In this phase 2 trial, selective blockade of interleukin-23 with risankizumab was associated with clinical responses superior to those associated with ustekinumab. This trial was not large enough or of long enough duration to draw conclusions about safety. (Funded by Boehringer Ingelheim; ClinicalTrials.gov number, NCT02054481 ).

Boehringer Ingelheim.

ObjectivesTo evaluate the efficacy and safety of risankizumab, a humanised monoclonal antibody targeting the p19 subunit of interleukin-23 (IL-23), in patients with active ankylosing spondylitis (AS).MethodsA total of 159 patients with biological-naïve AS, with active disease (Bath Ankylosing Spondylitis Disease Activity Index score of ≥4), were randomised (1:1:1:1) to risankizumab (18 mg single dose, 90 mg or 180 mg at day 1 and weeks 8, 16 and 24) or placebo over a 24-week blinded period. The primary outcome was a 40% improvement in Assessment in Spondylo Arthritis International Society (ASAS40) at week 12. Safety was assessed in patients who received at least one dose of study drug.ResultsAt week 12, ASAS40 response rates were 25.5%, 20.5% and 15.0% in the 18 mg, 90 mg and 180 mg risankizumab groups, respectively, compared with 17.5% in the placebo group. The estimated difference in proportion between the 180 mg risankizumab and placebo groups (primary endpoint) was –2.5% (95% CI –21.8 to 17.0; p=0.42). Rates of adverse events were similar in all treatment groups.ConclusionsTreatment with risankizumab did not meet the study primary endpoint and showed no evidence of clinically meaningful improvements compared with placebo in patients with active AS, suggesting that IL-23 may not be a relevant driver of disease pathogenesis and symptoms in AS.Trial registration number NCT02047110; Pre-results.

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The X-linked hyper-IgM (XHIGM) syndrome is an uncommon primary immunodeficiency disease caused by mutations in the gene for CD40 ligand and characterized by normal or elevated serum IgM, reduced levels of IgG and IgA, and defective T-cell function. Because of its rarity, it has been difficult for any single investigator or institution to develop a comprehensive clinical picture of this disorder. Accordingly, a national registry was developed in the United States to provide demographic, genetic, immunologic, and clinical information on a relatively large number of patients with the XHIGM syndrome.A total of 79 patients from 60 unrelated families were registered between January 1997 and July 2002. The estimated minimal incidence was approximately 1/1,030,000 live births. All of the patients had significant IgG deficiency and most had IgA deficiency, but only one-half had elevated IgM levels. Most patients presented initially with a history of an increased susceptibility to infection including Pneumocystis carinii pneumonia. The average age of diagnosis was significantly earlier in patients born into a family with a previously affected individual. However, only one-third of the patients born into a family with a previously affected individual were diagnosed exclusively because of the presence of the positive family history before any clinical symptoms developed. Over half the patients developed symptoms of immunodeficiency and were diagnosed by 1 year of age, and over 90% by 4 years of age. The most prominent clinical infections were pneumonia (81% of patients), upper respiratory infections (49%) including sinusitis (43%) and recurrent otitis (43%), recurrent/protracted diarrhea (34%), central nervous system infections (14%), sepsis (13%), cellulitis (13%), hepatitis (9%), and osteomyelitis (1%). In addition to infections caused by encapsulated bacteria, opportunistic infections were relatively common and were caused by P. carinii, members of the herpes virus family (including cytomegalovirus), Cryptosporidium, Cryptococcus, Candida, Histoplasma, and Bartonella. Sclerosing cholangitis occurred in 5 patients and in 4 of these was associated with Cryptosporidium infection. Eight patients had died at the time of their entry into the Registry; 2 of pneumonia (1 P. carinii and 1 cytomegalovirus), 2 of encephalitis (1 ECHO virus and 1 cytomegalovirus), 2 of malignancy (both hepatocellular carcinoma), 1 of sclerosing cholangitis caused by Cryptosporidium, and 1 of hemolytic uremic syndrome.

