A child with polyarthritis and chronic lung disease: a case report of ataxia-telangiectasia.

BACKGROUND: Ataxia-telangiectasia (A-T) is a rare autosomal recessive DNA repair disorder, characterized by progressive cerebellar degeneration, telangiectasia, immunodeficiency, recurrent sinopulmonary infections, radiation sensitivity, premature aging and predisposition to cancer. Although the association with autoimmune and chronic inflammatory conditions such as vitiligo, thrombocytopenia and arthritis has occasionally been reported, an onset with articular involvement at presentation is rare. CASE PRESENTATION: We herein report the case of a 7-year-old Caucasian girl who was admitted to the Rheumatology Department with a history of febrile chough and polyarthritis which led initially to the suspicion of an autoinflammatory disease. She had overt polyarthritis with knees deformities and presented with severe pneumonia. A chest Computed Tomography (CT) scan showed bilateral bronchiectasis, parenchymal consolidation and interstitial lung disease; rheumatoid factor and type I interferon signature resulted negative, therefore excluding COatomer Protein subunit Alpha (COPA) syndrome. A diagnosis of sarcoidosis had been suspected based on histological evidence of granulomatous liver inflammation, but ruled out after detecting normal angiotensin converting enzyme and chitotriosidase blood levels. Based on her past medical history characterized by at least six episodes of pneumonia in the previous 4 years, immunological phenotyping was performed. This showed complete IgA and IgE deficiency with defective antigen-specific antibodies to Pneumococcal, Tetanus toxin and Hemophilus Influenzae B vaccines. Additionally, low numbers of B cells and recent thymic emigrants (RTE) were found (CD4Ra 1.4%), along with a low CD4+/CD8 + T cells ratio (< 1). Finally, based on gait disturbances (wobbly wide-based walking), serum alfa-fetoprotein was dosed, which resulted increased at 276 ng/ml (normal value < 7 ng/ml). A diagnosis of Ataxia-Telangiectasia was made, strengthened by the presence of bulbar telangiectasia, and then confirmed by Whole Exome Sequencing (WES). CONCLUSIONS: Although rare, A-T should always be ruled out in case of pulmonary bronchiectasis and gait disturbances even in the absence of bulbar or skin telangiectasia. Autoimmune and granulomatous disorders must to be considered as differential diagnosis.

Haematological and other manifestations in the presence of antiphospholipid antibodies in a multicentric paediatric cohort.

OBJECTIVES: To identify the variables associated with the development of haematological manifestations in the presence of antiphospholipid antibodies (aPLs) in a paediatric cohort. METHODS: We conducted a multicentric retrospective cohort study of children under the age of 18 years. RESULTS: One hundred and thirty-four children were included; 12.2% had at least one thrombotic event (TE) and 67% at least one non-criterion manifestation. Of them, 90% did not develop any TE. Haematological manifestations were the most frequent (42%), followed by neurological (19.8%), cutaneous (17.6%), cardiac (16.8%) and renal (1.5%) manifestations. In those children with haematological disorders, the aPLs positivity rate was: 67.3% LA, 65.6% aß2GPI, 60% aCL, 45.5% single, 23.6% double and 30.9% triple. A univariate analysis showed that children with IgM aCL+, IgM aß2GPI+, triple positivity and with a SLE diagnosis had a significantly higher frequency of haematological manifestations (p<0.05). Finally, a stepwise regression analysis identified IgG aß2GPI positivity [OR 2.91, 95% CI (1.26-6.74), p=0.013], SLE [OR 2.67, 95% CI (1.13-6.3), p=0.026] and LA positivity [OR 2.53, 95% CI (1.08-5.94), p=0.033] as independent risk factors for the development of haematological manifestations. CONCLUSIONS: Non-criteria manifestations and among them haematological disorders, are the most frequent events in the presence of aPLs and/or LA in our paediatric cohort. Children with SLE, LA and/or IgG aß2GPI positivity showed a higher risk of haematological manifestations.

Tocilizumab for massive refractory pleural effusion in an adolescent with systemic lupus erythematosus.

