Deficiency of adenosine deaminase 2 (DADA2) is a recently described hereditary autoinflammatory disease with limited published literature [1-5]. There are no previous case series published from Asia.
Objectives:
To describe the clinical features and treatment responses of patients diagnosed with DADA2 from India.
Methods:
Patients diagnosed with DADA2 at 4 different centres in India were included. Details of clinical features, laboratory investigations, ADA2 activity, genetic analysis of CECR1 gene, therapy received and outcomes were noted.
Results:
A total of 13 patients (12 Indians and one Syrian) were diagnosed with DADA2 between April 2017 and January 2019. The median age was 22 years (range: 7-39 years) and 8 (61.5%) patients were males. The diagnosis was made at a median duration of 30 months (range: 1-360 months) from the onset of first symptom. Figure 1 shows the various clinical manifestations. One patient had unknown manifestation of bad obstetric history mimicking APLA syndrome. ESR (median: 49.5 mm/hr; range: 15-130 mm/hr) was raised in all except one patient who was in remission at the time of diagnosis. CRP value was available in 11 patients and was elevated in all (median: 51.4 mg/L; range: 17.6-140 mg/L). Immunoglobulin levels assessed in 4 patients were normal. Neuroimaging done in nine patients showed infarcts in 5, bleed in 3, multiple aneurysms and features of PRES in one patient each. Abdominal microaneurysms were noted in 5 patients. Arterial occlusion of peripheral limb vessels was noted in 2 patients. ADA2 activity was assessed in 9 patients and all had nearly undetectable activity. CECR1 gene mutation analysis was available in 9 patients: 8 patients were homozygous for p.(Gly47Arg) missense mutation at exon 2 of CECR1 gene while one patient displayed compound heterozygosity for two novel mutations, P.(Leu188Val) in exon 4 and C.753+2 T>A in intron 4 of CECR1 gene. Eight patients were started on anti-TNF drugs (adalimumab in 7 and etanercept in 1). One patient required higher doses of adalimumab (40mg followed by 120mg at week 1 and 80mg at week 2) for severe gastrointestinal involvement but later died due to disseminated herpes infection. Rest of the seven patients started on anti-TNF drugs achieved disease control. Our patients had CNS, eye and GI manifestations lower than those reported by Zhou et al1 but higher than those reported by Nanthapisal et al2 and Navon Elkan et al4
Conclusion:
The spectrum of clinical presentations in Indian patients is different from those reported in previous cohorts. Anti TNF therapy was effective in majority.
References
[1] Zhou Q, Yang D, Ombrello AK, et al. Early onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med. 2014; 370: 911–920. [2] Nanthapisal S, Murphy C, Omoyinmi E, et al. Deficiency of adenosine deaminase Type 2: a description of phenotype and genotype in fifteen cases. Arthritis Rheumatol. 2016; 68: 2314–2322. [3] Caorsi R, Penco F, Grossi A, et al. ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study. Ann Rheum Dis. 2017; 76: 1648–1656. [4] Navon Elkan P, Pierce SB, Segel R, et al. Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. N Engl J Med. 2014; 370: 921-31. [5] Sharma A, Naidu GSRSNK, Chattopadhyay A, et al. Novel CECR1 gene mutations causing deficiency of adenosine deaminase 2, mimicking antiphospholipid syndrome. Rheumatology. 2019; 58: 181-2.
Systemic juvenile idiopathic arthritis (sJIA) is an aggressive form of childhood arthritis accompanied by persistent systemic inflammation. Patients with sJIA often exhibit poor response to conventional disease-modifying antirheumatic drugs, and chronic glucocorticoid use is associated with significant adverse effects. Although biologics used to target interleukin 1 and interleukin 6 are efficacious, the long-term commitment to frequent injections or infusions remains a challenge in young children. Janus-activated kinase (JAK) inhibitors block the signaling of numerous proinflammatory cytokines and are now used clinically for the treatment of rheumatoid arthritis in adults. Whether this new class of medication is effective for sJIA has not been reported. Here, we describe the case of a 13-year-old girl with recalcitrant sJIA characterized by polyarticular arthritis, fever, lymphadenopathy, and serological features of inflammation. She showed minimal response to nonsteroidal antiinflammatory drugs, glucocorticoids, conventional disease-modifying antirheumatic drugs, and etanercept. She also developed osteoporosis and vertebral compression fracture as the result of chronic glucocorticoid therapy. Oral therapy with the JAK inhibitor tofacitinib was initiated, and the patient experienced steady improvement of both arthritis and systemic features. Complete remission was achieved after 3 months, and no evidence of disease activity or adverse effects was seen through 6 months of follow-up. Our experience reveals the effectiveness of JAK inhibition in a case of refractory sJIA. Tofacitinib is an intriguing oral alternative to the available biologics for children with sJIA, and its efficacy and safety should be further assessed by clinical trial.
