Arvin Ighani

Short-term reasons for withdrawal and adverse events associated with apremilast therapy for psoriasis in real-world practice compared to clinical trials: a multicenter retrospective study

To the Editor: Psoriasis management relies on long-term therapies that control symptoms and reduce disease manifestations. Apremilast is a safe and effective agent for treating psoriasis according to its randomized controlled trials (RCTs), ESTEEM 1 and 2. However, it is important to evaluate apremilast’s safety in real-world practice (RWP) because RCTs are primarily powered to measure efficacy. Hence, institutions such as the US Food and Drug Administration often rely on real-world postmarketing safety surveillance when approving regulatory actions. We evaluated the short-term reasons for withdrawal and safety of apremilast in RWP compared with in RCTs. A retrospective review of 208 patients was conducted at 2 academic hospitals. The project was approved by the research ethics board of Women’s College Hospital and Sunnybrook Health Sciences Centre. Patients with psoriasis who were treated with apremilast and at least 18 years old were included. Patients were permitted to use concurrent therapies alongside apremilast. Safety (reported adverse events [AEs]) and tolerability (withdrawal due to AEs) were assessed from baseline to week 16. The Pearson test was used to compare outcomes between patients in RWP and RCTs (P # .05 was considered significant). Our results demonstrated that fewer patients in RWP reported 1 or more AEs than did patients in RCTs (58.7% in RWP vs 68.9% in an RCT [P 1⁄4 .005]) (Table I). However, many common AEs reported in RWP were shown in proportions similar to those reported in RCTs: diarrhea (P 1⁄4 .624), headache (P1⁄4 .298), and nausea (P1⁄4 .447). In all, 39 patients in RWP withdrew treatment on account of AEs, and this number was proportionately greater than in RCTs (18.8% in RWP vs 5.3% in an RCT [P .001]) (Table II). Accordingly, many AEs leading to withdrawal in RWP were reported in greater proportions than in RCTs: diarrhea (P1⁄4 .001), nausea (P 1⁄4 .004), and headache (P .001). These real-world findings support the apremilast RCT data. Most patients in RWP experiencedmild-tomoderate AEs similar to those experienced by patients in RCTs: diarrhea (P 1⁄4 .624), headache (P 1⁄4 .298), and nausea (P 1⁄4 .447). Moreover, we had no reports of tuberculosis reactivation, malignancy, opportunistic infections, or life-threatening AEs. In fact, the proportion of patients in RWP who experienced 1 or more AEs was lower than in RCTs (P 1⁄4 .005). This may be explained by the fact that AEs were not actively elicited in RWP, as reflected by our lower proportion of reports of upper respiratory tract infection (P 1⁄4 .003). As expected, there were proportionately more withdrawals in RWP than in RCTs (P .001). The real-world AEs resulting in discontinuation paralleled those in RCTs but were reported in greater proportions: diarrhea (P 1⁄4 .001), nausea (P 1⁄4 .004), and headache (P .001). These larger withdrawal proportions can be attributed to several factors. First, most patients in RWP had insurance coverage, allowing them to easily switch medications. Second, patients in RCTs generally had more frequent clinical visits, which encouraged tolerability. Third, proportionately more patients in RWP had failed a prior systemic/biologic therapy (P .001), implying they had more challenging psoriasis and the disadvantages associated with AEs may have outweighed the therapeutic benefits of apremilast. Overall, this study suggests that patients with psoriasis in RWP who were using apremilast expectedly reported less tolerability compared with patients in RCTs and may have experienced proportionately fewer mild-to-moderate AEs, bearing in mind that AEs were not actively elicited in RWP.

Efficacy and safety of secukinumab in treating moderate to severe plaque psoriasis in two real‐world Canadian dermatology clinics: a multicenter retrospective study

diomyopathy during therapy with dabrafenib and trametinib. When myocarditis was first reported during treatment with dabrafenib and trametinib, a warning was published by the European Medicine Agency and myocarditis added to the serious side-effects. Differential diagnoses of myocarditis include infectious, immune-mediated and toxic causes. Granulomatous infiltration in the heart may be associated with rheumatic fever, metabolic disorders, sarcoidosis, Wegener’s granulomatosis, giant cell myocarditis and infectious diseases such as tuberculosis. In our case, autopsy confirmed inconspicuous heart valves, and no infectious focus was found. Moreover, sarcoidosis or rheumatoid arthritis was judged less probable, as there was no evidence of these generally systemic diseases. To recognize significant cardiac impairment during targeted therapy, echocardiography is recommended at baseline, after 1 month, and every 2–3 months thereafter. Our patient did not reveal any cardiac complaints or impairment. Increased CK is a common, frequently asymptomatic side effect of MEK inhibitors. However, based on our report we suggest to further investigate persistent elevation of CK during targeted therapy to rule out myocarditis. Altogether, our report contributes to expand knowledge about rare side-effects associated with contemporary oncological treatment.

