Successful Therapy in Cases Series of Systemic Autoinflammatory Disease and Literature Review

Objectives: Systemic autoinflammatory disease (SAID) is a rare systemic auto-inflammatory and progressive disorders. There have been some reports with various therapies in SAID patients. The objective of this study is to describe the chareatercis of four cases of NAIDs benefiting from JAK 1/2 inhibitor baricitinib.Methods: We reported the four cases with SAID including two cases of Blau syndrome, one case of FMF and one case of FCAS3 syndrome. These four different patients were either resistant to currently available therapies or biologics were unaccessible during COVID-19 pandemic. We also conducted a systematic literature review about the current therapies of SAID.Results: Although genetically and phenotypically different, four cases of SAID that were treated with single use baricitinib 4 mg per day achieved improvement over eight weeks. We further identified 132 manuscripts providing more than 100 cases of SAID. Among these patients, 24 underwent biological treatments and 22 of them recovered. In these 132 manuscripts, 2 underwent JAK 1/3 inhibitor tofacitinib treatment and recovered fully.Conclusions: Case series study on the use of Jak inhibitor agents have yielded positive results in our study. For SAID patients baricitinib may be a better choice compared to injection biological treatments.

Genetics of Behçet’s Disease

Behçet’s disease (BD; MIM 109650) is an autoinflammatory disease characterized by with recurrent oral aphthae, genital ulcers and vasculitis involving the skin, joints, eyes, veins, arteries, nervous and gastrointestinal systems. Although the pathogenesis remains uncertain, genome-wide and validation studies have demonstrated that genetic predisposition is a major factor in disease susceptibility. Several gene polymorphisms that are involved in the response to pathogens and modulate inflammation have been associated with the pathophysiology of BD. Understanding the genetic association with BD may ensure insight into the pathogenesis and for development of targeted therapies for this autoinflammatory disease. This chapter will deal the role of genetic and epigenetic factors as contributing factors in the pathogenesis of BD.

The ADAR1 editome reveals drivers of editing-specificity for ADAR1-isoforms

Adenosine deaminase acting on RNA (ADAR) (also known as ADAR1) promotes A-to-I conversion in double-stranded and highly structured RNAs. ADAR1 has two isoforms transcribed from different promoters: ADAR1p150, which is mainly cytoplasmic and interferon-inducible, and constitutively expressed ADAR1p110 that is primarily localized in the nucleus. Mutations in ADAR1 cause Aicardi – Goutières syndrome (AGS), a severe autoinflammatory disease in humans associated with aberrant IFN production. In mice, deletion of ADAR1 or selective knockout of the p150 isoform alone leads to embryonic lethality driven by overexpression of interferon-stimulated genes. This phenotype can be rescued by concurrent deletion of cytoplasmic dsRNA-sensor MDA5. These findings indicate that the interferon-inducible p150 isoform is indispensable and cannot be rescued by the ADAR1p110 isoform. Nevertheless, editing sites uniquely targeted by ADAR1p150 but also mechanisms of isoform-specificity remain elusive. Here we combine RIP-seq on human cells expressing ADAR1 isoforms and combine this with analysis of isoform-specific editing patterns in genetically modified mouse cells to extensively investigate ADAR1-isoform binding- and editing characteristics. Moreover, using mutated ADAR variants, we examine the effect of two unique features of ADAR1p150 on its target specificity: 1) cytoplasmic localization and 2) Z-DNA binding domain α. Our findings indicate that ZBDa contributes only minimally to p150 editing-specificity and that isoform-specific editing is directed mainly by the cytoplasmic localization of the editase.

A Case of Deficiency of Adenosine Deaminase 2: 28 years of Diagnostic Challenges

Deficiency of adenosine deaminase 2 (DADA2) is a unique monogenic autoinflammatory disease caused by autosomal recessive loss-of-function mutations in the CECR1 gene which presents as childhood-onset small- and medium-vessel vasculitis. Previously, many of these patients were misdiagnosed and thought to have clinical features of systemic polyarteritis nodosum, which negatively influenced its outcome, since TNF inhibitors seem to have efficacy on the vasculitic phenotype of DADA2. We present a case of a 28-year-old woman with a lifelong unknown syndrome and unique clinical manifestations recently recognized as DADA2. The first manifestation, at 3 months of age, was an episode of facial paralysis during which renovascular hypertension was diagnosed. Later, she developed episodes of prolonged fever, polyarthritis, Raynaud’s phenomenon, gastrointestinal bleeding, and intracerebral hemorrhage. This inflammatory state ultimately led to the development of amyloid A amyloidosis and renal insufficiency.

