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Purpose of ReviewThis report provides an overview of the current knowledge of molecular characterization, clinical description, and treatment of Erdheim-Chester disease (ECD), a multi-systemic adult histiocytosis of the L group.Recent FindingsThe recent identification of several MAPK mutations in histiocytes of ECD lesions. Leading to targeted therapies.SummaryThe discovery of the BRAFV600E mutation in ECD lesions followed by several other kinase mutations in the MAPK pathway has revolutionized our understanding of the disease pathogenesis and led to trials with targeted therapies that demonstrated robust efficacy.

Purpose of ReviewFirst recognized in 1974, eosinophilic fasciitis (EF) is a fibrosing disorder of the fascia with characteristic cutaneous and hematologic manifestations. This review discusses recent trends in the diagnosis and treatment of EF.Recent FindingsAlthough fascial biopsy has classically been considered the gold standard for making a diagnosis of EF, radiologic imaging, particularly magnetic resonance imaging, has been increasingly used for both diagnosis and monitoring of treatment response. Systemic corticosteroids remain the first-line treatment for EF; however, their often prolonged use in the treatment of EF has prompted a search for adjunctive therapies. Methotrexate has emerged as the leading corticosteroid-sparing agent for EF.SummarySince EF was initially described over 40 years ago, important diagnostic and therapeutic progress has been made. Future efforts should be directed at the pursuit of prospective studies including clinical trials and evidence-based guidelines.

The literature reports approximately 300 cases of multicentric reticulohistiocytosis (MRH) worldwide, mostly women of Caucasian origin. MRH manifests as a symmetric erosive polyarthritis mimicking rheumatoid arthritis with the subsequent appearance of typical papulonodular skin lesions. The disease may rapidly progress towards mutilans arthritis in the majority of cases, but it generally remits spontaneously in 10 years. The only diagnostic hallmark for MRH is the observation at histology of numerous histiocytes and multinucleated giant cells and ground glass eosinophilic cytoplasm. Despite its rarity, clinical and pathogenetic challenging features characterize the condition. First, the differential diagnosis with other forms of arthritis and the frequent coexistence of neoplasms or autoimmune diseases warrant a careful evaluation of suspected cases. Second, data from isolated MRH cases are consistent in supporting a role for monocyte/macrophage cells and for an enhanced osteoclastic activity in the affected tissues. Third, beside anti-inflammatory treatments, promising reports suggest that biologics targeting TNF-alpha and bisphosphonates may prove beneficial in MRH. Based on these observations, we are convinced that our understanding of this rare condition may prove beneficial in mechanistic advancement for other more prevalent inflammatory conditions such as arthritidies and other bone diseases.

SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis) is a rare autoimmune disease which, due to its clinical presentation and symptoms, is often misdiagnosed and unrecognized. Its main features are prominent inflammatory cutaneous and articular manifestations. Treatments with immunosuppressive drugs have been used for the management of SAPHO with variable results. To date, the use of anti-TNF-α agents has proved to be an effective alternative to conventional treatment for unresponsive or refractory SAPHO cases. TNF-α is a pro-inflammatory cytokine and pivotal regulator of other cytokines, including IL-1 β, IL-6, and IL-8, involved in inflammation, acute-phase response induction, and chemotaxis. IL-1 inhibition strategies with anakinra have shown efficacy as first and second lines of treatment. In this review, we will describe the main characteristics of biological drugs currently used for SAPHO syndrome. We also describe some of the promising therapeutic effects of ustekinumab, an antibody against the p40 subunit of IL-12 and IL-23, after failure of multiple drugs including anti-TNF-α and anakinra. We discuss the use and impact of the new anti-IL-1 antagonists involved in the IL-17 blockade, in particular for the most difficult-to-treat SAPHO cases.

Erdheim–Chester disease (ECD) is a rare (approximately 500 known cases worldwide), non-inherited, non-Langerhans form of histiocytosis of unknown origin, first described in 1930. It is characterized by xanthomatous or xanthogranulomatous infiltration of tissues by foamy histiocytes, “lipid-laden” macrophages, or histiocytes, surrounded by fibrosis. Diagnosis of ECD involves the analysis of histiocytes in tissue biopsies: these are typically foamy and CD68+ CD1a− in ECD, whereas in Langerhans cell histiocytosis (LCH) they are CD68+ CD1a+. 99Technetium bone scintigraphy revealing nearly constant tracer uptake by the long bones is highly suggestive of ECD, and a “hairy kidney” appearance on abdominal CT scan is observed in approximately half of ECD cases. Central nervous system involvement is a strong prognostic factor and an independent predictor of death in cases of ECD. Optimum initial therapy for ECD seems to be administration of interferon α (or pegylated interferon α), and prolonged treatment significantly improves survival; however, tolerance may be poor. Cases of ECD present with strong systemic immune activation, involving IFNα, IL-1/IL1-RA, IL-6, IL-12, and MCP-1, consistent with the systemic immune Th-1-oriented disturbance associated with the disease. More than half of ECD patients carry the BRAFV600E mutation, an activating mutation of the proto-oncogene BRAF. A small number of patients harboring this mutation and with severe multisystemic and refractory ECD have been treated with vemurafenib, a BRAF inhibitor, which was proved very beneficial.

