Secukinumab treatment leads to normalization of quality of life and disease symptoms in psoriasis patients with or without prior systemic psoriasis therapy: the PROSE study results.

INTRODUCTION: Psoriatic disease is associated with considerable impairment of quality of life (QoL). The PROSE study (NCT02752776) investigated the impact of secukinumab treatment on patient-reported outcomes (PRO) in patients with moderate to severe psoriasis stratified by their treatment history. METHODS: PROSE was a prospective, non-randomised, multicentre study. Patients were categorized at baseline according to treatment history as naïve [naïve to any systemic therapy (N = 663)], conventional systemic [previously exposed to ≥1 conventional systemic (CS) therapy (N = 673)] and biologics [previously exposed to ≥1 biologic therapy (N = 324)]. QoL PROs, efficacy and safety of secukinumab 300 mg were assessed for a period of 52 weeks. RESULTS: The primary objective was met with 70.8% patients achieving a Dermatology Life Quality Index (DLQI) 0/1 response at Week 16 (naϊve, 74.7%; CS, 71.3%; biologic, 61.7%), with effects sustained up to Week 52. Mean Family DLQI (FDLQI) score decreased from 11.5 at baseline (naϊve, 11.3; CS, 11.4; biologic, 12.1) to 2.5 at Week 16 (naϊve, 2.5; CS, 2.3; biologic: 3.5). Substantial improvements in EuroQoL 5-Dimension Health Questionnaire, Numeric Rating Scale for pain, itching and scaling, Health Assessment Questionnaire-Disability Index, Treatment Satisfaction Questionnaire for Medication, and Patient Benefit Index were also observed at Week 16. The QoL gains were associated with substantial improvements in Psoriasis Area and Severity Index and Investigator Global Assessment mod 2011 0/1 response. No meaningful difference was observed in the efficacy or QoL improvements across patient subpopulations. All QoL and efficacy parameter improvements were sustained up to Week 52. Secukinumab treatment was well-tolerated, and no new safety signals were observed. CONCLUSION: Secukinumab treatment resulted in complete normalization of QoL in a substantial proportion of psoriasis patients, and their families, regardless of their prior treatment history.

Secukinumab dosing optimization in patients with moderate-to-severe plaque psoriasis: results from the randomized, open-label OPTIMISE study.

BACKGROUND: Secukinumab is a fully human monoclonal antibody that selectively binds to and neutralizes interleukin-17A. OBJECTIVES: To assess the efficacy and safety of different maintenance dosing regimens of secukinumab 300 mg based on Psoriasis Area and Severity Index (PASI) response at week 24 in patients with moderate-to-severe plaque psoriasis. METHODS: OPTIMISE was a randomized, open-label, rater-blinded phase IIIb study. Patients (n = 1647) received secukinumab 300 mg at baseline; weeks 1, 2, 3 and 4; and every 4 weeks (q4w) to week 24. At week 24, PASI 90 responders (≥ 90% improvement in PASI; n = 1306) were randomized to secukinumab 300 mg q4w (n = 644) or q6w (n = 662) to week 52, and PASI ≥ 75 to < 90 responders (n = 206) were randomized to secukinumab 300 mg q4w (n = 114) or q2w (n = 92) to week 52. RESULTS: PASI 90 response was maintained at week 52 by 85·7% of patients with q4w dosing vs. 74·9% with q6w dosing (odds ratio 1·91, 95% confidence interval 1·44-2·55). The primary end point, noninferiority of q6w vs. q4w dosing, was not met. In PASI ≥ 75 to < 90 responders, the proportion of patients with PASI 90 response at week 52 was numerically higher in the q2w vs. the q4w group (57% vs. 46·5%, respectively, P = 0·10). Heavier patients (≥ 90 kg) demonstrated numerically higher PASI 90 response with the q2w (57·1%) vs. the q4w regimen (40%, P = 0·11). CONCLUSIONS: Standard q4w dosing of secukinumab 300 mg is the optimal dosing regimen to achieve and maintain clear or almost clear skin. Patients with body weight ≥ 90 kg not achieving PASI 90 at week 24 may benefit from the q2w dosing regimen. What's already known about this topic? Individual responses to biologics in patients with psoriasis vary considerably and there may be a need to individualize treatment. Dose optimization strategies of currently available biologic drugs have been investigated mainly in rheumatic disorders. Secukinumab has shown long-term PASI 90/100 responses (percentage improvement in Psoriasis Area and Severity Index) to year 5 in patients with moderate-to-severe plaque psoriasis when used at the dose of 300 mg every 4 weeks. What does this study add? Standard every 4 week (q4w) dosing of secukinumab 300 mg is the optimal regimen to achieve and maintain clear or almost clear skin at week 52; the majority of the patients (85·7%) maintain PASI 90 at week 52. Superiority of intensified (q2w) dosing over the q4w regimen could not be claimed. However, patients with a higher body weight (≥ 90 kg) not achieving PASI 90 response at week 24 may benefit from q2w dosing.