BACKGROUND: Pleural effusion in systemic lupus erythematous (SLE) is a common symptom, and recent studies demonstrated that IL-6 has a pivotal role in its pathogenesis. CASE PRESENTATION: We report a case of a 15 years old Caucasian boy with a history of persistent pleural effusion without lung involvement or fever. Microbiological and neoplastic aetiologies were previously excluded. Based on the presence of pleuritis, malar rash, reduction of C3 and C4 levels and positivity of antinuclear antibody (ANA) and anti-double stranded DNA (dsDNA), the diagnosis of juvenile SLE (JSLE) was performed. Treatment with high dose of intravenous glucocorticoids and mycophenolate mofetil was started with partial improvement of pleural effusion. Based on this and on adults SLE cases with serositis previously reported, therapy with intravenous tocilizumab (800 mg every two weeks) was started with prompt recovery of pleural effusion. CONCLUSION: To the best of our knowledge, this is the first case of JSLE pleuritis successfully treated with tocilizumab.

Assessment of disease activity using a whole-body MRI derived radiological activity index in chronic nonbacterial osteomyelitis.

BACKGROUND: Based on the recently developed ChRonic nonbacterial Osteomyelitis MRI Scoring tool (CROMRIS), we developed a radiological activity index (RAI-CROMRIS) to obtain a quantification of the overall bone involvement in individual patients. METHODS: Whole Body Magnetic Resonance Imaging (WB-MRI) images were scored according to parameters included in the RAI-CROMRIS: bone marrow hyperintensity, signal extension, soft tissue/periosteal hyperintensity, bony expansion, vertebral collapse. These parameters were evaluated for each bone unit yielding a score from 0 to 7 and summed up as RAI-CROMRIS including all bone units. We assessed clinical disease activity using a physician global assessment (PGA) and radiological findings in 76 treatment-naïve patients; 46 of 76 were evaluated at 6 and 12 months after initial WB-MRI. Quantitative variables were compared using the Mann-Whitney U test for unmatched groups and the Wilcoxon signed-rank test for paired groups. Correlation was evaluated using Spearman's rank coefficient (rs). RESULTS: There was a significant correlation between RAI-CROMRIS and PGA (rs = 0.32; p = 0.0055), between RAI-CROMRIS and presence of elevated erythrocyte sedimentation rate (p = 0.013) and C-reactive protein (p = 0.0001) at baseline. The RAI-CROMRIS decreased from a median of 17 at baseline to 12 at 6 months (p = 0.004) and remained stable (median 11) at 12 months. A correlation between the RAI-CROMRIS and the PGA was observed at baseline (rs = 0.41; p = 0.004) and during follow up at 6 months (rs = 0.33; p = 0.025) and 12 months (rs = 0.38; p = 0.010). The baseline RAI-CROMRIS (median 20) was significantly higher in patients who subsequently received bisphosphonates than in patients who received other treatments (median 12) and decreased significantly after bisphosphonates (p = 0.008). CONCLUSIONS: The RAI-CROMRIS was correlated with clinical and laboratory measures of disease activity showing significant short-term changes following treatment with bisphosphonates. This tool could be used in clinical practice and clinical trials after validation.

High prevalence of rare FBLIM1 gene variants in an Italian cohort of patients with Chronic Non-bacterial Osteomyelitis (CNO).

BACKGROUND: FBLIM1 gene has been recently demonstrated to be involved in the pathogenesis of bone sterile inflammation. The aim of the study is to evaluate the prevalence of FBLIM1 gene variants in a cohort of 80 Italian patients with Chronic Non-bacterial Osteomyelitis (CNO). METHODS: The coding regions of FBLIM1 gene were sequenced in a cohort of 80 patients with CNO using DNA extracted from blood lymphocytes, and PCR products were sequenced. Only rare (global MAF < 2%), coding variants detected were considered. Clinical evaluation of patients with rare variants and those without was performed. Fisher's exact test was used to compare categorical and ordinal data, and Student's t-test was used to analyze continuous data. RESULTS: Eighteen out of 80 patients (~ 22%) presented at least one rare coding variant in FBLIM1. Eight patients presented a variant never associated before with CNO. All patients presented classical features of CNO and no statistical difference between patients with presence of FBLMI1 variants and those without were found in terms of clinical manifestation, treatment, and outcome. CONCLUSION: Considering the high frequency of rare variants in our CNO cohort, our data seem to confirm a possible role of FBLIM1 in the pathogenesis of CNO suggesting that CNO is a disorder of chronic inflammation and imbalanced bone remodeling.

