Different diagnostic and classification criteria are available for hereditary recurrent fevers (HRF)-familial Mediterranean fever (FMF), tumour necrosis factor receptor-associated periodic fever ...syndrome (TRAPS), mevalonate kinase deficiency (MKD) and cryopyrin-associated periodic syndromes (CAPS)-and for the non-hereditary, periodic fever, aphthosis, pharyngitis and adenitis (PFAPA). We aimed to develop and validate new evidence-based classification criteria for HRF/PFAPA.
Step 1: selection of clinical, laboratory and genetic candidate variables; step 2: classification of 360 random patients from the Eurofever Registry by a panel of 25 clinicians and 8 geneticists blinded to patients' diagnosis (consensus ≥80%); step 3: statistical analysis for the selection of the best candidate classification criteria; step 4: nominal group technique consensus conference with 33 panellists for the discussion and selection of the final classification criteria; step 5: cross-sectional validation of the novel criteria.
The panellists achieved consensus to classify 281 of 360 (78%) patients (32 CAPS, 36 FMF, 56 MKD, 37 PFAPA, 39 TRAPS, 81 undefined recurrent fever). Consensus was reached for two sets of criteria for each HRF, one including genetic and clinical variables, the other with clinical variables only, plus new criteria for PFAPA. The four HRF criteria demonstrated sensitivity of 0.94-1 and specificity of 0.95-1; for PFAPA, criteria sensitivity and specificity were 0.97 and 0.93, respectively. Validation of these criteria in an independent data set of 1018 patients shows a high accuracy (from 0.81 to 0.98).
Eurofever proposes a novel set of validated classification criteria for HRF and PFAPA with high sensitivity and specificity.
Apolipoprotein E (apoE) is associated with senile plaques in Alzheimer's disease (AD), and present in amyloid deposits in a variety of systemic amyloidoses. Recently, studies have shown that apoE4 ...allelic frequency is increased in patients with sporadic and familial late-onset AD and that apoE4 may represent a susceptibility gene for late-onset AD. We addressed the issue of whether a similar association of apoE4 exists in a number of systemic amyloidoses. Tissue was obtained from control subjects, AD patients, familial Mediterranean fever (FMF) patients, amyloid A (AA) amyloid secondary to juvenile chronic arthritis (JCA), and amyloid of the light chain type (myeloma or AL). There was a strong correlation of the apoE4 allele with sporadic and late-onset AD, but no significant increase in apoE4 with other amyloidoses. These data suggest that whereas apoE4 may be a risk factor in AD, it is not in other amyloidoses. However, given the association of apoE with all these amyloidoses, the possibility cannot be excluded that this apolipoprotein could be involved in systemic amyloidoses on an isotype non-selective basis.
Systemic autoinflammatory diseases are caused by mutations in genes that function in innate immunity. Here, we report an autoinflammatory disease caused by loss-of-function mutations in OTULIN ...(FAM105B), encoding a deubiquitinase with linear linkage specificity. We identified two missense and one frameshift mutations in one Pakistani and two Turkish families with four affected patients. Patients presented with neonatal-onset fever, neutrophilic dermatitis/panniculitis, and failure to thrive, but without obvious primary immunodeficiency. HEK293 cells transfected with mutated OTULIN had decreased enzyme activity relative to cells transfected with WT OTULIN, and showed a substantial defect in the linear deubiquitination of target molecules. Stimulated patients’ fibroblasts and peripheral blood mononuclear cells showed evidence for increased signaling in the canonical NF-κB pathway and accumulated linear ubiquitin aggregates. Levels of proinflammatory cytokines were significantly increased in the supernatants of stimulated primary cells and serum samples. This discovery adds to the emerging spectrum of human diseases caused by defects in the ubiquitin pathway and suggests a role for targeted cytokine therapies.
Deficiency of adenosine deaminase 2 (DADA2) is a recessively inherited autoinflammatory disorder caused by a loss of functional ADA2 protein. TNF inhibition (TNFi) has proven to be highly effective ...in treating inflammatory manifestations.
We sought to explore the pathophysiology and the underlying mechanisms of TNF-inhibitor response in these patients.
We performed Sanger sequencing of the ADA2 gene. We used flow cytometry, intracellular cytokine staining, transcriptome analysis, immunohistochemistry, and cell differentiation experiments to define an inflammatory signature in patients with DADA2 and studied their response to TNF-inhibitor treatment.
We demonstrated increased inflammatory signals and overproduction of cytokines mediated by IFN and nuclear factor kappa B pathways in patients’ primary cells. Treatment with TNFi led to reduction in inflammation, rescued the skewed differentiation toward the proinflammatory M1 macrophage subset, and restored integrity of endothelial cells in blood vessels. We also report 8 novel disease-associated variants in 7 patients with DADA2.
Our data explore the cellular mechanism underlying effective treatment with TNFi therapies in DADA2. DADA2 vasculitis is strongly related to the presence of activated myeloid cells, and the endothelial cell damage is rescued with anti-TNF treatment.
Systemic autoinflammatory diseases are driven by abnormal activation of innate immunity. Herein we describe a new disease caused by high-penetrance heterozygous germline mutations in TNFAIP3, which ...encodes the NF-κB regulatory protein A20, in six unrelated families with early-onset systemic inflammation. The disorder resembles Behçet's disease, which is typically considered a polygenic disorder with onset in early adulthood. A20 is a potent inhibitor of the NF-κB signaling pathway. Mutant, truncated A20 proteins are likely to act through haploinsufficiency because they do not exert a dominant-negative effect in overexpression experiments. Patient-derived cells show increased degradation of IκBα and nuclear translocation of the NF-κB p65 subunit together with increased expression of NF-κB-mediated proinflammatory cytokines. A20 restricts NF-κB signals via its deubiquitinase activity. In cells expressing mutant A20 protein, there is defective removal of Lys63-linked ubiquitin from TRAF6, NEMO and RIP1 after stimulation with tumor necrosis factor (TNF). NF-κB-dependent proinflammatory cytokines are potential therapeutic targets for the patients with this disease.