Baseline characteristics of patients with moderate-to-severe psoriasis according to previous systemic treatment exposure: the PROSE study population.

INTRODUCTION: Psoriatic disease is associated with considerable impairment of Quality of Life (QoL). The PROSE study (NCT02752776) examined the impact of secukinumab on patient-reported outcomes in patients with moderate-to-severe psoriasis (PsO) stratified by previous exposure to systemic treatment. METHODS: In this prospective, non-randomized, multicentre study, patients were categorized at baseline according to previous exposure to systemic treatment: naïve [naïve to any systemic treatment (N = 663)], conventional systemic [previously exposed to ≥1 conventional systemic therapy (N = 673)] and biologics [previously exposed to ≥1 biologic (N = 324)]. Baseline demographics including age, gender, race, body weight and body mass index, disease characteristics and patient-reported QoL outcomes [Dermatology Life Quality Index (DLQI), Family DLQI (F-DLQI)] of patients enrolled in the study are reported here. RESULTS: Baseline demographic characteristics were well balanced across the three subpopulations. Naïve patients had a shorter time since diagnosis (15.5 ± 12.1 years) compared with the conventional systemic (19.1 ± 12.5 years) and biologic patients (23.0 ± 12.5 years), and lower rates of psoriatic arthritis (6.6% vs. 17.4% and 27.8%, respectively). Metabolic syndrome (37.6-43.5%), obesity (16.9-19.1%), hyperlipidaemia (15.3-21.9%) and diabetes mellitus (6.8-14.2%) were reported at numerically higher rate in the biologic group. The mean PASI (19.7 ± 7.9), affected Body Surface Area (28.2 ± 15.3%) as well as the Investigator Global Assessment score (patients with score 4: 33.7%) indicated severe disease at baseline and were comparable for the three groups. QoL impairment was evident from mean DLQI (14.1 ± 7.1: naïve = 13.5 ± 6.8; conventional systemic = 14.3 ± 7.0; biologic = 14.8 ± 7.7) and mean F-DLQI (11.5 ± 7.0: naïve = 11.3 ± 7.1; conventional systemic = 11.4 ± 6.7; biologic = 12.1 ± 7.7) also indicated derangement of QoL of patients and their families. CONCLUSION: Patients naïve to systemic treatment had shorter disease journey compared with patients previously exposed to systemic treatments; despite this, the severe impact of disease on patient and family QoL outcomes can be as apparent in naïve patients as in systemically treated patients at baseline.

Modeling chronic myeloid leukemia in immunodeficient mice reveals expansion of aberrant mast cells and accumulation of pre-B cells.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm that, if not treated, will progress into blast crisis (BC) of either myeloid or B lymphoid phenotype. The BCR-ABL1 fusion gene, encoding a constitutively active tyrosine kinase, is thought to be sufficient to cause chronic phase (CP) CML, whereas additional genetic lesions are needed for progression into CML BC. To generate a humanized CML model, we retrovirally expressed BCR-ABL1 in the cord blood CD34(+) cells and transplanted these into NOD-SCID (non-obese diabetic/severe-combined immunodeficient) interleukin-2-receptor γ-deficient mice. In primary mice, BCR-ABL1 expression induced an inflammatory-like state in the bone marrow and spleen, and mast cells were the only myeloid lineage specifically expanded by BCR-ABL1. Upon secondary transplantation, the pronounced inflammatory phenotype was lost and mainly human mast cells and macrophages were found in the bone marrow. Moreover, a striking block at the pre-B-cell stage was observed in primary mice, resulting in an accumulation of pre-B cells. A similar block in B-cell differentiation could be confirmed in primary cells from CML patients. Hence, this humanized mouse model of CML reveals previously unexplored features of CP CML and should be useful for further studies to understand the disease pathogenesis of CML.

