Ixekizumab Efficacy in Patients with Severe Peripheral Psoriatic Arthritis: A Post Hoc Analysis of a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study (SPIRIT-P1).

INTRODUCTION: The efficacy and safety of ixekizumab, an anti-interleukin-17A antibody, in patients with severe symptoms of psoriatic arthritis are largely unexplored. We report the efficacy and safety of ixekizumab in a post hoc analysis of the SPIRIT-P1 trial. METHODS: Patients were treated with placebo, ixekizumab 80 mg every 2 weeks (Q2W) or 4 weeks (Q4W), or adalimumab 40 mg Q2W for 24 weeks. In this subgroup analysis of SPIRIT-P1, the population with severe psoriatic arthritis was defined using the modified composite psoriatic activity index total score > 7 and peripheral arthritis score = 3 (> 4 tender or swollen joint count and ≥ 0.5 Health Assessment Questionnaire-Disability Index). Efficacy was measured by joint and skin endpoints including disease progression. RESULTS: In the severe population, significantly more patients (p ≤ 0.001) treated with ixekizumab than placebo achieved 20% improvement according to the American College of Rheumatology criteria (ACR 20): 63.3% for ixekizumab Q4W, 60.4% for ixekizumab Q2W, and 24.5% for placebo. Statistically greater responses compared with placebo were observed in the severe population for ACR 50, ACR 70, ACR core set, disease activity index for psoriatic arthritis (DAPSA) low disease activity and DAPSA remission, and 28-joint disease activity score using C-reactive protein, as well as Psoriasis Area and Severity Index (PASI) 75, PASI 90, and PASI 100 (p ≤ 0.001). Efficacy findings and the safety profile of ixekizumab in the severe population were consistent with those of the overall population, with no new safety concerns identified. CONCLUSIONS: In patients with severe psoriatic arthritis, 24 weeks of treatment with ixekizumab resulted in improvements in both joint and skin symptoms. The safety profile in the severe population was consistent with the established safety profile of ixekizumab. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01695239.

A multicentre study of clinical features and HLA typing in Japanese patients with ankylosing spondylitis.

OBJECTIVES: Due to the low prevalence of HLA-B27 and ankylosing spondylitis (AS) in Japan, rheumatologists have little experience with AS. We conducted a multicentre study to identify the characteristics and frequency of HLA-B types. METHODS: We analysed epidemiological and clinical data, blood tests, spine radiographs, and HLA-B types in Japanese AS patients. RESULTS: We evaluated 111 AS patients, predominantly men (82.9%). The mean age, disease onset, diagnosis, and time from onset to diagnosis were 43.7, 24.2, 36.0, and 11.6 years, respectively. Inflammatory low back pain was found in 96 cases (86.5%); peripheral arthritis in 59 (53.2%), enthesitis in 35 (31.5%), and dactylitis in 6 (5.4%). Extra-articular symptoms included uveitis, psoriasis, and inflammatory bowel disease in 41 (36.9%), 1 (0.9%), and 5 (4.5%) cases, respectively. HLA-B27 was positive in 83 cases (74.8%; odds ratio, 1146.0); and HLA-B48 in 9 (8.1%; odds ratio, 3.0). HLA-B27-positive patients were younger at onset and had a shorter diagnostic delay. CONCLUSIONS: AS clinical symptoms were almost the same as other countries except for the low coexistence of psoriasis. HLA-B27 positivity in Japanese patients was 78%. HLA-B27-positive patients were younger and diagnosed earlier. In addition to HLA-B27, a relationship with HLA-B48 was suggested.

Treatment patterns and health care resource utilization among Japanese patients with ankylosing spondylitis: A hospital claims database analysis.

OBJECTIVES: To understand the current state of treatment patterns and health care resource utilization among patients in Japan with ankylosing spondylitis (AS) managed in the real-world setting. METHODS: Patient records from the Medical Data Vision database were analyzed to identify patients with ICD-10 AS from April 2009 through July 2017. Measures evaluated included demographic, clinical, and other characteristics at diagnosis; treatment patterns; health care resource utilization; and costs. RESULTS: Four hundred and seventeen patients met the study's inclusion criteria. Treatments observed during the first year after the initial AS diagnosis included nonsteroidal anti-inflammatory drugs (79.6%), corticosteroids (39.3%), methotrexate (22.3%), sulfasalazine (16.8%), adalimumab (14.2%), and infliximab (12.2%). At any time during the mean 33 months of study follow-up, biologic disease-modifying antirheumatic drugs (bDMARDs) were initiated by 115 patients. During the study follow-up, patients who initiated bDMARDs had higher median total per-patient annual health care costs ($26,937 vs $15,323), lower median per-patient hospitalization costs ($29,817 vs. $39,509), and fewer median hospital days per admission (7.0 vs. 11.0 days) compared with the overall group of patients diagnosed with AS. CONCLUSION: This database study provides knowledge of patient characteristics, treatment patterns, HCRU, and costs for patients with AS in Japan. The study outcomes demonstrate a need for increased awareness of proper AS management.

