Distinct Effects of Interleukin-1β Inhibition upon Cytokine Profile in Patients with Adult-Onset Still’s Disease and Active Articular Manifestation Responding to Canakinumab

Adult-onset Still’s disease (AOSD) is a systemic auto-inflammatory disease characterized by the presence of immunologically mediated inflammation and deficient resolution of inflammation. Canakinumab is an approved IL-1β inhibitor in the treatment of AOSD with a balanced efficacy and safety profile. Since inflammatory cytokines play a major role in the pathogenesis of AOSD, we investigated the effects of canakinumab on the cytokine profile of AOSD patients from a randomized controlled trial. Multiplex analysis and ELISA were used to test the concentrations of several cytokines at three time points—week 0 (baseline), week 1 and week 4—in two patient groups—placebo and canakinumab. Two-way repeated-measures analysis of variance revealed a significant temporal effect on the concentrations of MRP 8/14, S100A12, IL-6 and IL-18 with a significant decrease at week 4 in the canakinumab group exclusively. Comparing responders with non-responders to canakinumab showed a significant decrease in MRP 8/14, IL-1RA, IL-18 and IL-6 in responders at week 4, while S100A12 levels decreased significantly in responders and non-responders. In summary, canakinumab showed a striking effect on the cytokine profile in patients with AOSD, exhibiting a clear association with clinical response.

Insights into the Pathogenesis of HS and Therapeutical Approaches

Hidradenitis suppurativa (HS) is a debilitating, chronic, (auto)inflammatory disease primarily affecting apocrine gland-rich areas of the body. Although pathogenic mechanisms responsible for HS have not yet been fully elucidated, it is a multifactorial process whose main target is the terminal follicle. The role of the inflammatory process (and consequently of cytokine milieu) and of several other factors (genetics, lifestyle, hormonal status, microbiome, innate and adaptive immune systems) involved in HS pathogenesis has been investigated (and often defined) over the years with a view to transferring research results from bench to bedside and describing a unique and universally accepted pathogenetic model. This review will update readers on recent advances in our understanding of HS pathogenesis and novel (potential) medical therapies for patients with moderate-to-severe HS.

Zoledronate Associated Seizure in Chronic Recurrent Multifocal Osteomyelitis

Chronic recurrent multifocal osteomyelitis (CRMO) is an auto-inflammatory disease characterized by sterile bone lesions. We report a case of a patient with CRMO who developed a seizure post bisphosphonate administration. Although, the treatment of CRMO is currently not codified, the most promising results have been observed in patients under treatment with bisphosphonates. Keywords: CRMO; Bisphosphonate; tonico-clonic seizure.

Autophagy and Mitophagy-Related Pathways at the Crossroads of Genetic Pathways Involved in Familial Sarcoidosis and Host-Pathogen Interactions Induced by Coronaviruses

Sarcoidosis is a multisystem disease characterized by the development and accumulation of granulomas, the hallmark of an inflammatory process induced by environmental and/or infectious and or genetic factors. This auto-inflammatory disease mainly affects the lungs, the gateway to environmental aggressions and viral infections. We have shown previously that genetic predisposition to sarcoidosis occurring in familial cases is related to a large spectrum of pathogenic variants with, however, a clustering around mTOR (mammalian Target Of Rapamycin)-related pathways and autophagy regulation. The context of the COVID-19 pandemic led us to evaluate whether such genetic defects may increase the risk of a severe course of SARS-CoV2 infection in patients with sarcoidosis. We extended a whole exome screening to 13 families predisposed to sarcoidosis and crossed the genes sharing mutations with the list of genes involved in the SARS-CoV2 host-pathogen protein-protein interactome. A similar analysis protocol was applied to a series of 100 healthy individuals. Using ENRICH.R, a comprehensive gene set enrichment web server, we identified the functional pathways represented in the set of genes carrying deleterious mutations and confirmed the overrepresentation of autophagy- and mitophagy-related functions in familial cases of sarcoidosis. The same protocol was applied to the set of genes common to sarcoidosis and the SARS-CoV2-host interactome and found a significant enrichment of genes related to mitochondrial factors involved in autophagy, mitophagy, and RIG-I-like (Retinoic Acid Inducible Gene 1) Receptor antiviral response signaling. From these results, we discuss the hypothesis according to which sarcoidosis is a model for studying genetic abnormalities associated with host response to viral infections as a consequence of defects in autophagy and mitophagy processes.

