ISG15 deficiency is a rare disease caused by autosomal recessive variants in the
gene, which encodes the ISG15 protein. The ISG15 protein plays a dual role in both the type I and II interferon (IFN) ...immune pathways. Extracellularly, the ISG15 protein is essential for IFN-γ-dependent anti-mycobacterial immunity, while intracellularly, ISG15 is necessary for USP18-mediated downregulation of IFN-α/β signalling. Due to this dual role, ISG15 deficiency can present with various clinical phenotypes, ranging from susceptibility to mycobacterial infection to autoinflammation characterised by necrotising skin lesions, intracerebral calcification, and pulmonary involvement. In this report, we describe novel variants found in two different families that result in complete ISG15 deficiency and severe skin ulceration. Whole exome sequencing identified a heterozygous missense p.Q16X
variant and a heterozygous multigene 1p36.33 deletion in the proband from the first family. In the second family, a homozygous total
gene deletion was detected in two siblings. We also conducted further analysis, including characterisation of cytokine dysregulation, interferon-stimulated gene expression, and p-STAT1 activation in lymphocytes and lesional tissue. Finally, we demonstrate the complete and rapid resolution of clinical symptoms associated with ISG15 deficiency in one sibling from the second family following treatment with the Janus kinase (JAK) inhibitor baricitinib.
Cryopyrin-associated periodic syndrome (CAPS) is caused by
mutations. Recently, somatic
mosaicism has been reported in some CAPS patients who were previously classified as "mutation-negative." We ...describe here the clinical and laboratory findings in eight British adult patients who presented with symptoms typical of CAPS other than an onset in mid-late adulthood. All patients underwent comprehensive clinical and laboratory investigations, including analysis of the
gene using Sanger and amplicon-based deep sequencing (ADS) along with measurements of extracellular apoptosis-associated speck-like protein with CARD domain (ASC) aggregates. The clinical phenotype in all subjects was consistent with mid-spectrum CAPS, except a median age at disease onset of 50 years. Sanger sequencing of
was non-diagnostic but ADS detected a somatic
mutation in each case. In one patient, DNA isolated from blood demonstrated an increase in the mutant allele from 5 to 45% over 12 years. ASC aggregates in patients' serum measured during active disease were significantly higher than healthy controls. This series represents 8% of CAPS patients diagnosed in a single center, suggesting that acquired
mutations may not be an uncommon cause of the syndrome and should be sought in all patients with late-onset symptoms otherwise compatible with CAPS. Steadily worsening CAPS symptoms in one patient were associated with clonal expansion of the mutant allele predominantly affecting myeloid cells. Two patients developed AA amyloidosis, which previously has only been reported in CAPS in association with life-long germline
mutations.
Rare chronic childhood vasculitides lack a reliable disease activity assessment tool. With emerging new treatment modalities such a tool has become increasingly essential for both clinical practice ...and therapeutic trials to reproducibly quantify change in disease state.
To develop and validate a paediatric vasculitis activity assessment tool based on modification of the Birmingham Vasculitis Activity Score (BVASv.3).
A paediatric vasculitis registry was reviewed to identify clinical features missing in the BVASv.3. A modified nominal group technique was used to develop a working version of the Paediatric Vasculitis Activity Score (PVAS). Prospective validation provided tool reliability, reproducibility and responsiveness to change. Training of assessors was done according to the BVAS principles.
BVAS items were redefined (n=22) and eight paediatric items added in Cutaneous (n=4), Cardiovascular (n=3) and Abdominal (n=1) sections. The final PVAS has 64 active items in nine categories. The principles of new/worse and persistently active disease were retained as were the overall score and weighting of categories. The median PVAS in 63 children with systemic vasculitis was 4/63 (0-38/63). There was a high interobserver agreement for the overall as well as for subsystem scores (linear-weighted-κ ≥0.87). PVAS correlated with physician's global assessment (p<0.01); treatment decision (p=<0.01) and erythrocyte sedimentation rate (ESR) (p=0.01). In response to treatment, 15/19 patients assessed demonstrated a significant fall in PVAS (p=0.002), with good agreement among assessors for this change.
