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.

Congenital heart block and immune mediated sensorineural hearing loss: possible cross reactivity of immune response.

Immune-mediated sensorineural hearing loss may complicate systemic autoimmune diseases. We have previously reported the presence of antibodies directed against inner ear antigens in patients with Cogan syndrome, a disease characterized by sudden hearing loss and interstitial keratitis. Such autoantibodies cross-react with an epitope of SSA/Ro60 protein. Anti-Ro/SSA antibodies in pregnant women cross the placenta and reach the fetal tissues inducing an immune-mediated damage of the cardiac conduction system. We wanted to evaluate whether mothers with anti-Ro/SSA antibodies who gave birth to children with congenital heart block have antibodies directed against inner ear antigens and whether these antibodies are connected with the presence of immune-mediated sensorineural hearing loss. We did not find anti-inner ear antibodies in the majority of the mothers. On the contrary a 13-year-old boy with congenital heart block and sensorineural hearing loss was positive for the presence of anti-inner ear antigens antibodies. Moreover his serum was positive for the presence of anti-Ro60 peptide antibodies but did not recognize the entire protein Ro60 (TROVE2), a behaviour similar to that of sera from patients with Cogan syndrome. In conclusion the data obtained so far show that anti-inner ear antibodies do not recognize the entire protein TROVE2 and do not support the hypothesis that such antibodies may be involved in the pathogenesis of congenital heart block.

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.

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.