司库奇尤单抗治疗红皮病型银屑病一例并文献复习

报道一例司库奇尤单抗治疗红皮病型银屑病治疗效果并复习相关文献.41岁红皮病型银屑病男性患者,在排除肝炎、结核的基础上,经知情同意后,给予司库奇尤单抗标准方案:0～4周每周皮下注射300 mg,随后每4周注射300 mg.在第4周达到PASI 75,第8周达到PASI 100.随访32周未见明显复发及不良反应.     

Efficacy and safety of secukinumab in Taiwanese patients with moderate to severe plaque psoriasis: Subanalysis from ERASURE phase III study

The efficacy and safety of secukinumab, a fully human anti‐interleukin‐17A monoclonal antibody, has been evaluated for moderate to severe plaque psoriasis in global trials which have included a low proportion of Asian subjects. We analyzed the efficacy and safety of secukinumab in Taiwanese patients in a phase III global clinical trial (ERASURE). Fifty‐one Taiwanese patients were randomized into s.c. placebo, 150 and 300 mg secukinumab treatment groups. The proportions of patients who achieved 75% or more improvement in Psoriasis Area and Severity Index (PASI‐75) at week 12 were 87.5% with 300 mg secukinumab, 70% with 150 mg secukinumab, 0% with placebo. Of the patients receiving 300 mg secukinumab, 68.8% achieved PASI‐90 at week 12. Analysis of overall patients receiving 300 mg secukinumab for 12 weeks showed that the proportion of PASI‐75 responders was less in patients with body mass index of 25 or more than less than 25. During the entire 52 weeks, the incidence of adverse events (AE) was consistent with the overall population in ERASURE. The most common AE (cases/per 100 patient‐year) during the entire treatment period were upper respiratory tract infection and pruritus. The duration of upper respiratory tract infection per 100 patient‐year was approximately 399 days in placebo, 1261 days in 150 mg secukinumab and 1805 days in 300 mg secukinumab. The safety and efficacy of secukinumab in Taiwanese patients was compatible with the global phase III study in the treatment of moderate to severe plaque psoriasis.     

Secukinumab efficacy and safety in Japanese patients with moderate‐to‐severe plaque psoriasis: Subanalysis from ERASURE,a randomized,placebo‐controlled,phase 3 study

Secukinumab, a fully human anti‐IL‐17A monoclonal antibody, neutralizes IL‐17A, a key cytokine in the pathogenesis of psoriasis. Efficacy and safety of secukinumab was evaluated in Japanese patients with moderate‐to‐severe plaque psoriasis as part of a large Phase 3 global study (ERASURE). In this 52‐week, double‐blind study (ClinicalTrials.gov Identifier: NCT01365455, JapicCTI‐111529), 87 patients from Japan (11.8% of 738 patients randomized in the overall study population) were equally randomized to receive secukinumab 300 mg or 150 mg, or placebo once weekly at baseline and at Weeks 1, 2, 3 and 4, then every 4 weeks. Co‐primary endpoints (Week 12) were ≥75% improvement in psoriasis area‐and‐severity index (PASI 75) from baseline and a score of 0 (clear) or 1 (almost clear) on a 5‐point Investigator's Global Assessment scale (IGA mod 2011 0/1) versus placebo. PASI 75 and IGA mod 2011 0/1 responses at Week 12 were superior with secukinumab 300 mg (82.8% and 55.2%, respectively) or 150 mg (86.2% and 55.2%, respectively) versus placebo (6.9% and 3.4%, respectively; P < 0.0001 for all). Greater than 90% improvement in PASI (PASI 90) was also superior with secukinumab 300 mg (62.1%) or 150 mg (55.2%) versus placebo (0.0%) at Week 12 (P < 0.0001 for both). Clinical responses were sustained up to Week 52 in the majority of patients. During a 12‐week induction period, adverse event incidences were 48.3% with secukinumab 300 mg, 55.2% with 150 mg, and 41.4% with placebo. Secukinumab showed robust and sustainable efficacy in symptom reduction for moderate‐to‐severe plaque psoriasis in the Japanese patients.     

