Posts Tagged ‘pro-inflammatory cytokine’

Success in Psoriasis Treatment

Larry H. Bernstein, MD, FCAP, Curator




Anti-IL17A Tx Clears Most Cases of Psoriasis

Durable long-term responses with ixekizumab, secukinumab

  • Note that these studies were published as abstracts and presented at a conference.
  • These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
  • More than half of patients with moderate-to-severe plaque psoriasis remained clear of lesions after a year of treatment with the interleukin-17A inhibitor ixekizumab.
  • Note that in another study, comparing two monoclonal antibodies for secukinumab (Cosentyx) or ustekinumab (Stelara) in patients with moderate to severe plaque psoriasis. showed sustained superiority for secukinumab (Cosentyx) over ustekinumab (Stelara).

More than half of patients with moderate-to-severe plaque psoriasis remained clear of lesions after a year of treatment with the interleukin-17A inhibitor ixekzumab, according to data reported here.

The 60-week follow-up data showed that 54% of patients treated with either of two doses of ixekizumab had 100% improvement in the Psoriasis Area and Severity Index (PASI 100). More than 70% achieved PASI 90, and more than 80% met criteria for PASI 75 response.

In general, the monoclonal antibody demonstrated good tolerability, associated with a discontinuation rate of about 5%, Andrew Blauvelt, MD, of Oregon Medical Research Center in Portland, reported at the American Academy of Dermatology meeting.

“Izekizumab treatment led to high clinical response rates and sustained efficacy in a majority of patients,” Blauvelt said. “More than half of ixekizumab-treated patients achieved complete resolution of psoriatic plaques at week 60. The safety profile for ixekizumab was similar to what was observed during the 12-week induction period.”

Ixekizumab is a specific inhibitor of the IL-17A receptor. The antibody was compared against placebo and etanercept (Enbrel) in two phase III trials that evaluated two ixekizumab dosing schedules (administration every 2 or 4 weeks). More than 1,200 patients were randomized 1:2:2:2 to placebo, etanercept (Enbrel) or one of the ixekizumab schedules.

As previously reported, the antibody demonstrated superior efficacy after a 12-week induction period. PASI 75 response rates were 7.3% with placebo, 53.4% with etanercept, and 84.2% and 87.3% with the two ixekizumab regimens. PASI 90 rates were 3.1%, 25.7%, 65.3%, and 68.1%. PASI 100 responses were attained by 0%, 73%, 35%, and 37.7%.

Upon completion of the induction phase, all patients transitioned to open-label ixekizumab, administered every 4 weeks. Blauvelt reported findings for patients who received only ixekizumab for the entire 60-week follow-up period.

The data showed that response rates attained at 12 weeks with ixekizumab held up through the 60-week follow-up period. The intention-to-treat analysis (n=771) showed response rates of 82%, 72%, and 54% for PASI 75, PASI 90, and PASI 100. A per-protocol analysis (n=722) showed a PASI 75 response rate of 87%, PASI 90 response rate of 77%, and PASI 100 response rate of 57%.

Cosentyx Versus Stelara

In another study reported here, long-term follow-up from a randomized trial comparing two other biologic drugs showed sustained superiority for secukinumab (Cosentyx) over ustekinumab (Stelara) in patients with moderate to severe plaque psoriasis.

The randomized comparison of secukinumab (Cosentyx) and ustekinumab involved almost 700 patients who had a baseline mean PASI score ≥12, an investigator global assessment score ≥3, and body surface area involvement ≥10%. They were randomized to the monclonal antibodies, and the primary endpoint was PASO 90 response at 16 weeks. As reported last year, secukinumab resulted in a PASI 90 rate of 80.1% versus 59.0% for ustekinumab (P<0.0001). PASI 100 rates were 45% and 29.2% (P<0.0001).

Follow-up in both groups continued to week 52, during which time patients treated with secukinumab continued to have better psoriasis clearance rates compared with those treated with ustekinumab, said Diamant Thaci, MD, of the University of Lubeck in Germany. The secukinumab group had a PASI 90 rate of 76.2% compared with 60.6% for the ustekinumab group (P<0.0001). PASI 100 rates (a secondary endpoint) were 45.9% and 35.8% with secukinumab and ustekinumab, respectively (P<0.05).

Investigators in the trial collected quality of life data by means of the Dermatology Qualty of Life Index (DLQI). A secondary endpoint was the proportion of patients with a DLQI score of 0 or 1 at week 52 (responder). Response rates were 71.6% with secukinumab and 59.2% with ustekinumab (P=0.0008). A significant between-group difference emerged at 4 weeks and persisted throughout the 52-week follow-up period, Thaci said.