Skin Inflammation and Testicular Function: Dermatitis Causes Male Infertility via Skin-Derived Cytokines.

The medical comorbidities including skin diseases are associated with male infertility. The most common cause of male infertility is the inability of testes to produce sperm; however, the influence of persistent dermatitis on testicular function has not been elucidated so far. We investigated the relationship between skin inflammation and impaired sperm production using a spontaneous dermatitis mouse model. We examined the breeding records of dermatitis mice and their wild-type littermates. Sperm count, motility, and viability were analyzed by direct microscopic observation and flow cytometry. In addition, testis and epididymis were histologically examined. Finally, sperm viability was evaluated in another dermatitis mouse model and in wild-type mice in which inflammatory cytokines were intraperitoneally administered. Compared to wild-type littermate mice, the number of children born was lower in mice with dermatitis. The body weight and testis size were decreased age-dependently. In the skin disease group, the sperm count and movement ratio were clearly decreased, and reduced sperm viability was observed. Histological examination revealed the detachment of Sertoli cells and reduced spermatogenesis. The fibrosis of epididymal stroma was severe, and it might affect defective sperm maturation in the epididymis. In addition, this phenomena was reproduced by a hapten applied dermatitis mouse model and the intraperitoneal administration of inflammatory cytokines. Once the skin is inflamed, inflammatory cytokines are produced and released, which may affect testicular and sperm function. Additional studies are needed to determine the relationship between male infertility and severe dermatitis in human.

Inflammatory Skin-Derived Cytokines Accelerate Osteoporosis in Mice with Persistent Skin Inflammation.

Secondary osteoporosis can also be caused by chronic inflammatory skin disease as well as rheumatoid arthritis or inflammatory bowel disease. However, the exact role of osteoporosis in inflammatory skin conditions has not been elucidated. Using a mouse model of dermatitis, we investigated the pathophysiology of osteoporosis in inflammatory skin conditions and the therapeutic impact of osteoporosis medication on inflammatory skin disease. We employed model mice of spontaneous skin inflammation, specifically overexpressing human caspase-1 in the epidermis. Bone density and the expression of various mRNAs in the femur were examined by micro CT and RT-PCR. The effects of minodronate and anti-RANKL antibody on bone structure, histology, and femur blood flow were studied. The mouse model of skin inflammation showed a marked decrease in bone density compared to wild-type littermates with abnormalities in both bone resorption and formation. Minodronate improved bone density by decreasing osteoclasts, but anti-RANKL antibody did not improve. In the dermatitis model, the blood flow in the bone marrow was decreased, and minodronate restored this parameter. A model of persistent dermatitis exhibited marked osteoporosis, but the impact of chronic dermatitis on osteoporosis has not been thoroughly investigated. We should explore the pathogenesis of osteoporosis in skin inflammatory diseases.

Elimination Half-Lives of Acute Phase Proteins in Rats and Beagle Dogs During Acute Inflammation.

The half-lives of typical acute phase proteins in rats and beagle dogs during acute inflammation were investigated. Acute inflammation was induced by injection of turpentine oil in rats and administration of indomethacin in beagle dogs. Serum concentrations of α2-macroglobulin (α2M) and C-reactive protein (CRP) were measured by enzyme-linked immunosorbent assay and α1-acid glycoprotein (AAG) was measured by single radial immunodiffusion. Half-life was calculated as 0.693/elimination rate constant (K). The mean half-lives in the terminal elimination phase of α2M and AAG were 68.1 and 164.8 h, respectively. The half-life of AAG was significantly longer than that of α2M. Mean half-lives in the terminal elimination phase of CRP and AAG were 161.9 and 304.4 h, respectively. The half-life of AAG was significantly longer than that of CRP in beagle dogs. No significant differences in the half-life of AAG were observed between rats and beagle dogs. Furthermore, serum concentrations in the terminal elimination phase could be simulated with the K data acquired in this study.