Dealing with Chronic Non-Bacterial Osteomyelitis: A practical approach

BACKGROUND: Chronic Non-Bacterial Osteomyelitis (CNO) is an inflammatory disorder that primarily affects children. Although underestimated, its incidence is rare. For these reasons, no diagnostic and no therapeutic guidelines exist. The manuscript wants to give some suggestions on how to deal with these patients in the every-day clinical practice. MAIN BODY: CNO is characterized by insidious onset of bone pain with local swelling. Systemic symptoms such as fever, skin involvement and arthritis may be sometimes present. Radiological findings are suggestive for osteomyelitis, in particular if multiple sites are involved. CNO predominantly affects metaphyses of long bones, but clavicle and mandible, even if rare localizations of the disease, are very consistent with CNO diagnosis. CNO pathogenesis is still unknown, but recent findings highlighted the crucial role of cytokines such as IL-1\u3b2 and IL-10 in disease pathogenesis. Moreover, the presence of non-bacterial osteomyelitis among autoinflammatory syndromes suggests that CNO could be considered an autoinflammatory disease itself. Differential diagnosis includes infections, malignancies, benign bone tumors, metabolic disorders and other autoinflammatory disorders. Radiologic findings, either with Magnetic Resonance or with Computer Scan, may be very suggestive. For this reason in patients in good clinical conditions, with multifocal localization and very consistent radiological findings bone biopsy could be avoided. Non-Steroidal Anti-Inflammatory Drugs are the first-choice treatment. Corticosteroids, methotrexate, bisphosphonates, TNF\u3b1-inhibitors and IL-1 blockers have also been used with some benefit; but the choice of the second line treatment depends on bone lesions localizations, presence of systemic features and patients' clinical conditions. CONCLUSION: CNO may be difficult to identify and no consensus exist on diagnosis and treatment. Multifocal bone lesions with characteristic radiological findings are very suggestive of CNO. No data exist on best treatment option after Non-Steroidal Anti-Inflammatory Drugs failure

Efficacy and safety of emapalumab in macrophage activation syndrome

OBJECTIVES: Macrophage activation syndrome (MAS) is a severe, life-threatening complication of systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD). The objective of this study was to confirm the adequacy of an emapalumab dosing regimen in relation to interferon-γ (IFNγ) activity by assessing efficacy and safety. The efficacy outcome was MAS remission by week 8, based on clinical and laboratory criteria. METHODS: We studied emapalumab, a human anti-IFNγ antibody, administered with background glucocorticoids, in a prospective single-arm trial involving patients who had MAS secondary to sJIA or AOSD and had previously failed high-dose glucocorticoids, with or without anakinra and/or ciclosporin. The study foresaw 4-week treatment that could be shortened or prolonged based on investigator's assessment of response. Patients entered a long-term (12 months) follow-up study. RESULTS: Fourteen patients received emapalumab. All patients completed the trial, entered the long-term follow-up and were alive at the end of follow-up. The investigated dosing regimen, based on an initial loading dose followed by maintenance doses, was appropriate, as shown by rapid neutralisation of IFNγ activity, demonstrated by a prompt decrease in serum C-X-C motif chemokine ligand 9 (CXCL9) levels. By week 8, MAS remission was achieved in 13 of the 14 patients at a median time of 25 days. Viral infections and positive viral tests were observed. CONCLUSIONS: Neutralisation of IFNγ with emapalumab was efficacious in inducing remission of MAS secondary to sJIA or AOSD in patients who had failed high-dose glucocorticoids. Screening for viral infections should be performed, particularly for cytomegalovirus. TRIAL REGISTRATION NUMBER: NCT02069899 and NCT03311854

Drug Retention Rate and Predictive Factors of Drug Survival for Interleukin-1 Inhibitors in Systemic Juvenile Idiopathic Arthritis