Efficacy and safety of secukinumab in patients with generalized pustular psoriasis: A 52‐week analysis from phase III open‐label multicenter Japanese study

Generalized pustular psoriasis (GPP) is a severe inflammatory skin disease characterized by the presence of sterile pustules covering almost the entire body and systemic symptoms such as fever. Secukinumab, a fully human‐recombinant anti‐interleukin‐17A monoclonal antibody was indicated for psoriasis vulgaris and psoriatic arthritis in Japan but is not yet investigated for GPP. In this phase III, open‐label multicenter single arm study, the efficacy and safety of secukinumab as monotherapy or with co‐medication was evaluated in 12 Japanese patients with GPP. All the patients received secukinumab 150 mg s.c. at baseline, week 1, 2, 3 and 4, and then every 4 weeks. Two non‐responders were up‐titrated to 300 mg. Change in GPP severity from baseline was evaluated by clinical global impression (CGI) categorized as “worsened”, “no change”, “minimally improved”, “much improved” or “very much improved”. Treatment success was achieved by 83.3% (n = 10) of patients at week 16 (primary end‐point) with CGI evaluated as “very much improved” (n = 9) and “much improved” (n = 1). Moreover, the area of erythema with pustules improved as early as week 1 and resolved by week 16 in most of the patients. The improvements were sustained throughout 52 weeks. Over the 52‐week treatment period, secukinumab was well tolerated with no unexpected safety signals. Nasopharyngitis, urticaria, diabetes mellitus and arthralgia were the frequent adverse events reported. The data from this study shows that secukinumab can become one of the potent treatment options for GPP.     

Evidence that a neutrophil–keratinocyte crosstalk is an early target of IL‐17A inhibition in psoriasis

The response of psoriasis to antibodies targeting the interleukin (IL)‐23/IL‐17A pathway suggests a prominent role of T‐helper type‐17 (Th17) cells in this disease. We examined the clinical and immunological response patterns of 100 subjects with moderate‐to‐severe psoriasis receiving 3 different intravenous dosing regimens of the anti‐IL‐17A antibody secukinumab (1 × 3 mg/kg or 1 × 10 mg/kg on Day 1, or 3 × 10 mg/kg on Days 1, 15 and 29) or placebo in a phase 2 trial. Baseline biopsies revealed typical features of active psoriasis, including epidermal accumulation of neutrophils and formation of microabscesses in >60% of cases. Neutrophils were the numerically largest fraction of infiltrating cells containing IL‐17 and may store the cytokine preformed, as IL‐17A mRNA was not detectable in neutrophils isolated from active plaques. Significant clinical responses to secukinumab were observed 2 weeks after a single infusion, associated with extensive clearance of cutaneous neutrophils parallel to the normalization of keratinocyte abnormalities and reduction of IL‐17‐inducible neutrophil chemoattractants (e.g. CXCL1, CXCL8); effects on numbers of T cells and CD11c‐positive dendritic cells were more delayed. Histological and immunological improvements were generally dose dependent and not observed in the placebo group. In the lowest‐dose group, a recurrence of neutrophils was seen in some subjects at Week 12; these subjects relapsed faster than those without microabscesses. Our findings are indicative of a neutrophil–keratinocyte axis in psoriasis that may involve neutrophil‐derived IL‐17 and is an early target of IL‐17A‐directed therapies such as secukinumab.     

Assessment of serum biomarkers in patients with plaque psoriasis on secukinumab

The molecular basis of interleukin (IL)-17A in driving psoriasis pathogenesis is not fully elucidated yet. To investigate the underlying mechanisms and biomarkers associated with IL-17A and the role in psoriasis pathogenesis, over 30 serum proteins were evaluated in a study assessing the effectiveness and safety of secukinumab, where treatment was directly switched from cyclosporin A to secukinumab. Serum β-defensin 2 (BD-2) levels rapidly and robustly reduced following secukinumab treatment. BD-2 levels were well-correlated with Psoriasis Area and Severity Index (PASI) score; changes in BD-2 levels preceded change in PASI score. Serum BD-2, an easily measurable protein, can possibly be used as a suitable surrogate biomarker to monitor responses to IL-17A-targeted therapies for psoriasis in clinical practice.     