Purpose of ReviewWe focus on recent advances in diagnosis and therapeutic strategies, as well as on pathogenesis of Schnitzler syndrome.Recent FindingsNew diagnostic criteria were established, and their external validity was assessed in a retrospective cohort study. The cytokine interleukin-1 (IL-1) plays a crucial role in the pathogenesis of the Schnitzler syndrome, and this explains the spectacular efficiency of IL-1 blocking therapies.SummaryThe Schnitzler syndrome is now considered as a late-onset acquired autoinflammatory syndrome in which the cytokine IL-1 plays a crucial role. IL-1 blocking therapies are efficient on the inflammation-linked symptoms but not on the monoclonal component. Therefore, they probably don’t reduce the risk of the development of lymphoproliferative disorders that remains the main prognostic issue. The link between autoinflammation and the monoclonal component needs to be further elucidated.

Purpose of ReviewA new autoinflammatory disease, deficiency of adenosine deaminase 2 (DADA2), caused by mutations in the CECR1 gene, was first reported in 2014. This review aims to update progress in defining, treating, and understanding this multi-faceted disorder.Recent FindingsDADA2 was first described in patients with systemic inflammation, mild immune deficiency, and vasculopathy manifested as recurrent stroke or polyarteritis nodosa (PAN). More than 125 patients have now been reported, and the phenotype has expanded to include children and adults presenting primarily with pure red cell aplasia (PRCA), or with antibody deficiency. Age of onset and clinical severity vary widely, even among related patients, and are not clearly related to CECR1 genotype. Inflammatory features often respond to anti-TNF agents, but marrow failure and severe immune deficiency may require hematopoietic stem cell transplantation.SummaryADA2 is expressed and secreted by monocytes and macrophages, but its biological function and the pathogenesis of DADA2 are uncertain and will remain an important area of research. Pre-clinical investigation of ADA2 replacement therapy and CECR1-directed gene therapy are warranted, but complicated by the absence of a suitable animal model.

Purpose of ReviewHypophosphatasia (HPP) is a rare genetic disorder caused by mutations of the ALPL gene. ALPL encodes the tissue-non-specific isoenzyme of alkaline phosphatase (TNSALP). Consequently, bone mineralization is decreased leading to fractures, arthralgia, and extra-skeletal manifestations including tissue calcification, respiratory failure, and neurological complications. This review summarizes the most important clinical findings, diagnosis, and treatment options for HPP.Recent FindingsAsfotase alfa is a recombinant human alkaline phosphatase, used as treatment for the underlying cause of HPP. Asfotase alfa enhances the survival in life-threatening HPP and improves bone mineralization, muscle strength, and pulmonary function. However, discontinuation of asfotase alfa leads to reappearance of bone hypomineralization.SummaryDue to its varied manifestations, HPP often mimics rheumatological and other bone diseases, thereby delaying its diagnosis. Asfotase alfa, a recombinant alkaline phosphatase, is available for the long-term enzyme replacement therapy in patients with pediatric-onset HPP to treat the bone manifestations of the disease.

Relapsing polychondritis is a rare multisystemic disease widely accepted as a complex autoimmune disorder affecting proteoglycan-rich structures and cartilaginous tissues, especially the auricular pinna, cartilage of the nose, tracheobronchial tree, eyes, and heart’s connective components. The clinical spectrum may vary from intermittent inflammatory episodes leading to unesthetic structural deformities to life-threatening cardiopulmonary manifestations, such as airway collapse and valvular regurgitation. The frequent association with other rheumatologic and hematologic disorders has been extensively reported over time, contributing to define its complexity at a diagnostic and also therapeutic level. Diagnosis of relapsing polychondritis is mainly based on clinical clues, while laboratory data have only a supportive contribution. Conversely, radiology is showing a relevant role in estimating the rate of systemic involvement as well as disease activity. The present review is aimed at providing an update on scientific data reported during the last 3 years about relapsing polychondritis in terms of pathogenesis, clinical features, diagnosis, and new treatment options.

Purpose of ReviewWe aim to review traditional concepts and recent developments on the nosology, pathophysiology, clinical phenotypes and treatment of chronic periaortitis (CP).Recent FindingsCP is a rare disorder hallmarked by a periaortic fibro-inflammatory tissue. It can present as an isolated disease, but it can also be associated with other autoimmune and fibro-inflammatory lesions (e.g., fibrosing mediastinitis, sclerosing pancreato-cholangitis) that are part of the spectrum of IgG4-related disease. In a subgroup of patients, it also involves the thoracic aorta (so-called “diffuse periaortitis”), which supports the notion of an inflammatory disorder of large arteries. The pathogenesis of CP is multifactorial: recent studies have elucidated the predisposing role of immunogenetic variants and exposures to environmental agents such as smoking and asbestos.SummaryCP is a rare immune-mediated disease that affects the abdominal aorta and the iliac arteries and, in some cases, the thoracic aorta. It may overlap with manifestations of IgG4-related disease, and its treatment comprises glucocorticoids, conventional and biological immunosuppressive agents.