Toxic shock syndrome toxin 1 (TSST-1) is a 22-kDa exotoxin produced by strains of Staphylococcus aureus and implicated in the pathogenesis of toxic shock syndrome. In common with other staphylococcal exotoxins, TSST-1 has diverse immunological effects. These include the induction of interleukin 2 receptor expression, interleukin 2 synthesis, proliferation of human T lymphocytes, and stimulation of interleukin 1 synthesis by human monocytes. Toxic shock syndrome is a severe and often fatal disorder consistently associated with Staphylococcus aureus infection and characterized by multiple organ dysfunction (1-3). The exotoxin toxic shock syndrome toxin 1 (TSST-1) is a 22-kDa protein (4) produced by most strains of S. aureus isolated from patients with toxic shock syndrome (5, 6) and capable of inducing the disease in animal models (7). TSST-1 induces interleukin 1 synthesis by human monocytes (8, 9), accessory-cell-dependent proliferation of human T lymphocytes (10, 11), and the suppression of pokeweed mitogeninduced immunoglobulin synthesis by human lymphocytes (12). All three activities appear to reside in a 14-kDa internal toxin fragment and could not be dissected with multiple monoclonal antibodies (mAbs) (13,14). The identification of a cellular receptor for TSST-1 is important for the understanding of the mechanism of action of this toxin. TSST-1 has been reported to bind to cultured epithelial cells (15) and to T cells but not to monocytes or B cells (16). To the best of our knowledge, the nature of the binding site has not been described. In the present study we demonstrate that TSST-1 binds to human major histocompatibility complex (MHC) class II molecules.MATERIALS AND METHODS Cell Preparations. Peripheral blood mononuclear cells (PBMCs) were isolated by standard methods (11). Highly purified populations of T lymphocytes and monocytes were prepared as described (11,17). The preparation of B cells (18) from surgical specimens of human tonsil and of thymocytes (19) obtained from surgical specimens removed during open heart surgery were as described.Normal human fibroblasts were grown from skin biopsies, propagated, and harvested as described (20). Interferon y (IFN-y) treatment of fibroblasts was performed as described (20) L-Cell Transfectants. The L-cell transfectants expressing HLA class II molecules used in this study were gifts of R. Karr (University of Iowa, IA) and were prepared by transfection of the respective full-length cDNA clones (DRa, DR4f3I, DPw4a, DPw4p, DQ7a, and DQw3,8) in the expression vector pcD together with the pSV2-neo plasmid into DAP.3 murine L-cell fibroblasts (21). Cells were grown in tissue culture plates in complete RPMI 1640 medium containing G418 (250 jug/ml; GIBCO, Grand Island, NY) and were harvested by incubation for 15-20 min in isotonic phosphate-buffered saline (pH 7.4; PBS) containing 0.53 mM EDTA.Toxins. TSST-1 was prepared as described (22) and iodinated using chloramine-T. The mean specific activity of the labeled toxin was 950 Ci/mmol (range, 230-1700 Ci/m...

Several exoproteins from the bacterium Staphylococcus aureus are highly potent polyclonal activators of T cells in the presence of cells bearing class II antigens of the major histocompatibility complex (MHC). These toxins, including the toxic shock syndrome toxin (TSST-1), act at nanomolar concentrations, bind directly to class II molecules, and do not require the processing typical of nominal antigen. Each toxin is capable of stimulating a subpopulation of peripheral T lymphocytes bearing particular V beta sequences as part of their alpha beta T-cell receptors. It is not known how these so-called 'superantigens' bind to class II and how this binding stimulates T cells. In this study, the different affinities of TSST-1 for human class II molecules DR and DP were exploited to define the region of a class II molecule necessary for high-affinity binding. Using chimaeric alpha- and beta-chains of DR and DP expressed at the surface of transfected murine fibroblasts and a binding assay with TSST-1, it was shown that the alpha 1 domain of DR is essential for high-affinity binding, and further that TSST-1 binding did not prevent subsequent binding of a DR-restricted antigenic peptide. This is compatible with a model of superantigen making external contacts with both class II and T cell receptor, and suggests that the V beta portion of the T-cell receptor interacts with the nonpolymorphic alpha-chain of DR.

Purpose The United States Immunodeficiency Network (USIDNET) patient registry was used to characterize the presentation, genetics, phenotypes, and treatment of patients with Hyper IgM Syndrome (HIGM). Methods The USIDNET Registry was queried for HIGM patient data collected from October 1992 to July 2015. Data fields included demographics, criteria for diagnosis, pedigree analysis, mutations, clinical features, treatment and transplant records, laboratory findings, and mortality. Results Fifty-two physicians entered data from 145 patients of ages 2 months to 62 years (median 12 years); 131 were males. Using patients’ age at last entry, data from 2072 patient years are included. Mutations were recorded for 85 subjects; 82 were in CD40LG. Eighteen subjects had non-X-linked HIGM. 40 % had a normal serum IgM and 15 %, normal IgA. Infections were reported for 91 %, with pulmonary, ear, and sinus infections being the most common. 42 % had Pneumocystis jirovecii pneumonia; 6 % had Cryptosporidium. 41 % had neutropenia. 78 % experienced non-infectious complications: chronic diarrhea (n = 22), aphthous ulcers (n = 28), and neoplasms (n = 8) including colon cancer, adrenal adenoma, liver adenocarcinoma, pancreatic carcinoid, acute myeloid leukemia, hepatoma, and, in a female with an autosomal dominant gain of function mutation in PIK3CD, an ovarian dysgerminoma. Thirteen patients had a hematopoietic marrow or stem cell transplant; three had solid organ transplants. Thirteen were known to have died (median age = 14 years). Conclusions Analysis of the USIDNET Registry provides data on the common clinical features of this rare syndrome, and in contrast with previously published data, demonstrates longer survival times and reduced gastrointestinal manifestations.