Effectiveness and safety of secukinumab in 69 patients with moderate to severe plaque psoriasis: A retrospective multicenter study

Secukinumab (anti‐IL17A) is effective as treatment for moderate to severe plaque psoriasis, but real‐life data on effectiveness and safety lack. We aimed to present real‐life data of all Danish patients treated with secukinumab (n = 69). At baseline, before initiation of treatment with secukinumab 300 mg (47.8%) or off‐label treatment with secukinumab 150 mg (52.2%), the median PASI score was 7.1. A total of 66.7% (34/51) and 52.9% (27/51) of patients still on secukinumab at week 12 achieved a PASI (Psoriasis Area and Severity Index)‐50 and PASI‐75 of 66.7% and 52.9%, respectively. A total of 83.0% (44/53) and 60.4% (32/53) of the patients had a PASI‐score < 5 and PASI‐score < 2, respectively, after 12 weeks on treatment with secukinumab. A third of the patients had secukinumab discontinued due to limited clinical improvement or adverse events (n = 23) within a median of 92 days (interquartile range 51–212 days). Notably, the majority of the patients may represent a particularly difficult‐to‐treat group of patients, as 92.8% had been refractory to other biologic treatment. A total of 26.1% (n = 18) experienced adverse events. Secukinumab appears to be an effective treatment option with a favorable side effect profile in patients with plaque psoriasis who are refractory to or have side effects of traditional biologic drugs.     

Effectiveness of anti‐interleukin 23 biologic drugs in psoriasis patients who failed anti‐interleukin 17 regimens. A real‐life experience

Among the most recent biologic drugs available for psoriasis therapy, those targeting interleukin‐17 (secukinumab and ixekizumab) or its receptor (brodalumab) have been shown to be quickly effective. However, in those patients who failed one or more of the above‐cited drugs, real‐life data on the effectiveness of switching to one anti‐interleukin‐23 biologic (guselkumab, risankizumab, or tildrakizumab) are very scarce. Here, we report our experience in treating 12 multi‐failure psoriatic patients, prospectively followed‐up over 6 months, who showed a significant improvement in their psoriasis after switching from an anti‐interleukn‐17 to an anti‐interleukin‐23 drug.     

Secukinumab demonstrates superior efficacy and a faster response in clearing skin in Asian subjects with moderate to severe plaque psoriasis compared with ustekinumab: Subgroup analysis from the CLEAR study

The 52‐week results from the CLEAR (NCT02074982) study showed high and superior efficacy of secukinumab versus ustekinumab in clearing skin and improving patient‐reported outcomes, with comparable safety profile in subjects with moderate to severe psoriasis. Here, we analyzed the efficacy and safety of secukinumab in Asian subjects from the CLEAR study. In this double‐blind, phase IIIb study, eligible subjects with moderate to severe plaque psoriasis were randomized (1:1) to receive s.c. injection of secukinumab 300 mg or ustekinumab as per label. Of 62 subjects included in Asian subanalyses, 23 were randomized to secukinumab and 39 to ustekinumab. A significantly higher proportion of subjects achieved 90% or more improvement in Psoriasis Area and Severity Index (PASI 90) with secukinumab versus ustekinumab at week 16 (78.3% vs 35.9%, P = 0.0010) and at week 52 (60.9% vs 33.3%, P = 0.0196). Similarly, a higher proportion of subjects achieved PASI 100 with secukinumab versus ustekinumab at week 16 (43.5% vs 10.3%, P = 0.0029) and at week 52 (30.4% vs 12.8%, P = 0.0704). The median time to achieve 50% improvement in baseline PASI was 2.8 weeks in the secukinumab group versus 6.3 weeks in the ustekinumab group. The safety profile of secukinumab was in line with the known profile and no deaths occurred. Overall, 95.7% and 84.6% of subjects remained on secukinumab and ustekinumab, respectively. Similar to the core study, secukinumab showed sustained and superior efficacy with faster response versus ustekinumab, and no new or unexpected safety concerns were identified, in Asian subjects with moderate to severe plaque psoriasis.     

