The autoinflammatory diseases.

Summary The monogenic autoinflammatory syndromes are conditions caused by mutations of genes coding for proteins that play a pivotal role in the regulation of the inflammatory response. Due to their genetic nature, most of these disorders have an early onset. Clinically they are characterised by recurrent flares of systemic inflammation presenting most of the time as sudden fever episodes associated with elevation of acute phase reactants and with a number of clinical manifestations such as rash, serositis, lymphadenopathy and arthritis. Symptom-free intervals are characterised by complete wellbeing, normal growth and complete normalisation of acute phase reactants. Familial Mediterranean fever (FMF), mevalonate-kinase deficiency (MKD) and tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) are the three monogenic disorders subsumed under the term periodic fevers, while a systemic inflammation dominated by a characteristic urticarial rash associated with a number of other clinical manifestations is typical of familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and chronic infantile neurological cutaneous and articular syndrome (CINCA). These diseases represent the clinical spectrum of different mutations of a gene named cold-induced autoinflammatory syndrome 1 (CIAS-1, or NLRP3) coding for a protein called cryopyrin. Hence these disorders are also known as cryopyrin-associated periodic syndromes (CAPS). Other conditions are characterised by typical granulomatous formations (granulomatous disorders). Blau's syndrome (familial juvenile systemic granulomatosis) presents with non-caseating granulomatous inflammation affecting the joint, skin, and uveal tract (the triad of arthritis, dermatitis and uveitis) and is associated with mutations of the NACHT domain of the gene CARD15 (or NOD2)

Type I interferonopathies in pediatric rheumatology.

Defective regulation of type I interferon response is associated with severe inflammatory phenotypes and autoimmunity. Type I interferonopathies are a clinically heterogenic group of Mendelian diseases with a constitutive activation of this pathway that might present as atypical, severe, early onset rheumatic diseases. Skin vasculopathy with chilblains and livedo reticularis, interstitial lung disease, and panniculitis are common. Recent studies have implicated abnormal responses to nucleic acid stimuli or defective regulation of downstream effector molecules in disease pathogenesis. As observed for IL1-β and autoinflammatory diseases, knowledge of the defects responsible for type I interferonopathies will likely promote the development of targeted therapy

Pharmacologic P2X purinergic receptor antagonism in the treatment of collagen-induced arthritis

OBJECTIVE.: The aim of the present study was to assess the therapeutic potential of a P2X purinergic receptor antagonist, namely periodate oxidized ATP (oATP), in collagen-induced arthritis (CIA). METHODS.: Arthritis was induced in male DBA/1J mice by immunization with type II collagen. Animals showing digits inflammation and paw swelling were treated intraperitoneally each day for 10 days with 100 \u3bcl of 3 mM oATP. At the end of treatment animals were sacrificed and paws removed for histological analysis and evaluation of T-cell infiltration. Humoral response to type II collagen was analyzed and specific serum autoantibody levels were correlated to the clinical score observed in the different animal groups. RESULTS: oATP treatment resulted in a sustained reduction of disease activity, which was associated with a significant decrease in CD3+ T-cells infiltration in arthritic lesions and a significant amelioration of cartilage erosion. Peripheral regulatory T cells (Tregs) were significantly increased upon P2X blockade in lymph nodes. Moreover, a marked reduction of circulating autoantibodies directed against mouse collagen type II wasdetected. CONCLUSIONS.: Our findings indicate that P2X receptor antagonism has an important therapeutic potential for chronic inflammatory rheumatic disorders. The therapeutic efficacy was associated with an increase of Tregs in secondary lymphoid organs. Notably, we observed a significant correlation between serum autoantibodies and clinical efficacy exerted by oATP treatment. Together these results underscore the potential value of the P2X receptor signaling pathway as a potential pharmacological target for the modulation of adaptive immunity in CIA

Haploidentical α/β T-cell and B-cell Depleted Stem Cell Transplantation in Severe Mevalonate Kinase Deficiency

Objective: Mevalonic aciduria represents the most severe form of mevalonate kinase deficiency (MKD). Patients with mevalonic aciduria have an incomplete response even to high doses of anti-cytokine drugs such as anakinra or canakinumab and stem cell transplantation (SCT) represents a possible therapy for this severe disease. Methods: We report the first two children affected by severe MKD who received haploidentical α/β T-cell and B-cell depleted SCT. Both patients received a treosulfan-based conditioning regimen and one received a second haploidentical-SCT for secondary rejection of the first. Results: Both patients obtained a stable full donor engraftment with a complete regression of clinical and biochemical inflammatory signs, without acute organ toxicity or acute and chronic GvHD. In both, the urinary excretion of mevalonic acid remained high post-transplant in the absence of any inflammatory signs. Conclusion: Haploidentical α/β T-cell and B-cell depleted SCT represents a potential curative strategy in patients affected by MKD. The persistence of urinary excretion of mevalonic acid after SCT, probably related to the ubiquitous expression of MVK enzyme, suggests that these patients should be carefully monitored after SCT to exclude MKD clinical recurrence. Prophylaxis with anakinra in the acute phase after transplant could represent a safe and effective approach. Further biological studies are required to clarify the pathophysiology of inflammatory attacks in MKD in order to better define the therapeutic role of SCT.info:eu-repo/semantics/publishedVersio