treatment and the presence of inner ear auto-antibodies prompt us to consider autoimmune-SNHL as the most plausible diagnosis. The young age of our patient seems to suggest a genetic susceptibility to autoimmunity and supports the concept of associated autoimmune diseases.

Coeliac disease in patients with Kawasaki disease. Is there a link?

OBJECTIVE: Kawasaki disease (KD) is an acute febrile systemic vasculitis, mainly affecting infants and young children. Immunological abnormalities during the acute phase of KD have been described extensively. However, the occurrence of a second immunological disorder in a patient with a history of KD is rarely reported. We evaluated the presence of autoimmune thyroiditis and coeliac disease (CD) in patients with KD diagnosis. METHODS: Ninety consecutive children (57 males and 33 females, median age 5.2 yr, age range 1.6-14.1 yr) with KD were evaluated. All patients were evaluated for thyroid function (thyroid-stimulating hormone, thyroxine and triiodothyronine), anti-thyroglobulin (TgA) and anti-peroxidase (TPOA) antibodies, and antigliadin, anti-endomysium and antitransglutaminase antibodies. CD was confirmed by jejunal biopsy if the specific antibody profile was positive. One hundred and fifty Italian children, matched for age and sex and from the same geographic area, acted as controls. RESULTS: A total of five patients (three boys, two girls; 5.5%; P<0.05) were found positive for coeliac antibodies. In all of these patients the diagnosis of CD was confirmed histologically. Regarding thyroid function and autoantibodies, no patient showed subclinical hypothyroidism or autoimmune thyroiditis. No differences in the familial occurrence of autoimmune diseases between KD patients and controls were found (9.1 and 7.9%, respectively). CONCLUSIONS: Our data showed a higher prevalence of CD in children with KD, and this suggests that children with KD should be monitored carefully for CD. However, there was no increase in the prevalence of autoimmune thyroid diseases in patients with KD or the familial occurrence of autoimmune diseases.