Prevalence of cranial involvement in a cohort of Italian patients with chronic non-bacterial osteomyelitis.

OBJECTIVES: Chronic non-bacterial osteomyelitis (CNO) is a non-infectious inflammatory disease characterised by uni- or multi-focal bone lytic lesions. CNO mainly affects metaphysis of long bones, pelvis and shoulder girdle. Neurocranium lesions are extremely rare. The objective of the study is to describe the prevalence and clinical manifestations of CNO patients with neurocranium involvement in an Italian cohort of CNO patients. METHODS: This is a retrospective study. Medical records of patients with CNO admitted to eight paediatric rheumatology centres were reviewed. RESULTS: Among 86 patients with CNO enrolled in the study, three of them were female and presented neurocranium involvement - multifocal lesions. Two out of the 3 patients were completely asymptomatic for cranial involvement, while one of the 3 complained of cranial bossing. Cranial involvement was detected with bone scintigraphy and then confirmed by magnetic resonance imaging and/or computed tomography. Two patients presented fever and two with skin manifestations. Laboratory inflammatory markers were increased in two of them. All patients underwent bone biopsy confirming the diagnosis. They all received NSAIDs. Two patients received corticosteroids and then methotrexate and achieved clinical remission, while one patient received pamidronate. CONCLUSIONS: This is the first report of neurocranium involvement in a cohort of patients affected by CNO. In our cohort no patient showed significant signs attributable to cranial involvement.

A novel disorder involving dyshematopoiesis, inflammation, and HLH due to aberrant CDC42 function.

Hemophagocytic lymphohistiocytosis (HLH) is characterized by immune dysregulation due to inadequate restraint of overactivated immune cells and is associated with a variable clinical spectrum having overlap with more common pathophysiologies. HLH is difficult to diagnose and can be part of inflammatory syndromes. Here, we identify a novel hematological/autoinflammatory condition (NOCARH syndrome) in four unrelated patients with superimposable features, including neonatal-onset cytopenia with dyshematopoiesis, autoinflammation, rash, and HLH. Patients shared the same de novo CDC42 mutation (Chr1:22417990C>T, p.R186C) and altered hematopoietic compartment, immune dysregulation, and inflammation. CDC42 mutations had been associated with syndromic neurodevelopmental disorders. In vitro and in vivo assays documented unique effects of p.R186C on CDC42 localization and function, correlating with the distinctiveness of the trait. Emapalumab was critical to the survival of one patient, who underwent successful bone marrow transplantation. Early recognition of the disorder and establishment of treatment followed by bone marrow transplant are important to survival.

Efficacy and Adverse Events During Janus Kinase Inhibitor Treatment of SAVI Syndrome.

OBJECTIVES: Mutations affecting the TMEM173 gene cause STING-associated vasculopathy with onset in infancy (SAVI). No standard immunosuppressive treatment approach is able to control disease progression in patients with SAVI. We studied the efficacy and safety of targeting type I IFN signaling with the Janus kinase inhibitor, ruxolitinib. METHODS: We used DNA sequencing to identify mutations in TMEM173 in patients with peripheral blood type I IFN signature. The JAK1/2 inhibitor ruxolitinib was administered on an off-label basis. RESULTS: We identified three patients with SAVI presenting with skin involvement and progressive severe interstitial lung disease. Indirect echocardiographic signs of pulmonary hypertension were present in one case. Following treatment with ruxolitinib, we observed improvements of respiratory function including increased forced vital capacity in two patients, with discontinuation of oxygen therapy and resolution of echocardiographic abnormalities in one case. Efficacy was persistent in one patient and only transitory in the other two patients. Clinical control of skin complications was obtained, and one patient discontinued steroid treatment. One patient, who presented with kidney involvement, showed resolution of hematuria. One patient experienced increased recurrence of severe viral respiratory infections. Monitoring of peripheral blood type I interferon signature during ruxolitinib treatment did not show a stable decrease. CONCLUSIONS: We conclude that targeting type I IFN receptor signaling may represent a promising therapeutic option for a subset of patients with SAVI syndrome and severe lung involvement. However, the occurrence of viral respiratory infection might represent an important cautionary note for the application of such form of treatment.