SOCS2 is dispensable for BCR/ABL1-induced chronic myeloid leukemia-like disease and for normal hematopoietic stem cell function.

Suppressor of cytokine signaling 2 (SOCS2) is known as a feedback inhibitor of cytokine signaling and is highly expressed in primary bone marrow (BM) cells from patients with chronic myeloid leukemia (CML). However, it has not been established whether SOCS2 is involved in CML, caused by the BCR/ABL1 fusion gene, or important for normal hematopoietic stem cell (HSC) function. In this study, we demonstrate that although Socs2 was found to be preferentially expressed in long-term HSCs, Socs2-deficient HSCs were indistinguishable from wild-type HSCs when challenged in competitive BM transplantation experiments. Furthermore, by using a retroviral BCR/ABL1-induced mouse model of CML, we demonstrate that SOCS2 is dispensable for the induction and propagation of the disease, suggesting that the SOCS2-mediated feedback regulation of the JAK/STAT pathway is deficient in BCR/ABL1-induced CML.

Whole-exome sequencing of pediatric acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL), the most common malignant disorder in childhood, is typically associated with numerical chromosomal aberrations, fusion genes or small focal deletions, thought to represent important pathogenetic events in the development of the leukemia. Mutations, such as single nucleotide changes, have also been reported in childhood ALL, but these have only been studied by sequencing a small number of candidate genes. Herein, we report the first unbiased sequencing of the whole exome of two cases of pediatric ALL carrying the ETV6/RUNX1 (TEL/AML1) fusion gene (the most common genetic subtype) and corresponding normal samples. A total of 14 somatic mutations were identified, including four and seven protein-altering nucleotide substitutions in each ALL. Twelve mutations (86%) occurred in genes previously described to be mutated in other types of cancer, but none was found to be recurrent in an extended series of 29 ETV6/RUNX1-positive ALLs. The number of single nucleotide mutations was similar to the number of copy number alterations as detected by single nucleotide polymorphism arrays. Although the true pathogenetic significance of the mutations must await future functional evaluations, this study provides a first estimate of the mutational burden at the genetic level of t(12;21)-positive childhood ALL.

Two major classes in the M protein family in group A streptococci.

The M protein family of molecules in the group A streptococcus comprises a number of cell surface proteins that interact with the immune system of the host. One of the proteins in this family is the IgA receptor Arp4, which has C repeats similar to those that characterize the known M proteins. The streptococcal strain expressing Arp4 also expresses a second immunoglobulin-binding protein, Mrp4, which is shown here to be encoded by a gene located immediately upstream of the gene for Arp4. In addition to binding IgG, Mrp4 also binds fibrinogen, a property ascribed to M proteins. DNA sequence analysis demonstrated that the Mrp4 protein indeed is a member of the M protein family, but it was unexpectedly found to have a type of repeat that is identical to the A repeat described for FcRA76, a partially sequenced streptococcal Fc receptor. Purified FcRA76 was shown to bind fibrinogen and IgG, like Mrp4. These data show that the known molecules in the M protein family can be divided into two classes, A and C, according to the type of repeat region found. Hybridization studies with a panel of clinical isolates indicate that many streptococcal strains express class A and class C proteins, whereas some strains express only class C proteins. Class A molecules show amino-terminal sequence variation, like class C molecules, which suggests that proteins of both classes are targets for the immune response.

Insect glycobiology: a lectin multigene family in Drosophila melanogaster.

Glycodeterminants play an important role in mediating cellular and cell-substrate interactions during development and immune-related reactions enabling an organism to distinguish self determinants from non-self or modified-self determinants. One of the hallmarks of sugar recognition molecules (lectins) is their wide range of binding activities and their organisation in multigene families. Here we describe a group of Drosophila genes that are possible members of the C-type lectin family.