Recessive NLRC4-Autoinflammatory Disease Reveals an Ulcerative Colitis Locus

Purpose NLRC4-associated autoinflammatory disease (NLRC4-AID) is an autosomal dominant condition presenting with a range of clinical manifestations which can include macrophage activation syndrome (MAS) and severe enterocolitis. We now report the first homozygous mutation in NLRC4 (c.478G > A, p.A160T) causing autoinflammatory disease with immune dysregulation and find that heterozygous carriers in the general population are at increased risk of developing ulcerative colitis. Methods Circulating immune cells and inflammatory markers were profiled and historical clinical data interrogated. DNA was extracted and sequenced using standard procedures. Inflammasome activation assays for ASC speck formation, pyroptosis, and IL-1β/IL-18 secretion confirmed pathogenicity of the mutation in vitro. Genome-wide association of NLRC4 (A160T) with ulcerative colitis was examined using data from the IBD exomes portal. Results A 60-year-old Brazilian female patient was evaluated for recurrent episodes of systemic inflammation from six months of age. Episodes were characterized by recurrent low-grade fever, chills, oral ulceration, uveitis, arthralgia, and abdominal pain, followed by diarrhea with mucus and variable skin rash. High doses of corticosteroids were somewhat effective in controlling disease and anti-IL-1β therapy partially controlled symptoms. While on treatment, serum IL-1β and IL-18 levels remained elevated. Genetic investigations identified a homozygous mutation in NLRC4 (A160T), inherited in a recessive fashion. Increased ASC speck formation and IL-1β/IL-18 secretion confirmed pathogenicity when NLRC4 (A160T) was analyzed in human cell lines. This allele is significantly enriched in patients with ulcerative colitis: OR 2.546 (95% 1.778–3.644), P = 0.01305. Conclusion NLRC4 (A160T) can either cause recessively inherited autoinflammation and immune dysregulation, or function as a heterozygous risk factor for the development of ulcerative colitis.

Azacitidine (AZA) for Patients with Vexas and Myelodysplastic Syndrome (MDS): Data from the French Vexas Registry

Background MDS are associated in 10% to 25% of the cases with systemic inflammatory or auto-immune diseases (SIAD). The management of SIADs in this context includes glucocorticoids and biologics with variable response rates, but we and others found that hypomethylating agents, especially azacytidine (AZA), can have some efficacy in SIADs associated with lower risk MDS (Fraison, J.-B. et al. Leuk. Res. 43, 13-17 (2016).). The recently described VEXAS syndrome (Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic syndrome) (Beck et al, NEJM 2020) an autoinflammatory disease characterized by somatic mutation of the UBA1 gene, is often associated with hematological disorders, especially MDS, and its treatment is often unsuccessful Based on a French nationwide registry of patients with VEXAS syndrome, we described the efficacy and safety of AZA in VEXAS syndrome patients with concomitant MDS. Patients A French nationwide registry of 116 patients with VEXAS syndrome was established in Jan 2021. We collected in this registry patient cases with concomitant MDS (according to WHO 2016) who received at least 1 full cycle of AZA (5 to 7 days). Major response of autoinflammatory disease to AZA was defined by at least 50% steroids dose reduction to less than 10 mg/day during at least one month, and minor response by at least 50% steroid dose reduction but to > 10 mg/day, during at least one month. Results Of the 58 patients with concomitant MDS included in the French VEXAS registry, 11 had received at least 1 cycle of AZA. All patients were males and median age was 64 (range 54-73), WHO : MDS MLD (n=6) , MDS SLD (n=1), MDS EB1 (n=4) ) ,R-IPSS low (n=7), intermediate (n=3) high (n=1). Median time from MDS diagnosis to AZA onset was 8 (range 0-88) months. VEXAS phenotype mostly included skin lesions (100%), fever (91%) and constitutional symptoms (91%). All patients, except one, were steroid dependent at AZA onset. In addition to steroids, patients had received a median of 1 immunosuppressive treatment (IST) (range 0-6). The median number of AZA cycles was 11 (range 2-35). Median follow up from AZA onset was 32 months (range 12-75). Five (46%) patients discontinued AZA before the end of follow-up, after 2 to 10 cycles due to failure (n=4) and persistent response after 6 cycles (n=1). Response of autoinflammatory disease to AZA was achieved in 5 patients (45%) including major response in 2 patients, and minor response in 3, while 6 patients had no response. Best response was observed after 4 cycles (n=4) and after 6 cycles (n=1). In responders, prednisone could be discontinued in 1 patient. Duration of response was 6, 8+, 12, 21, 27+ months (Median 16.5). Three of the 5 responders subsequently received another IST. Of 10 anemic and 5 thrombocytopenic patients,3 obtained erythroid and 2 obtained platelet response, respectively (IWG 2006 criteria). Two patients experienced serious adverse events during AZA treatment, including pneumocystis pneumonia (n=1), severe colitis and bacterial pneumonia (n=1). Conclusions Our results, in a limited patient number, suggest that AZA can improve auto inflammatory symptoms in 45% of patients with VEXAS syndrome and underlying MDS, allowing decrease or even discontinuation of steroids, during a median time > 1 year, with concomitant hematological response in about 50% of the cases and limited side effects. A prospective study with more patients will be needed to confirm those results. Disclosures Comont: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Speakers Bureau. Riviere: Octapharma: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees. Terriou: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Terrier: LFB: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees. Georgin-Lavialle: Novartis: Membership on an entity's Board of Directors or advisory committees; Soby: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Fenaux: Syros Pharmaceuticals: Honoraria; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding.