Receptor Interacting Serine/Threonine Kinase 1 (RIPK1) is widely expressed and integral to inflammatory and cell death responses. Autosomal recessive RIPK1-deficiency, due to biallelic loss of function mutations in RIPK1, is a rare inborn error of immunity (IEI) resulting in uncontrolled necroptosis, apoptosis and inflammation. Although hematopoietic stem cell transplantation (HSCT) has been suggested as a potential curative therapy, the extent to which disease may be driven by extra-hematopoietic effects of RIPK1-deficiency, which are non-amenable to HSCT, is not clear. We present a multi-centre, international review of an additional 5 RIPK1-deficient children who underwent HSCT. All patients presented with very early onset inflammatory bowel disease, 2 also suffered from inflammatory arthritis. Median age at transplant was 3 years (range 1—5 years); 1 received matched sibling marrow, 1 matched unrelated peripheral blood stem cells (PBSC), 2 TCRαβ/CD19-depleted PBSC from maternal-haploidentical donors, and 1 had TCRαβ/CD19-depleted PBSC from a mismatched unrelated donor. All received reduced-toxicity conditioning, based on treosulfan (n = 4) or busulfan (n = 1); 1 patient underwent a successful second transplant following autologous reconstitution. Four of five patients (80

BACKGROUND:Elevated TCRαβ+CD4-CD8- double-negative T cells (DNT) and serum biomarkers help identify FAS mutant patients with autoimmune lymphoproliferative syndrome (ALPS). However, in some patients with clinical features and biomarkers consistent with ALPS, germline or somatic FAS mutations cannot be identified on standard exon sequencing (ALPS-undetermined: ALPS-U). OBJECTIVE:We sought to explore whether complex genetic alterations in the FAS gene escaping standard sequencing or mutations in other FAS pathway-related genes could explain these cases. METHODS:Genetic analysis included whole FAS gene sequencing, copy number variation analysis, and sequencing of FAS cDNA and other FAS pathway-related genes. It was guided by FAS expression analysis on CD57+DNT, which can predict somatic loss of heterozygosity (sLOH). RESULTS:Nine of 16 patients with ALPS-U lacked FAS expression on CD57+DNT predicting heterozygous "loss-of-expression" FAS mutations plus acquired somatic second hits in the FAS gene, enriched in DNT. Indeed, 7 of 9 analyzed patients carried deep intronic mutations or large deletions in the FAS gene combined with sLOH detectable in DNT; 1 patient showed a FAS exon duplication. Three patients had reduced FAS expression, and 2 of them harbored mutations in the FAS promoter, which reduced FAS expression in reporter assays. Three of the 4 ALPS-U patients with normal FAS expression carried heterozygous FADD mutations with sLOH. CONCLUSION:A combination of serum biomarkers and DNT phenotyping is an accurate means to identify patients with ALPS who are missed by routine exome sequencing.

Osteopetrosis (OPT) is a rare inherited bone disease characterized by a bone resorption defect, due to osteoclast malfunction (in osteoclast-rich, oc-rich, OPT forms) or absence (in oc-poor OPT forms). This causes severe clinical abnormalities, including increased bone density, lack of bone marrow cavity, stunted growth, macrocephaly, progressive deafness, blindness, hepatosplenomegaly, and severe anemia. The oc-poor subtype of OPT is ultra-rare in humans. It is caused by mutations in either the tumor necrosis factor ligand superfamily member 11 (TNFSF11) gene, encoding RANKL (Receptor Activator of Nuclear factor-kappa B [NF-κB] Ligand) which is expressed on cells of mesenchymal origin and lymphocytes, or the TNFRSF member 11A (TNFRSF11A) gene, encoding the RANKL functional receptor RANK which is expressed on cells of myeloid lineage including osteoclasts. Clinical presentation is usually severe with onset in early infancy or in fetal life, although as more patients are reported, expressivity is variable. Phenotypic variability of RANK-deficient OPT sometimes includes hypogammaglobulinemia or radiological features of dysosteosclerosis. Disease progression is somewhat slower in RANKL-deficient OPT than in other 'malignant' subtypes of OPT. While both RANKL and RANK are essential for normal bone turnover, hematopoietic stem cell transplantation (HSCT) is the treatment of choice only for patients with the RANK-deficient form of oc-poor OPT. So far, there is no cure for RANKL-deficient OPT.

Abstract Context Remission rates in young people with Graves hyperthyroidism are less than 25% after 2 years of thionamide antithyroid drug (ATD). Objective We explored whether rituximab (RTX), a B-lymphocyte–depleting agent, would increase remission rates when administered with a short course of ATD. Methods This was an open-label, multicenter, single-arm, phase 2 trial in young people (ages, 12-20 years) with Graves hyperthyroidism. An A’Hern design was used to distinguish an encouraging remission rate (40%) from an unacceptable rate (20%). Participants presenting with Graves hyperthyroidism received 500 mg RTX and 12 months of ATD titrated according to thyroid function. ATDs were stopped after 12 months and primary outcome assessed at 24 months. Participants had relapsed at 24 months if thyrotropin was suppressed and free 3,5,3′-triiodothyronine was raised; they had received ATD between months 12 and 24; or they had thyroid surgery/radioiodine. Results A total of 27 participants were recruited and completed the trial with no serious side effects linked to treatment. Daily carbimazole dose at 12 months was less than 5 mg in 21 of 27 participants. Thirteen of 27 participants were in remission at 24 months (48%, 90% one-sided CI, 35%-100%); this exceeded the critical value (9) for the A’Hern design and provided evidence of a promising remission rate. B-lymphocyte count at 28 weeks, expressed as a percentage of baseline, was related to likelihood of remission. Conclusion Adjuvant RTX, administered with a 12-month course of ATD, may increase the likelihood of remission in young people with Graves hyperthyroidism. A randomized trial of adjuvant RTX in young people with Graves hyperthyroidism is warranted.

Hematopoietic stem cell transplantation and gene therapy are the only curative therapies for severe combined immunodeficiency (SCID). In patients lacking a matched donor, TCRαβ/CD19-depleted haploidentical family donor transplant (TCRαβ-HaploSCT) is a promising strategy. Conditioned transplant in SCID correlates to better myeloid chimerism and reduced immunoglobulin dependency. We studied transplant outcome in SCID infants according to donor type, specifically TCRαβ-HaploSCT, and conditioning, through retrospective cohort analysis of 52 consecutive infants with SCID transplanted between 2013 and 2020. Median age at transplant was 5.1 months (range, 0.8–16.6). Donors were TCRαβ-HaploSCT (n = 16, 31.4%), matched family donor (MFD, n = 15, 29.4%), matched unrelated donor (MUD, n = 9, 17.6%), and matched unrelated cord blood (CB, n = 11, 21.6%). Forty-one (80%) received fludarabine/treosulfan-based conditioning, 3 (6%) had alemtuzumab only, and 7 (14%) received unconditioned infusions. For conditioned transplants (n = 41), 3-year overall survival was 91% (95% confidence interval, 52–99%) for TCRαβ-HaploSCT, 80% (41–98%) for MFD, 87% (36–98%) for MUD, and 89% (43–98%) for CB (p = 0.89). Cumulative incidence of grade II–IV acute graft-versus-host disease was 11% (2–79%) after TCRαβ-HaploSCT, 0 after MFD, 29% (7–100%) after MUD, and 11% (2–79%) after CB (p = 0.10). 9/10 patients who received alemtuzumab-only or unconditioned transplants survived. Myeloid chimerism was higher following conditioning (median 47%, range 0–100%) versus unconditioned transplant (median 3%, 0–9%) (p < 0.001), as was the proportion of immunoglobulin-free long-term survivors (n = 29/36, 81% vs n = 4/9, 54%) (p < 0.001). TCRαβ-HaploSCT has comparable outcome to MUD and is a promising alternative donor strategy for infants with SCID lacking MFD. This study confirms that conditioned transplant offers better myeloid chimerism and immunoglobulin freedom in long-term survivors.

Discovery that mutations in TCIRG1 (also known as Atp6i) gene are responsible for most instances of autosomal recessive osteopetrosis (ARO) heralded a new era for comprehension and treatment of this phenotypically heterogeneous rare bone disease. TCIRG1 encodes the a3 subunit, an essential isoform of the vacuolar ATPase proton pump involved in acidification of the osteoclast resorption lacuna and in secretory lysosome trafficking. TCIRG1 defects lead to inefficient bone resorption by nonfunctional osteoclasts seen in abundance on bone marrow biopsy, delineating this ARO as 'osteoclast-rich'. Presentation is usually in early childhood and features of extramedullary haematopoiesis (hepatosplenomegaly, anaemia, thrombocytopenia) due to bone marrow fibrosis, and cranial nerve impingement (blindness in particular). Impaired dietary calcium uptake due to high pH causes the co-occurrence of rickets, described as "osteopetrorickets". Osteoclast dysfunction leads to early death if untreated, and allogeneic haematopoietic stem cell transplantation is currently the treatment of choice. Studies of patients as well as of mouse models carrying spontaneous (the oc/oc mouse) or targeted disruption of Atp6i (TCIRG1) gene have been instrumental providing insight into disease pathogenesis and development of novel cellular therapies that exploit gene correction.

Abstract Hematopoietic cell transplantation (HCT) has become standard-of-care for an increasing number of inborn errors of immunity (IEI). This report is the first to compare transplant outcomes according to T-cell–replete (ie, T-replete) HLA-matched grafts using alemtuzumab (n = 117) and T-cell–depleted (ie, T-depleted) HLA-mismatched grafts using T-cell receptor-αβ (TCRαβ)/CD19 depletion (n = 47) in children with IEI who underwent first HCT between 2014 and 2019. All patients received treosulfan-based conditioning except patients with DNA repair disorders. For T-replete grafts, the stem cell source was marrow in 25 (21%) patients, peripheral blood stem cell (PBSC) in 85 (73%), and cord blood in 7 (6%). TCRαβ/CD19 depletion was performed on PBSCs from 45 haploidentical parental donors and 2 mismatched unrelated donors. The 3-year overall survival (OS) and event-free survival for the entire cohort were 85% (77%-90%) and 79% (69%-86%), respectively. Analysis according to age at transplant revealed a comparable 3-year OS between T-replete grafts (88%; 76%-94%) and T-depleted grafts (87%; 64%-96%) in younger patients (aged <5 years at HCT). For older patients (aged >5 years), the OS was significantly lower in T-depleted grafts (55%; 23%-78%) compared with T-replete grafts (87%; 68%-95%) (P = .03). Grade III to IV acute graft-versus-host disease was observed in 8% of T-replete marrow, 7% of T-replete PBSC, 14% of T-replete cord blood, and 2% of T-depleted PBSC (P = .73). Higher incidence of viremia (P < .001) and delayed CD3 reconstitution (P = .003) were observed after T-depleted graft HCT. These data indicate that mismatched donor transplant after TCRαβ/CD19 depletion represents an excellent alternative for younger children with IEI in need of an allograft.

Autoinflammatory diseases were first recognized as distinct rheumatological conditions caused by antigen-independent activation of the innate immune system's cells nearly 20 years ago. Initially, studies in families with the prototype periodic fever syndromes led to the identification of genes highly expressed in myeloid cells that regulate the production of pro-inflammatory cytokine IL-1β. With time, the concept of autoinflammatory diseases has expanded to encompass disorders arising from perturbations in NF-κB signaling, interferon production, cytokine receptors, actin cytoskeleton, protein folding, protein degradation, and enzyme deficiencies. Because most mutated proteins are primarily expressed in hematopoietic cells and their malfunction results in activation of various inflammatory pathways, patients present with recurrent or chronic fever and other systemic inflammation features. The clinical phenotype is also defined by a specific effect of the mutant protein in a particular cell type. The complexities of immune dysregulation are further illuminated by recognizing the expended immunological disease continuum that includes autoinflammation, immunodeficiency, autoimmunity, and atopy. Disease-associated variants can be inherited either in a recessive or dominant manner, and there is also evidence for a digenic inheritance and acquired somatic mutations, mainly in myeloid cells. A better understanding of molecular mechanisms of autoinflammation has paved the way for effective targeted therapies.

Purpose of review A small proportion of children affected by rheumatic diseases suffer from severe, progressive disease, resistant to conventional antirheumatic therapies and to biologic agents interfering with inflammatory cytokines, costimulatory molecules expressed on immune system cells and intracellular signalling pathways. Adding to the poor prognosis is a high risk from significant morbidity and mortality associated with long-term treatment with multiple, often combined anti-inflammatory and immunosuppressive agents. Carefully selected patients from this unfortunate group may benefit from treatment with haematopoietic stem cell transplantation. Recent findings The majority of patients with severe paediatric rheumatic and autoinflammatory diseases treated with autologous and/or allogeneic haematopoietic stem cell transplantation achieved long-term remission. However, the incidence of disease relapse and transplant related morbidity and mortality is still significant. Summary Careful patient and donor selection, timing of the transplant earlier in the course of disease rather than the ‘last resort’ and choosing the most suitable conditioning regimen for each individual patient are the major factors favouring successful outcome. Close co-operation between the patients, their family, and involved medical teams is essential.

A Correction to this paper has been published: https://doi.org/10.1038/s41409-020-01175-9

Biological disease-modifying antirheumatic drugs (DMARDs) significantly advanced the management and outcome of patients with juvenile idiopathic arthritis (JIA). However, even with early use of targeted biological DMARDs, disease flares are common after their withdrawal and concerns remain regarding the risks of potential side effects associated with their long-term use. For a small number of children affected by severe, active, and progressive disease despite treatment with multiple conventional and biological DMARDs, hematopoietic stem cell transplantation (HSCT) remains the "last resort" option. Both autologous and allogeneic HSCT may achieve complete drug-free remission for systemic (s)JIA or rheumatoid factor (RF)-negative polyarticular JIA if performed earlier in the course of disease. Patient selection and timing of HSCT is vital and requires close cooperation between the medical teams involved.

Introduction Studies focusing on post-HCT AIC in large cohorts of patients transplanted for primary immunodeficiency (PID) are lacking. Objectives We conducted a retrospective analysis of incidence, risk factors, outcome of post-HCT AIC in children with PID and B-cell function following rituximab treatment. Methods Between January 1987-December 2018, 502 PID patients who underwent first HCT for PID at our center were included. Cumulative incidence (CI) of post-HCT AIC was calculated using a competing risk analysis, considering death as a competing event. Fine-and-Gray test was used to identify risk factors of AIC. The selected variables: gender, age at HCT, indication for HCT (SCID versus non-SCID PID), pre-HCT AIC, donor type, donor-recipient ABO matching, stem cell source, ex-vivo T-cell depletion (TCD), stem cell doses, conditioning regimen, serotherapy, GvHD prophylaxis, acute GvHD, chronic GvHD and viraemia. B-lymphocyte immune reconstitution kinetics was compared between surviving patients with post-HCT AIC without rituximab (n=18), post-HCT treated with rituximab (n=12) and controls (n=24). Results 36 (CI, 9%) developed post-HCT AIC, with median onset at 6.5 months (2.5 months - 18.2 years). On univariate analysis, pre-HCT AIC (Fig. A), mismatched donor, alemtuzumab (Fig. B), ATG, acute GvHD (Fig. C) and chronic GvHD were significantly associated with post-HCT AIC. After multivariate analysis, alemtuzumab (p=0.02) was independently associated with post-HCT AIC. Corticosteroid and high-dose IVIg (2gm/kg) achieved remission in 50% (n=18), additional rituximab led to remission in 25% (n=9), and the remaining 25% were treated with various modalities including sirolimus (n=5), bortezomib (n=3), mycophenolate mofetil (n=2), splenectomy (n=2), and second HCT (n=3). The mortality of post-HCT AIC reduced from 25% (4/16) prior to 2011 to 5% (1/20) after 2011. The median follow-up of 5.8 years (0.4-29.1) showed that 26 of 30 survivors (87%) were in complete remission, 4 (13%) were in remission with sirolimus and low dose steroid. Of 12 survivors who were treated with rituximab, immunoglobulin substitution was discontinued in 7 (52%), and 5 (48%) required on-going IVIg replacement. The median interval between HCT and rituximab was 1.95 years (0.96-19.9) in patients who were IVIg dependent and 0.73 (0.30-2.3) in patients who were IVIg-free on last follow-up (p=0.17). B-lymphocyte immune reconstitution kinetics was significant slowly in patients with post-AIC with/without rituximab (Fig. D). Conclusions 5-year CI of post-HCT AIC in children with PID was 9% and there is risk of very late onset post-HCT AIC in patients with Artemis and RAG1 mutations, and activated PI3 delta syndrome. Alemtuzumab pk study might play a role in reducing the incidence of post-HCT AIC. Sirolimus is an effective steroid-sparing immunomodulator in refractory/frequently relapsing post-HCT AIC.