Variable Clinical Phenotypes and Relation of Interferon Signature with Disease Activity in ADA2 Deficiency.

OBJECTIVE: An upregulation of type I interferon (IFN) stimulated genes [IFN score (IS)] was described in patients with adenosine deaminase 2 deficiency (DADA2). We describe the clinical course of 5 such patients and the role of IS as a marker of disease activity and severity. METHODS: Expression levels of IS were determined by quantitative real-time PCR. RESULTS: Five white patients were identified as carrying CECR1 mutations. The IS before treatment was elevated in 4 out of 5 patients and decreased after treatment. CONCLUSION: Our data confirm the high variability of DADA2 and suggest type I IS as a biomarker of disease activity.

Predictors of Flare Following Etanercept Withdrawal in Patients with Rheumatoid Factor-negative Juvenile Idiopathic Arthritis Who Reached Remission while Taking Medication.

OBJECTIVE: To evaluate the rate of flare after etanercept (ETN) withdrawal in patients with juvenile idiopathic arthritis (JIA) who attained clinical remission while taking medication, and to identify predictors of flare. METHODS: Patients were included with oligo- (oJIA) and rheumatoid factor-negative polyarticular JIA (pJIA) who received a first course of ETN for at least 18 months, maintained clinically inactive disease (CID) for at least 6 months during treatment, and were followed for 12 months after ETN withdrawal. Demographic and clinical features were collected at onset, at baseline (initiation of ETN), and at time of disease flare. RESULTS: After ETN withdrawal, 66 of the 110 patients enrolled (60%) flared with arthritis (of whom 7 flared with concurrent anterior uveitis; none with uveitis alone). The median time to flare was 4.3 months (interquartile range 2.5-6.4) with no evident differences between oJIA and pJIA. The number and type of joints involved at baseline and characteristics of ETN treatment/discontinuation were not associated with flare. Patients who flared were more frequently males (p = 0.034), positive for antinuclear antibody (ANA; p = 0.047), and had higher values of C-reactive protein (CRP; p = 0.012) at baseline. These variables remained significantly associated with flare in a multivariate logistic analysis, a model accounting for only 14% of the variability of the occurrence of the flare. CONCLUSION: Our results show that a significant proportion of patients with JIA who maintain CID for at least 6 months experience a relapse after ETN withdrawal. Male sex, presence of ANA, and elevated CRP at baseline were associated with higher risk of flare.

Anakinra in a Cohort of Children with Chronic Nonbacterial Osteomyelitis.

OBJECTIVE: To report efficacy and safety in patients with chronic nonbacterial osteomyelitis (CNO) unresponsive to nonsteroidal antiinflammatory drugs (NSAID) and bisphosphonates and/or glucocorticoids treated with anakinra. METHODS: Nine patients (6 females) with refractory CNO were treated with anakinra for at least 6 months. We recorded, at baseline and after 6 months of treatment, clinical and laboratory features, and number and distribution of bone lesions detected by 99mTc-MDP bone scintigraphy. Disease activity was evaluated using a physician's global assessment (PGA). RESULTS: At baseline, 9/9 patients had mild to severe PGA. After 6 months of treatment, in 5 patients the PGA score was graded from none to minimal. At baseline, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were elevated in 8 out of 9 patients. After 6 months, 5/9 patients had normalized CRP and ESR and in all except 1, CRP and ESR decreased. Before starting anakinra, a total of 77 bone lesions were detected by bone scintigraphy. After 6 months of treatment of the 77 lesions, 42 had resolved and 35 were stable. In 7/9 patients, 20 new lesions appeared during treatment; 2 of these 7 patients were symptomatic. At the last followup visit (median 1.7 yrs, range 0.8-2.8), 6/9 patients maintained a PGA graded as none to minimal. CONCLUSION: Anakinra is a possible therapeutic alternative in patients with refractory CNO. The practical significance of clinically silent bone lesions detected by bone scintigraphy remains to be established.