Mild electrical stimulation with heat shock reduces inflammatory symptoms in the imiquimod‐induced psoriasis mouse model

Psoriasis is a chronic skin disease caused by immune disorder. The chronic skin inflammation involves inflammatory molecules that are released from T lymphocytes and keratinocytes. Therefore, developing an anti‐inflammatory therapy that is suitable for long‐term treatment is needed. Electrical stimulation induces biological responses by modulating intracellular signaling pathways. Our previous studies showed that the optimized combination treatment of mild electrical stimulation (MES, 0.1‐millisecond; ms, 55‐pulses per second; pps) and heat shock (HS, 42°C) modulates inflammatory symptoms of metabolic disorders and chronic kidney disease in mice models and clinical trials. Here, we investigated the effect of MES+HS treatment on imiquimod‐induced psoriasis mouse model. Topical application of imiquimod cream (15 mg) to mice ear induced keratinocyte hyperproliferation and psoriasis‐like inflammation. In MES+HS‐treated mice, imiquimod‐induced skin hyperplasia was significantly decreased. MES+HS treatment reduced the protein expression of IL‐17A and the infiltration of CD3‐positive cells in lesioned skin. In addition, MES+HS‐treated mice had decreased mRNA expression level of antimicrobial molecules (S100A8 and Reg3γ) which aggravate psoriasis. In IL‐17A‐stimulated HaCaT cells, MES+HS treatment significantly lowered the mRNA expression of aggravation markers (S100A8, S100A9 and β‐defensin2). Taken together, our study suggested that MES+HS treatment improves the pathology of psoriasis via decreasing the expression of inflammatory molecules.     

环孢素维持治疗银屑病随机对照研究的文献分析

检索MEDLINE、Embase、Cochrane图书馆、SinoMed、CNKI和万方数据库中1974年1月1日至2018年7月1日环孢素维持治疗银屑病的随机对照临床研究,评价不同环孢素给药方案治疗银屑病的疗效和安全性。共纳入9篇随机临床对照试验文献,均报道环孢素治疗银屑病有效,其中2篇文献研究发现连续治疗方案在长达24周的维持治疗期内是安全有效的,2篇发现间断治疗比连续治疗更安全有效。     

Efficacy and safety of cyclosporine versus methotrexate in severe psoriasis: a study from north India

Treatment of patients with severe psoriasis is difficult. Among the number of systemic drugs that are available, methotrexate has long been used, but cyclosporine has been recently recommended for the management of severe psoriasis. The purpose of this study was to compare the efficacy and safety of daily cyclosporine with weekly methotrexate in the management of severe psoriasis. Thirty consecutive patients with severe psoriasis were randomly assigned to treatment with cyclosporine or methotrexate. The initial dose of cyclosporine was 3 mg/kg/day, which was increased to a maximum of 4 mg/kg after two weeks of therapy when the response was not adequate. Methotrexate was administered weekly at a dose of 0.5 mg/kg. Clinical response was assessed by calculating PASI score in all patients at biweekly intervals. Patients were followed up fortnightly up to a maximum of 12 weeks. The doses of both drugs were gradually tapered once >75% reduction in disease severity was attained. Marked improvement (>75%) reduction in PASI was noted in all patients except for one in the cyclosporine group. The median time for marked improvement was 5.3 weeks with methotrexate and 6.8 weeks with cyclosporine. Patients on methotrexate were found to have more rapid and complete clearance than those on cyclosporine. Both drugs were well tolerated. Side effects in both the treatment groups were minor, transient, and manageable. At doses with comparable safety profiles, methotrexate resulted in more rapid and cost effective clearance of patients with severe psoriasis. Cyclosporine can provide an effective and safe alternative.     

Risk factors for increased serum creatinine level in patients with psoriasis treated with cyclosporine in a real‐world practice

Nephrotoxicity is a major concern for patients with psoriasis using cyclosporine. Here, we evaluated the impact of intermittent cyclosporine treatment on nephrotoxicity risk among patients with psoriasis in real‐world clinical practice. We retrospectively reviewed 611 patients with psoriasis treated with cyclosporine between January 2013 and January 2017, 398 of whom were considered eligible for analysis. Eighteen (4.5%) patients showed a greater than 25% increase in serum creatinine levels. Age over 60 years (relative risk [RR], 1.6; p = .015), diabetes (RR, 2.3; p < .001), and obesity (RR, 1.7; p = .011) were the significant risk factors of increased serum creatinine levels in patients with psoriasis. There was no significant association of the treatment duration or cumulative dose of cyclosporine with increased serum creatinine levels. In real clinical practice, intermittent cyclosporine use with regular serum creatinine tests can be used to treat psoriasis relatively safely. Age over 60 years, diabetes and obesity are significant risk factors for cyclosporine‐induced nephrotoxicity.     