The PVAS validity in children with systemic vasculitis was demonstrated. Like the BVAS, we anticipate that the PVAS will provide a robust tool to objectively define disease activity for clinical trials and future research.
Objective
Cyclophosphamide (CYC) is used in clinical practice off‐label for the induction of remission in childhood polyarteritis nodosa (PAN). Mycophenolate mofetil (MMF) might offer a less toxic ...alternative. This study was undertaken to explore the relative effectiveness of CYC and MMF treatment in a randomized controlled trial (RCT).
Methods
This was an international, open‐label, Bayesian RCT to investigate the relative effectiveness of CYC and MMF for remission induction in childhood PAN. Eleven patients with newly diagnosed childhood PAN were randomized (1:1) to receive MMF or intravenous CYC; all patients received the same glucocorticoid regimen. The primary end point was remission within 6 months while compliant with glucocorticoid taper. Bayesian distributions for remission rates were established a priori for MMF and CYC by experienced clinicians and updated to posterior distributions on trial completion.
Results
Baseline disease activity and features were similar between the 2 treatment groups. The primary end point was met in 4 of 6 patients (67%) in the MMF group and 4 of 5 patients (80%) in the CYC group. Time to remission was shorter in the MMF group compared to the CYC group (median 7.1 weeks versus 17.6 weeks). No relapses occurred in either group within 18 months. Two serious infections were found to be likely linked to MMF treatment. Physical and psychosocial quality‐of‐life scores were superior in the MMF group compared to the CYC group at 6 months and 18 months. Combining the prior expert opinion with results from the present study provided posterior estimates of remission of 71% for MMF (90% credibility interval 90% CrI 51, 83) and 75% for CYC (90% CrI 57, 86).
Conclusion
The present results, taken together with prior opinion, indicate that rates of remission induction in childhood PAN are similar with MMF treatment and CYC treatment, and MMF treatment might be associated with better health‐related quality of life than CYC treatment.
Considerable therapeutic advances for the treatment of vasculitis of the young have been made in the past 10 years, including the development of outcome measures that facilitate clinical trial ...design. Notably, these include: a recognition that some patients with Kawasaki Disease require corticosteroids as primary treatment combined with IVIG; implementation of rare disease trial design for polyarteritis nodosa to deliver the first randomised controlled trial for children; first clinical trials involving children for anti-neutrophil cytoplasmic antibody (ANCA) vasculitis; and identification of monogenic forms of vasculitis that provide an understanding of pathogenesis, thus facilitating more targeted treatment. Robust randomised controlled trials for Henoch Schönlein Purpura nephritis and Takayasu arteritis are needed; there is also an over-arching need for trials examining new agents that facilitate corticosteroid sparing, of particular importance in the paediatric population since glucocorticoid toxicity is a major concern.
Objective
To assess long‐term efficacy and safety of canakinumab and the response to vaccination in children ages ≤5 years with cryopyrin‐associated periodic syndrome (CAPS).
Methods
CAPS patients ...(ages ≤5 years) received 2 mg/kg canakinumab subcutaneously every 8 weeks; patients with neonatal‐onset multisystem inflammatory disease (NOMID) received a starting dose of 4 mg/kg in this open‐label trial. Efficacy was evaluated using physician global assessment of disease activity and serum levels of C‐reactive protein (CRP) and amyloid A (SAA). Adverse events (AEs) were recorded. Vaccination response was evaluated using postvaccination antibody titers at 4 and 8 weeks after immunization.
Results
Of the 17 patients enrolled, 12 (71%) had Muckle‐Wells syndrome, 4 (24%) had NOMID, and 1 (6%) had familial cold autoinflammatory syndrome. All 17 patients had a complete response to canakinumab. Disease activity improved according to the physician global assessment, and for 65% of the patients autoinflammatory disease was characterized as “absent” at the end of the study. Median CRP levels decreased over time. No such change was evident in SAA levels. During the extension study, postvaccination antibody titers increased above protective levels in 16 (94%) of 17 assessable vaccinations. Ten of the patients (59%) had AEs suspected to be related to canakinumab; 8 (47%) experienced at least 1 serious AE (SAE). None of the AEs or SAEs required interruption of canakinumab therapy.