Secukinumab and ustekinumab had similar and favorable safety profiles. No new or unexpected adverse events or toxicities occurred in either group. No patient developed tuberculosis, Crohn’s disease, or ulcerative colitis. The only notable difference was a higher incidence of candida infection with secukinumab (6.4% versus 1.6%). Thaci said none of the infections were serious.


The ixekizumab trial was supported by Eli Lilly.

Blauvelt disclosed relevant relationships with AbbVie, Amgen, Boehringer Ingelheim, Celgene, Dermira, Genentech, Janssen Ortho Biotech, Eli Lilly, Merck, Novartis, Pfizer, Regeneron, and Sandoz.

The secukinumab trial was supported by Novartis.

Thaci disclosed relevant relationships with AbbVie, Almiral, Amgen, Astellas, Biogen-Idec, Boehringer Ingelheim, Celgene, Dignity, Eli Lilly, Forward Pharma, GlaxoSmithKline, LEO Pharma, Janssen-Cilag, Maruho, Merck Sharp & Dohme, Mitsubishi Pharema, Novartis, Pfizer, Roche, Sandoz, Galapagos, Xenoport, Roche, and Mundipharma.



Lancet. 2015 Aug 8;386(9993):541-51. Epub 2015 Jun 10.
Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials.


Ixekizumab is a humanised monoclonal antibody against the proinflammatory cytokine interleukin 17A. We report two studies of ixekizumab compared with placebo or etanercept to assess the safety and efficacy of specifically targeting interleukin 17A in patients with widespread moderate-to-severe psoriasis.


In two prospective, double-blind, multicentre, phase 3 studies (UNCOVER-2 and UNCOVER-3), eligible patients were aged 18 years or older, had a confirmed diagnosis of chronic plaque psoriasis at least 6 months before baseline (randomisation), 10% or greater body-surface area involvement at both screening and baseline visits, at least a moderate clinical severity as measured by a static physician global assessment (sPGA) score of 3 or more, and a psoriasis area and severity index (PASI) score of 12. Participants were randomly assigned (1:2:2:2) by computer-generated random sequence with an interactive voice response system to receive subcutaneous placebo, etanercept (50 mg twice weekly), or one injection of 80 mg ixekizumab every 2 weeks, or every 4 weeks after a 160 mg starting dose. Blinding was maintained with a double-dummy design. Coprimary efficacy endpoints were proportions of patients achieving sPGA score 0 or 1 and 75% or greater improvement in PASI at week 12. Analysis was by intention to treat. These trials are registered with, numbers NCT01597245 and NCT01646177.


Between May 30, 2012, and Dec 30, 2013, 1224 patients in UNCOVER-2 were randomly assigned to receive subcutaneous placebo (n=168), etanercept (n=358), or ixekizumab every 2 weeks (n=351) or every 4 weeks (n=347); between Aug 11, 2012, and Feb 27, 2014, 1346 patients in UNCOVER-3 were randomly assigned to receive placebo (n=193), etanercept (n=382), ixekizumab every 2 weeks (n=385), or ixekizumab every 4 weeks (n=386). At week 12, both primary endpoints were met in both studies. For UNCOVER-2 and UNCOVER-3 respectively, in the ixekizumab every 2 weeks group, PASI 75 was achieved by 315 (response rate 89·7%; [effect size 87·4% (97·5% CI 82·9-91·8) vs placebo; 48·1% (41·2-55·0) vs etanercept]) and 336 (87·3%; [80·0% (74·4-85·7) vs placebo; 33·9% (27·0-40·7) vs etanercept]) patients; in the ixekizumab every 4 weeks group, by 269 (77·5%; [75·1% (69·5-80·8) vs placebo; 35·9% (28·2-43·6) vs etanercept]) and 325 (84·2%; [76·9% (71·0-82·8) vs placebo; 30·8% (23·7-37·9) vs etanercept]) patients; in the placebo group, by four (2·4%) and 14 (7·3%) patients; and in the etanercept group by 149 (41·6%) and 204 (53·4%) patients (all p<0·0001 vs placebo or etanercept). In the ixekizumab every 2 weeks group, sPGA 0/1 was achieved by 292 (response rate 83·2%; [effect size 80·8% (97·5% CI 75·6-86·0) vs placebo; 47·2% (39·9-54·4) vs etanercept]) and 310 (80·5%; [73·8% (67·7-79·9) vs placebo; 38·9% (31·7-46·1) vs etanercept]) patients; in the ixekizumab every 4 weeks group by 253 (72·9%; [70·5% (64·6-76·5) vs placebo; 36·9% (29·1-44·7) vs etanercept]) and 291 (75·4%; [68·7% (62·3-75·0) vs placebo; 33·8% (26·3-41·3) vs etanercept]) patients; in the placebo group by four (2·4%) and 13 (6·7%) patients; and in the etanercept group by 129 (36·0%) and 159 (41·6%) patients (all p<0·0001 vs placebo or etanercept). In combined studies, serious adverse events were reported in 14 (1·9%) of 734 patients given ixekizumab every 2 weeks, 14 (1·9%) of 729 given ixekizumab every 4 weeks, seven (1·9%) of 360 given placebo, and 14 (1·9%) of 739 given etanercept; no deaths were noted.