Efficacy and safety of ixekizumab treatment in Japanese patients with moderate‐to‐severe plaque psoriasis: Subgroup analysis of a placebo‐controlled,phase 3 study (UNCOVER‐1)

The present study describes a subgroup analysis of 33 Japanese patients participating in UNCOVER‐1, an international, placebo‐controlled, phase 3 study of ixekizumab in patients with moderate‐to‐severe psoriasis. Patients were randomized to a placebo (n = 13) or ixekizumab 80 mg every 4 (IXEQ4W, n = 12) or 2 (IXEQ2W, n = 8) weeks, from week 0–12. At week 12, ixekizumab‐treated patients with a static Physician Global Assessment score 0 or 1 (sPGA [0,1]; n = 16) were re‐randomized to a placebo (n = 6), ixekizumab 80 mg every 12 (IXEQ12W, n = 5) or 4 (IXEQ4W, n = 5) weeks, from week 12–60. At week 12, more ixekizumab‐treated versus placebo‐treated patients achieved sPGA (0,1) (≥66.7% vs 0%), ≥75% improvement in Psoriasis Area and Severity Index (≥75% vs 0%), and sPGA (0) or 100% improvement in Psoriasis Area and Severity Index (both ≥33.3% vs 0%), with improved symptoms and quality of life. At week 60, 100% (IXEQ4W), 40.0% (IXEQ12W) and 16.7% (placebo) had maintained sPGA (0,1). From week 0–12, treatment‐emergent adverse events were 76.9% (placebo), 75.0% (IXEQ4W) and 87.5% (IXEQ2W), and from week 12–60 were 66.7% (placebo) and 100% (IXEQ12W, IXEQ4W). Ixekizumab‐treated patients had no severe treatment‐emergent adverse events, and one serious TEAE (IXEQ4W); infection was the most frequent treatment‐emergent adverse event. In conclusion, ixekizumab for 60 weeks was effective and safe for Japanese patients with moderate‐to‐severe psoriasis, in line with the overall findings from UNCOVER‐1.     

Secukinumab and acitretin as a combination therapy for three clinical forms of severe psoriasis in multi‐drug refractory patients: A case series of high efficacy and safety profile

Secukinumab, the first monoclonal antibody that inhibits interleukin‐17A, has been shown to have rapid and long‐lasting efficacy in the treatment of moderate‐to‐severe psoriasis. However, there are still difficult‐to‐treat cases in which even dose‐escalation fails to provide a clinical response. In such cases, combining secukinumab with a conventional systemic agent may be a rational approach. Although methotrexate is most commonly preferred, acitretin may also be considered a good alternative, with its lower hepatotoxic potential. Data are limited regarding the use of combination therapy of secukinumab and acitretin for psoriasis. We herein present three patients with chronic plaque, generalized pustular and erythrodermic psoriasis, respectively, accompanied by multiple comorbidities, in whom skin clearance could not be achieved with several conventional and biologic therapies (including escalated dose regimens of secukinumab in two patients). Alternatively, we used a combination of secukinumab with low‐dose acitretin, which resulted in a complete or almost complete skin clearance in all patients, with no adverse events or increased toxicity. Based on our real‐life clinical experience with those patients, acitretin seems an effective and safe option to be used in combination with secukinumab. Even in patients who are refractory to multiple drugs including escalated doses of secukinumab, the addition of low‐dose acitretin may be helpful in achieving treatment goals, decreasing the need for switching to another biologic therapy.     