Anakinra in Systemic Juvenile Idiopathic Arthritis: A Single-center Experience.

OBJECTIVE: To assess anakinra as a therapy for systemic juvenile idiopathic arthritis (sJIA) in a single-center series. METHODS: We reviewed 25 patients with sJIA treated with anakinra for at least 6 months. The primary outcome was the number of patients who achieved clinically inactive disease at 6 months, according to preliminary criteria for inactive disease and clinical remission of JIA. RESULTS: Among 25 patients evaluated, 14 (56%) met the criteria for inactive disease at 6 months and were classified as responders. For each individual patient, we compared the dose administered with the ideal dose of anakinra and we found that there was no relation with response. We also compared demographic characteristics and clinical and laboratory features at baseline in responders and non-responders: no differences were observed in relation with the number of active joints before starting anakinra or concomitant glucocorticoids treatment. The only variable significantly associated with response was the time from disease onset to receiving anakinra, with earlier treatment being associated with a better outcome. CONCLUSION: Anakinra is associated with rapid attainment of inactive disease in a significant portion of patients. We found that only the earlier treatment is associated with better outcome. However, formal studies on early treatment and on the pathophysiology and response to treatments, including anakinra, of early- and late-onset sJIA are needed to optimize the management of this challenging disease.

Wandering spleen: 'presentation in adolescent with high thrombotic risk'.

The term 'wandering spleen' refers to an abnormal hypermobility of the spleen, which may be congenital or acquired. The absence or abnormal laxity of splenic ligaments combined with an abnormally long and mobile vascular pedicle predispose to complications such as torsion of the splenic pedicle, infarction and splenic vein thrombosis. The clinical presentation of such disease is highly variable. In this case, we describe an asymptomatic case of wandering spleen in high thrombotic risk patients with cavernoma of splenic vein and infarction of the spleen. Physical examination was normal except the enlarged and no tender consistency spleen palpable at left iliac fossa. Ultrasonography revealed enlarged spleniform mass below its normal position suggesting vascular impairment and subsequently has been confirmed by colour Doppler ultrasound and computed tomography. The family history was positive for ischemic thrombotic vascular diseases and the screening for thrombotic risk has revealed hyperhomocysteinemia, thrombophilic homozygous gene mutations for factor V (H1299R) and MTHFR (C677T). For high thrombotic risk, prophylaxis postsplenectomy was suggested according to the international recommendations with subcutaneous low molecular weight heparin, associated with a preventive treatment with acetyl salicylic acid and folic acid along with B-vitamin. This case report may be helpful for clinicians involved in the care of splenectomized patients, because it has shown the importance of an appropriate pre and postoperative antithrombotic management to reduce as soon as possible the risk of thrombotic events in such patients after splenectomy.

Genetic prothrombotic factors in children with otogenic lateral sinus thrombosis: five case reports.

Lateral sinus thrombosis (LST) is an uncommon, but life-threatening complication of both acute and chronic otitis media. There is some evidence that acquired or hereditary prothrombotic disorders are risk factors for LST. The aim of this work was to evaluate the role of thrombotic screening, anticoagulant therapy or prophylaxis in patients with either acute or chronic otitis media and LST. The medical records of five children hospitalized at Pediatric Hospital Bambino Gesù of Rome because of acute or chronic otitis media complicated by mastoiditis and LST were reviewed. All children underwent laboratory workup for hypercoagulability. All the five children were found to be heterozygote for the C677T MTHFR mutation and a child presented also heterozygosity for factor V Leiden mutation. They have been successfully treated with anticoagulant therapy without sequels. Children with acute or chronic otitis media may have a prothrombotic tendency that becomes clinically evident because of the inflammatory state. Patients with a family and/or personal history of thrombosis and/or thrombophilic conditions need anticoagulant prophylaxis also in the absence of clear signs of LST. Treatment with low molecular weight is successful in patients with LST.