Aanhoudende koorts zonder focus met lymfadenopathieën: infectie, inflammatie of maligniteit?

Persistent fever without focus but with lymphadenopathy: infection, inflammation or malignancy? Adult-onset Still’s disease (AOSD) is a rare auto-inflammatory disease in which four cardinal signs have been described: rash, spiking fever, arthritis or arthralgia and hyperleucocytosis with neutrophilia. Nevertheless, diagnosis can be challenging as infectious, other inflammatory or neoplastic diseases need to be ruled out. It affects typically young adults (from 16 to 35 years). The disease can be controlled with non-steroidal anti-inflammatory agents and glucocorticoids. To date, treatments as Il-6, IL-1 or anti-TNFα can be used in glucocorticoid-dependent or refractory patients. We present a case of a 22-year old woman with all four cardinal symptoms in which all cultures and infectious serology resulted negative. Also, auto-immune markers were negative. Because of diffuse bilateral supra- and infradiaphragmatic enlarged lymph nodes up to 1.6 cm in size on computed tomography (CT), additional positron emission tomography-computed tomography imaging (PET-CT-scan) was performed. Besides the multiple enlarged lymph nodes, increased tracer capture was shown in the spleen and bone marrow. All of this was suspicious for high-grade lymphoma. Eventually, an additional bone marrow biopsy with aspiration and lymph node biopsy could rule out a lymphoproliferative process and the diagnosis of AOSD could be made. This case report highlights the importance of a profound diagnostic work-up in fever of unknown origin.

HSCT corrects primary immunodeficiency and immune dysregulation in patients with POMP-related auto-inflammatory disease

Inborn errors of immunity that present with concomitant immunodeficiency and auto-inflammation are therapeutically challenging; furthermore, complexity is added when they are caused by mutations in genes that encode for proteins expressed beyond immune cells. The ubiquitin-proteasome system is the main intracellular proteolytic machinery and participates in most cellular processes by degrading ubiquitinated proteins. Mutations in proteasome subunits resulting in proteasome deficiency cause a severe auto-inflammatory disease characterized by chronic auto-inflammation neutrophilic dermatosis and fever, collectively referred to as Proteasome Associated Auto-inflammatory Syndromes (PRAAS). POMP is a chaperone for proteasome assembly and AD mutations in POMP cause a form of PRAAS with prominent immunodeficiency referred to as POMP-related auto-inflammation and immune dysregulation (PRAID) manifesting with recurrent, severe and opportunistic infections in addition to inflammatory features that are characteristic for all PRAAS disorders, most importantly early-onset neutrophilic dermatosis. JAK inhibitors partially control the disease in individuals with PRAAS, however life-threatening, recurrent and opportunistic infections in patients with POMP mutations limit immunosuppressive therapies and prompted consideration of hematopoietic stem cell transplant (HSCT). We describe successful HSCT in two patients with POMP deficiency. Despite POMP being ubiquitously expressed, the immunologic and auto-inflammatory phenotype were both ameliorated through HSCT which suggests that the clinical and immunological features of PRAID are predominantly derived from a proteasome defect in hematopoietic cells. To our knowledge, these are the first patients with a form of PRAAS cured by HSCT, opening new therapeutic possibilities for these diseases.

CANDLE Syndrome: Case Report of a Rare Type of Auto- Inflammatory Disease

CANDLE syndrome (chronic atypical neutophilic dermatosis with lipodystrophy and elevated temperature) is an autoinflammatory disease/syndrome characterized by recurrent fever, skin lesions, and multisystem inflammatory manifestations. Most of the patients have shown mutation in PSMB8 gene. Here, we report a 9-year-old girl with recurrent fever, atypical facies, widespread skin lesions, generalized lymphadenopathy, hepato-splenomegaly, lipodystrophy, and failure to thrive. Considering the clinical features and laboratory investigations including skin biopsy findings, diagnosis was consistent with CANDLE syndrome. Therefore, it is recommended to consider CANDLE syndrome in a young child who presents with recurrent fever, characteristics rashes, organomegaly and failure to thrive. Bangladesh J Child Health 2020; VOL 44 (3) :174-177