Safety and efficacy profile of oral cyclosporine vs oral methotrexate vs oral acitretin in palmoplantar psoriasis: A hospital based prospective investigator blind randomized controlled comparative study

Palmoplantar psoriasis (PPP) is a variant of psoriasis which affects only 5% body surface area, but has a devastating impact on affected individual's quality of life. There are few studies assessing efficacy of individual drugs, and few comparative studies of efficacy of two drugs in the literature, however randomized control trial comparing all three drugs against each other has not been done. A total of 75 patients of PPP were enrolled for study and randomly divided into three groups A, B, C of 25 each and assigned for treatment with cyclosporine (CSA) (2.5‐5 mg/kg/d), methotrexate (MTX)(7.5‐15 mg/week), and acitretin (ACT) (25‐50 mg/d), respectively. Modified psoriasis area and severity index (PASI), psoriasis severity scale, visual analogue scale, physician global assessment, and PPQOL were used for monitoring response to therapy and improvement in quality of life up to end of study, and thereafter monthly follow‐up was done to find duration of remission for next 90 days. Side effects if any were recorded. There was a statistically significant difference in modified PASI for CSA, MTX, and ACT. The mean modified PASI at baseline was 12.8 ± 4.8 for CSA, 12.57 ± 3.8 for MTX, and 11.92 ± 3.28 for ACT (P = .75). Mean modified PASI reduced to 2.91 ± 1.8 for CSA, 6.57 ± 2.2 for MTX, and 4.7 ± 2.2 for ACT at week 5 (P = <.01). Mean modified PASI further reduced to 0.095 ± 0.35 for CSA, 2.12 ± 1.4 for MTX, and 0.78 ± 0.97 for ACT at end of study (P = <.01). However, average duration of remission was 9 weeks for ACT group, followed by 6.47 and 3 weeks for CSA and MTX group, respectively. Adverse events were comparatively more in ACT group as compared to MTX and CSA groups. PPP affects quality of life tremendously and warrants systemic treatment for the same. CSA provides fastest resolution of lesions and have highest efficacy. MTX and ACT have similar efficacy, but ACT provides longer duration of remission.     

Real world data from the use of secukinumab in the treatment of moderate‐to‐severe psoriasis,including scalp and palmoplantar psoriasis: A 104‐week clinical study

Several clinical studies demonstrated the safety and efficacy of the interleukin‐17 inhibitor secukinumab in the systemic treatment of moderate‐to‐severe psoriasis, as well as psoriatic arthritis (PsA) in adults, whereas real‐world data is limited. A single‐center clinical study was performed to evaluate in real‐world practice the efficacy of secukinumab up to Week 104 of treatment in moderate‐to‐severe chronic plaque psoriasis, including scalp and palmoplantar involvement, according to Physician Global Assessment (PGA), PASI75/90/100 and scalp, and palmoplantar PGA. Drug survival, the safety profile of secukinumab, and patient's quality of life were also assessed during a 2‐year observation period. Out of 83 patients included, 56.3% were biologic‐naïve, and 94% had scalp, 25.3% palmoplantar, and 43.9% joint involvement. At Week 16, PASI75/PASI90/PASI100 were observed in 83.8/70.0/46.3%, respectively. Scalp and palmoplantar PGA were rapidly improved, with 98.7 and 95.5%, respectively, reaching clear/almost clear skin at Week 16. After 104 weeks, drug survival was 74.5%. A significant improvement of the quality of life was observed. Biologic‐naïve patients without coexisting PsA benefited the most. Real‐world data demonstrated secukinumab efficacious in chronic plaque psoriasis, including specific locations such as scalp and palmoplantar psoriasis with a safety profile similar to that in clinical trials.     

The plot thickens while the scope broadens: a holistic view on IL‐17 in psoriasis and other inflammatory disorders

Psoriasis is an instructive example highlighting our growing knowledge about pathophysiological functions of interleukin (IL)‐17. IL‐17A is the predominant isoform implicated in key pathogenic features in this and other chronic inflammatory disorders. Several monoclonal antibodies targeting IL‐17A (secukinumab, ixekizumab) or its IL‐17RC/RA receptor (brodalumab) are currently in late stages of clinical development, where they have shown impressive efficacy. While the eponymous IL‐17 has been thought to originate primarily from T helper (Th)17 cells, more recent investigations by several groups suggest that other cell types in psoriatic lesions, such as neutrophils and mast cells, are rich sources of IL‐17, thus presumably contributing to the disease process to an as yet underestimated extent. This recent paradigm shift provides a plausible explanation for the rapid and strong efficacy of the novel compounds targeting IL‐17 functions in psoriasis and other inflammatory disorders, and provide a more comprehensive view on the complex cytokine network in these conditions.