Both ixekizumab dose regimens had greater efficacy than placebo and etanercept over 12 weeks in two independent studies. These studies show that selectively neutralising interleukin 17A with a high affinity antibody potentially gives patients with psoriasis a new and effective biological therapy option.


Eli Lilly and Co.

Copyright © 2015 Elsevier Ltd. All rights reserved.


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Cigarette smoke induces pro-inflammatory cytokine release by activation of NF-kappaB and posttranslational modifications of histone deacetylase as seen in macrophages

Reporter and Curator: Dr. Sudipta Saha, Ph.D.


Chronic obstructive pulmonary disease (COPD)

Reactive oxygen species (ROS)

Hydroxyl radicals (·OH)

Glutathione (GSH)

Histone deacetylase (HDAC)

TNF (Tumour necrosis factor)

IκB kinase complex (IKK)

Interleukin (IL)

Cigarette smoking is the major etiologic factor in the pathogenesis of chronic obstructive pulmonary disease (COPD), which is characterized by an abnormal inflammatory response in the lungs to cigarette smoke with a progressive and irreversible airflow limitation. Chronic airway inflammation is an archetypal feature of COPD, and increased oxidative stress has been suggested to be responsible for triggering inflammatory events observed within the lungs of smokers and COPD patients. Although the precise mechanisms behind the pathogenesis of COPD are yet to be fully dissected, the current hypothesis suggests that cigarette smoke causes airway inflammation by activating macrophages, neutrophils, and T lymphocytes, which release proteases and reactive oxygen species (ROS) leading to cellular injury. As a consequence, chronic inflammatory processes are triggered that lead to small airway obstruction. An increased oxidant burden in smokers may be derived from the fact that cigarette smoke contains an estimated 1017 oxidants/free radicals and 4,700 chemical compounds, including reactive aldehydes (carbonyls) and quinones, per puff. Many of these are relatively long-lived, such as tar-semiquinone, which can generate hydroxyl radicals (·OH) and H2O2 by the Fenton reaction. One consequence of this increased oxidative stress is activation of redox-sensitive transcription factors, such as NF-κB and activator protein-1 (AP-1), which are critical to transcription of proinflammatory genes (IL-8, IL-6, and TNF-α). However, the precise transcriptional mechanisms leading to enhanced gene expression in response to cigarette smoke are still not clearly understood.

Cigarette smoke-mediated oxidative stress induces an inflammatory response in the lungs by stimulating the release of proinflammatory cytokines. Chromatin remodeling due to histone acetylation and deacetylation is known to play an important role in transcriptional regulation of proinflammatory genes. The aim of this study was to investigate the molecular mechanism(s) of inflammatory responses caused by cigarette smoke extract (CSE) in the human macrophage-like cell line MonoMac6 and whether the treatment of these cells with the antioxidant glutathione (GSH) monoethyl ester, or modulation of the thioredoxin redox system, can attenuate cigarette smoke-mediated IL-8 release. Exposure of MonoMac6 cells to CSE (1% and 2.5%) increased IL-8 and TNF-alpha production vs. control at 24 h and was associated with significant depletion of GSH levels associated with increased reactive oxygen species release in addition to activation of NF-kappaB. Inhibition of IKK ablated the CSE-mediated IL-8 release, suggesting that this process is dependent on theNF-kappaB pathway. CSE also reduced histone deacetylase (HDAC) activity and HDAC1, HDAC2, and HDAC3 protein levels. This was associated with posttranslational modification of HDAC1, HDAC2, and HDAC3 protein by nitrotyrosine and aldehyde-adduct formation. Pretreatment of cells with GSH monoethyl ester, but not thioredoxin/thioredoxin reductase, reversed cigarette smoke-induced reduction in HDAC levels and significantly inhibited IL-8 release. Thus cigarette smoke-induced release of IL-8 is associated with activation of NF-kappaB via IKK and reduction in HDAC levels/activity in macrophages. Moreover, cigarette smoke-mediated proinflammatory events are regulated by the redox status of the cells.

Source References:

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