Intraperitoneal (ip) injection of pristane in normal mice induces antinuclear antibodies and immune‐complex (IC) glomerulonephritis similar to human systemic lupus erythematosus (SLE). In addition, C57BL/6 (B6) mice frequently develop alveolar hemorrhage (AH), leading to 10–50% early mortality. AH is an uncommon but often fatal complication of human SLE and is thought to be mediated by IC. The role of IC, apoptosis and T‐ and B‐cells in pristane‐induced AH was investigated. B6, B6 RAG1−/−, B6 FcR γ1 −/−, and B6/ lpr , received ip pristane and the lungs were examined for pathology, IC deposition, apoptosis and cytokines and chemokines. In some experiments, bone marrow, spleen, or peritoneal cells from pristane‐treated B6 mice were transferred to RAG1−/− mice to examine their ability to induce AH. Two‐weeks after pristane ip, nearly all of B6, B6 RAG1−/− or B6 FcRγ1 −/− mice developed AH, indicating IC, autoantibody‐binding to lung tissue, or T‐ or B‐cells is not necessary for AH. B6/ lpr are resistant to pristane‐induced lupus yet developed AH, indicating that Fas‐mediated apoptosis is not essential and that AH and other pathology induced by pristane are regulated differently. Short term transfer of pristane treated B6 cells into RAG1−/− mice did not induce AH while some long term transfers did induce AH. We conclude that the induction of AH by pristane does not require IC or antibodies, B‐ or T cells, or Fas. Supported by NIH.
Objectives We aim to investigate the genetic basis of a case of late-onset autoinflammatory disease characterised by arthritis, recurrent fever and skin rashes. Methods We performed whole-exome/genome sequencing and digital droplet PCR (ddPCR) to identify the pathogenic somatic mutation. We used single-cell RNA sequencing (scRNA-seq), intracellular cytokine staining, quantitative PCR, immunohistochemistry and western blotting to define inflammatory signatures and to explore the pathogenic mechanism. Results We identified a somatic mutation in NLRC4 (p.His443Gln) with the highest mosaicism ratio in the patient’s monocytes (5.69%). The somatic mutation resulted in constitutive NLRC4 activation, spontaneous apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC) aggregation, caspase-1 hyperactivation and increased production of interleukin (IL)-1β and IL-18. Moreover, we demonstrated effective suppression of inflammatory cytokine production by targeting gasdermin D, an approach that could be considered as a novel treatment strategy for patients with NLRC4 -associated autoinflammatory syndrome. Conclusions We reported a case of a late-onset autoinflammatory disease caused by a somatic NLRC4 mutation in a small subset of leucocytes. We systemically analysed this condition at a single-cell transcriptomic level and revealed specific enhancement of inflammatory response in myeloid cells.
Kawasaki disease (KD) is a systemic vasculitis of young children that can lead to development of coronary artery aneurysms. We aimed to identify diagnostic markers to distinguish KD from other pediatric inflammatory diseases.
Most lupus patients produce autoantibodies against small ribonucleoproteins such as Sm/RNP and Ro 60 (containing U1 and Y1-Y5 RNAs, respectively). We undertook this study to investigate whether the RNA components of these antigens, which contain extensive tracts of single- and double-stranded RNA, signatures of viral infection, activate innate immunity.U1 and Y RNAs were affinity purified from K562 cells. Murine bone marrow-derived dendritic cells (DCs), human HEK 293 cells, and murine RAW264.7 cells were stimulated with U1 RNA and other known Toll-like receptor (TLR) ligands. Expression of the interferon (IFN)-inducible gene Mx1 and other genes was quantified using real-time polymerase chain reaction, and cytokine production was measured by enzyme-linked immunosorbent assay. DC maturation was assessed using flow cytometry.Purified U1 and Y1-Y5 RNAs and synthetic stem-loop II of U1 RNA stimulated type I IFN (IFN-I) production by cell lines and murine bone marrow-derived DCs and promoted DC maturation (CD86 expression). U1 RNA-stimulated, but not TLR-3 ligand-stimulated, IFN-I was blocked by bafilomycin A1, indicating that immunostimulation by U1 RNA requires endosomal acidification. Myeloid differentiation factor 88-deficient cells responded poorly to U1 RNA, suggesting that an endosomal TLR, probably TLR-7, mediates the stimulatory effects of U1 RNA. U1 RNA-induced IFN-I and interleukin-6 production also were protein kinase R (PKR) dependent (abrogated by 2-aminopurine and greatly reduced in PKR-/- cells).We conclude that the RNA components of the Ro 60 (Y1-Y5 RNA) and Sm/RNP (U1 RNA) small ribonucleoproteins act as endogenous adjuvants that could play a role in the pathogenesis of autoimmunity by stimulating DC maturation and IFN-I production.