Background and Objectives: Few studies have reported the drug retention rate (DRR) of biologic drugs in juvenile idiopathic arthritis (JIA), and none of them has specifically investigated the DRR of interleukin (IL)-1 inhibitors on systemic JIA (sJIA). This study aims to describe IL-1 inhibitors DRR and evaluate predictive factors of drug survival based on data from a real-world setting concerning sJIA.Methods: Medical records from sJIA patients treated with anakinra (ANA) and canakinumab (CAN) were retrospectively analyzed from 15 Italian tertiary referral centers.Results: Seventy seven patients were enrolled for a total of 86 treatment courses. The cumulative retention rate of the IL-1 inhibitors at 12-, 24-, 48-, and 60-months of follow-up was 79.9, 59.5, 53.5, and 53.5%, respectively, without any statistically significant differences between ANA and CAN (p = 0.056), and between patients treated in monotherapy compared to the subgroup co-administered with conventional immunosuppressors (p = 0.058). On the contrary, significant differences were found between biologic-naive patients and those previously treated with biologic drugs (p = 0.038) and when distinguishing according to adverse events (AEs) occurrence (p = 0.04). In regression analysis, patients pre-treated with other biologics (HR = 3.357 [CI: 1.341-8.406], p = 0.01) and those experiencing AEs (HR = 2.970 [CI: 1.186-7.435], p = 0.020) were associated with a higher hazard ratio of IL-1 inhibitors withdrawal. The mean treatment delay was significantly higher among patients discontinuing IL-1 inhibitors (p = 0.0002).Conclusions: Our findings suggest an excellent overall DRR for both ANA and CAN that might be further augmented by paying attention to AEs and employing these agents as first-line biologics in an early disease phase

BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes

Current recommendations for the pharmacologic therapy in Kawasaki syndrome and management of its cardiovascular complications

Kawasaki syndrome is a potentially life-threatening disease of early childhood that untreated holds a risk of severe coronary involvement. Its diagnosis is made via a list of clinical signs because etiology and pathophysiology are still unknown and no specific laboratory tool is available. Appropriate therapy with intravenous immunoglobulins and aspirin reduces the incidence of coronary abnormalities to less than 5%. Immunoglobulins have been shown to be highly effective in reducing disease symptoms or their severity and chiefly in reducing the rate of coronary artery aneurysm development. Aspirin is firstly used in high dose for its anti-inflammatory properties and then in low dose for its anti-thrombotic effects. Timely diagnosis and precociously administered treatment are two crucial points in the definition of prognosis for Kawasaki syndrome. In this review heart complications are discussed and therapeutic options stratified according to both severity of coronary involvement and grading of cardiovascular risk

Exercise -unrelated sudden death as the first event of anomalous origin of the left coronary artery from the right aortic sinus

Congenital anomalous origins of the coronary arteries represents a rare but well-described cause of myocardial ischemia and sudden death. Left coronary artery (LCA) arising from the right sinus of Valsalva is a rare congenital coronary anomaly that seems to be commonly associated with sudden death in young trained athletes. The possibility of a coronary artery anomaly should always be considered in young individuals with a history of chest pain or syncope, particularly if the episodes are triggered by exercise. We describe a case of congenital LCA anomaly in an asymptomatic 10-year-old girl with no family history of sudden death; no previous unexplained syncopal episodes or exercise-induced symptoms were reported. She experienced a cardiac arrest while she was resting at school and was not recoverable despite early emergency department admission and intensive prolonged cardiopulmonary resuscitation attempts. Post-mortem pathological findings revealed a single origin from the right sinus of Valsalva for both right and left coronary arteries. The LCA was compressed between the aorta and the pulmonary trunk. Histologic features suggested recent ischemia. Although sudden death can be the first manifestation of this condition, it is important to be particularly aware of prodromic symptoms: exertional dyspnea, chest pain, syncope or dizziness. Recognition during life of this coronary anomaly is mandatory to prevent the risk of sudden death and to plan surgical correction if clinically indicated

What do parents know about the malformations afflicting the hearts of their children?

Traditionally, medical professionals have entrusted the parents of children with chronic illness with the task of imparting knowledge about the illness to the children. This practice assumes that parents understand the illness, and that they pass on their knowledge in a manner appropriate for the individual child. The aim of our study was to assess the knowledge that parents of children with a cardiac defect have about the malformation in the heart of their child. We sent a modified version of the Leuven questionnaire to 350 families. The questionnaire was filled in and sent back to our centre by 148 families. Parents showed a good knowledge of the name and anatomical characteristics of the cardiac disease suffered by their child. Parents with a child taking drugs were not very knowledgeable about the regime, side effects, and interaction with other drugs or food. Only one-quarter of the parents knew the definition of endocarditis, although almost two-fifths were aware that unexplained fever for more than 5 days was the most typical symptom. Less than half of the parents knew that endocarditis could recur. About two-fifths of parents knew the real possibility of their child being involved in competitive sports; but almost half of parents were unable to answer this question. The poor knowledge about particular aspects of the disease, treatment, and preventive measures revealed by our parents may have major consequences. The results of our study are relevant to general daily clinical practice