The stimulator of interferon genes (STING) protein bridges sensors of cytosolic DNA and the inflammatory pathway mediated by interferon-β. Activating mutations in the
STING
gene cause a vascular and ...pulmonary syndrome.
Studies involving children with monogenic autoinflammatory disease have provided insights into the regulation of key proinflammatory cytokine pathways and their role in causing systemic and organ-specific inflammation.
1
,
2
We studied six patients who presented in early infancy with systemic inflammation and violaceous, scaling lesions of fingers, toes, nose, cheeks, and ears that progressed to acral necrosis in most of the patients and did not respond to therapy. A mixed histologic pattern was observed, consisting of a prominent dermal inflammatory infiltrate with features of leukocytoclastic vasculitis and microthrombotic angiopathy of small dermal vessels. Three of the patients had severe interstitial lung . . .
Chronic distal radioulnar joint (DRUJ) instability is a complex clinical condition that is difficult to treat. Currently, there is no gold standard treatment. We present a novel technique using ...Arthrex Mini Tightrope for DRUJ stabilization. In this case series, a 1.6 mm K-wire was passed transversely through the distal ulna and radius. The Mini Tightrope was inserted into the end of the K-wire and pulled through the bone tunnels. Appropriate tension was achieved to stabilize the joint according to individual laxity comparable to the contralateral side. Five patients (3 males and 2 females) comprised this pilot series, with a mean age of 27.1 years. All sustained a traumatic injury at an average of 12.4 months before surgery (range: 5 to 32 mo). In addition, 3 patients had central triangular fibrocartilage complex tears treated with arthroscopy at the time of Mini Tightrope placement. While one patient was lost to follow-up after 7 weeks postoperative due to incarceration, 4 patients demonstrated coronal and sagittal stability in the context of DRUJ motion and a satisfactory range of motion. The mean time for the return to work for the two patients who were laborers or normal activity postoperatively was 5.2 weeks (range: 1 to 16.4 wk). Unrestricted activity was generally allowed 8 weeks postoperatively but varied by patient. The same 4 patients underwent hardware removal at an average of 31 weeks (range: 15 to 44 wk). Although this is only a pilot series, this suggests that temporary Mini Tightrope stabilization of the DRUJ may be a viable solution while upholding the benefits of minimally invasive surgery.
While platinum-based chemotherapeutic agents have established themselves as indispensable components of anticancer therapy, they are accompanied by a variety of side effects and the rapid occurrence ...of drug resistance. A promising strategy to address these challenges is the use of platinum(
iv
) prodrugs, which remain inert until they reach the tumor tissue, thereby mitigating detrimental effects on healthy cells. Typically, platinum drugs are part of combination therapy settings. Consequently, a very elegant strategy is the development of platinum(
iv
) prodrugs bearing a second, clinically relevant therapeutic in axial position. In the present study, we focused on gemcitabine as an approved antimetabolite, which is highly synergistic with platinum drugs. In addition, to increase plasma half-life and facilitate tumor-specific accumulation, an albumin-binding maleimide moiety was attached. Our investigations revealed that maleimide-cisplatin(
iv
)-gemcitabine complexes cannot carry sufficient amounts of gemcitabine to induce a significant effect
in vivo
. Consequently, we designed a carboplatin(
iv
) analog, that can be applied at much higher doses. Remarkably, this novel analog demonstrated impressive
in vivo
results, characterized by significant improvements in overall survival. Notably, these encouraging results could also be transferred to an
in vivo
xenograft model with acquired gemcitabine resistance, indicating the high potential of this approach.
An albumin-binding cisplatin(
iv
)-gemcitabine complex was step-by-step improved based on stability, reduction, albumin-binding and
in vivo
data yielding a carboplatin(
iv
) complex with distinctly improved overall survival and anticancer activity.
To characterise the clinical features, immune manifestations and molecular mechanisms in a recently described autoinflammatory disease caused by mutations in
, a tRNA processing enzyme, and to ...explore the use of cytokine inhibitors in suppressing the inflammatory phenotype.
We studied nine patients with biallelic mutations in
and the syndrome of congenital sideroblastic anaemia with immunodeficiency, fevers and developmental delay (SIFD). Genetic studies included whole exome sequencing (WES) and candidate gene screening. Patients' primary cells were used for deep RNA and tRNA sequencing, cytokine profiling, immunophenotyping, immunoblotting and electron microscopy (EM).
We identified eight mutations in these nine patients, three of which have not been previously associated with SIFD. Three patients died in early childhood. Inflammatory cytokines, mainly interleukin (IL)-6, interferon gamma (IFN-γ) and IFN-induced cytokines were elevated in the serum, whereas tumour necrosis factor (TNF) and IL-1β were present in tissue biopsies of patients with active inflammatory disease. Deep tRNA sequencing of patients' fibroblasts showed significant deficiency of mature cytosolic tRNAs. EM of bone marrow and skin biopsy samples revealed striking abnormalities across all cell types and a mix of necrotic and normal-appearing cells. By immunoprecipitation, we found evidence for dysregulation in protein clearance pathways. In 4/4 patients, treatment with a TNF inhibitor suppressed inflammation, reduced the need for blood transfusions and improved growth.
Mutations of
lead to a severe and often fatal syndrome, linking protein homeostasis and autoinflammation. Molecular diagnosis in early life will be crucial for initiating anti-TNF therapy, which might prevent some of the severe disease consequences.
PDF