Conclusion
Our findings indicate that canakinumab effectively maintains efficacy through 152 weeks and appears to have no effect on the ability to produce antibodies against standard childhood non‐live vaccines. The safety profile of canakinumab was consistent with previous studies, supporting long‐term use of canakinumab for CAPS in children ≤5 years of age.
We describe a novel, severe autoinflammatory syndrome characterized by neuroinflammation, systemic autoinflammation, splenomegaly, and anemia (NASA) caused by bi-allelic mutations in
IRAK4
. IRAK-4 ...is a serine/threonine kinase with a pivotal role in innate immune signaling from toll-like receptors and production of pro-inflammatory cytokines. In humans, bi-allelic mutations in
IRAK4
result in IRAK-4 deficiency and increased susceptibility to pyogenic bacterial infections, but autoinflammation has never been described. We describe 5 affected patients from 2 unrelated families with compound heterozygous mutations in
IRAK4
(c.C877T (p.Q293*)/c.G958T (p.D320Y); and c.A86C (p.Q29P)/c.161 + 1G>A) resulting in severe systemic autoinflammation, massive splenomegaly and severe transfusion dependent anemia and, in 3/5 cases, severe neuroinflammation and seizures. IRAK-4 protein expression was reduced in peripheral blood mononuclear cells (PBMC) in affected patients. Immunological analysis demonstrated elevated serum tumor necrosis factor (TNF), interleukin (IL) 1 beta (IL-1β), IL-6, IL-8, interferon α2a (IFN-α2a), and interferon β (IFN-β); and elevated cerebrospinal fluid (CSF) IL-6 without elevation of CSF IFN-α despite perturbed interferon gene signature. Mutations were located within the death domain (DD; p.Q29P and splice site mutation c.161 + 1G>A) and kinase domain (p.Q293*/p.D320Y) of IRAK-4. Structure-based modeling of the DD mutation p.Q29P showed alteration in the alignment of a loop within the DD with loss of contact distance and hydrogen bond interactions with IRAK-1/2 within the myddosome complex. The kinase domain mutation p.D320Y was predicted to stabilize interactions within the kinase active site. While precise mechanisms of autoinflammation in NASA remain uncertain, we speculate that loss of negative regulation of IRAK-4 and IRAK-1; dysregulation of myddosome assembly and disassembly; or kinase active site instability may drive dysregulated IL-6 and TNF production. Blockade of IL-6 resulted in immediate and complete amelioration of systemic autoinflammation and anemia in all 5 patients treated; however, neuroinflammation has, so far proven recalcitrant to IL-6 blockade and the janus kinase (JAK) inhibitor baricitinib, likely due to lack of central nervous system penetration of both drugs. We therefore highlight that bi-allelic mutation in
IRAK4
may be associated with a severe and complex autoinflammatory and neuroinflammatory phenotype that we have called NASA (neuroinflammation, autoinflammation, splenomegaly and anemia), in addition to immunodeficiency in humans.
Monogenic autoinflammatory diseases Russo, Ricardo A G; Brogan, Paul A
Rheumatology (Oxford, England),
11/2014, Letnik:
53, Številka:
11
Journal Article
Recenzirano
Odprti dostop
During the past 15 years, a growing number of monogenic inflammatory diseases have been described and their respective responsible genes identified. The proteins encoded by these genes are involved ...in the regulatory pathways of inflammation and are mostly expressed in cells of the innate immune system. Diagnosis remains clinical, with genetic confirmation where feasible. Although a group of patients exhibit episodic systemic inflammation (periodic fevers), these disorders are mediated by continuous overproduction and release of pro-inflammatory mediators, such as IL-1 and IL-6, and TNF and are best considered as autoinflammatory diseases rather than periodic fevers. Treatment with biologic agents that block these cytokines, particularly IL-1, has proved to be dramatically effective in some patients. Still, in many cases of autoinflammation no genetic abnormalities are detected and treatment remains suboptimal, raising the question of novel pathogenic mutations in unexplored genes and pathways.
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