Drug survival of secukinumab in real-world plaque psoriasis patients: A 52-week, multicenter, retrospective study

REFERENCES 1. Sahni K, Parsad D. Stability in vitiligo: is there a perfect way to predict it? J Cutan Aesthet Surg. 2013; 6:75-82. 2. Parsad D, Gupta S. Standard guidelines of care for vitiligo surgery. Indian J Dermatol Venereol Leprol. 2008;74(Suppl S1): 37-45. 3. Li W, Wang S, Xu AE. Role of in vivo reflectance confocal microscopy indetermining stability in vitiligo: a preliminary study. Indian J Dermatol. 2013;58:429-432. 4. Chuh AA, Zawar V. Demonstration of residual perifollicular pigmentation in localized vitiligo-a reverse and novel application of digital epiluminescence dermoscopy. Comput Med Imaging Graph. 2004;28:213-217. 5. Meng R, Zhao G, Cai RK, Xiao M, Jiang Z. Application of polarized light dermoscopy in the early diagnosis of vitiligo and its differential diagnosis from other depigmented diseases. Chinese J Dermatol. 2009;42:810-813.

A comparison of apremilast monotherapy and combination therapy for plaque psoriasis in clinical practice: A Canadian multicenter retrospective study

REFERENCES 1. Kubica AW, Brewer JD. Melanoma in immunosuppressed patients. Mayo Clin Proc. 2012;87:991-1003. 2. Pratt G, Goodyear O, Moss P. Immunodeficiency and immunotherapy in multiple myeloma. Br J Haematol. 2007;138: 563-579. 3. Yang J, Terebelo HR, Zonder JA. Secondary primary malignancies in multiple myeloma: an old NEMESIS revisited. Adv Hematol. 2012;2012:801495. 4. Dong C, Hemminki K. Second primary neoplasms among 53 159 haematolymphoproliferative malignancy patients in Sweden, 1958-1996: a search for common mechanisms. Br J Cancer. 2001;85:997-1005. 5. Mailankody S, Pfeiffer RM, Kristinsson SY, et al. Risk of acute myeloid leukemia and myelodysplastic syndromes after multiple myeloma and its precursor disease (MGUS). Blood. 2011; 118:4086-4092.

Efficacy and safety of switching to ixekizumab in secukinumab non-responders with plaque psoriasis: a multicenter retrospective study of interleukin (IL)-17A antagonist therapies

REFERENCES 1. Olazagasti JM, Baez PJ, Wetter DA, Ernste FC. Cancer risk in dermatomyositis: a meta-analysis of cohort studies. Am J Clin Dermatol. 2015;16(2):89-98. 2. Yang Z, Lin F, Qin B, Liang Y, Zhong R. Polymyositis/ dermatomyositis and malignancy risk: a metaanalysis study. J Rheumatol. 2015;42(2):282-291. 3. Bohan A, Peter JB. Polymyositis and dermatomyositis ( first of two parts). N Engl J Med. 1975;292(7):344-347. 4. Euwer RL, Sontheimer RD. Amyopathic dermatomyositis: a review. J Invest Dermatol. 1993;100(1):124S-127S. 5. Lu X, Yang H, Shu X, et al. Factors predicting malignancy in patients with polymyositis and dermatomyostis: a systematic review and meta-analysis. PLoS One. 2014;9(4):e94128.

Medical, Surgical, and Wound Care Management of Ulcerated Infantile Hemangiomas: A Systematic Review:

Ulcerated infantile hemangiomas may present a therapeutic challenge, especially if there is concurrent hemorrhage or infection. The aim of this study was to systematically review the published evidence on the treatment of ulcerated hemangiomas, focusing on wound healing as the outcome of interest. We searched MEDLINE, Embase, SCOPUS, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Web of Science from inception to July 2016. Seventy-seven studies met our inclusion criteria. One study was a randomized controlled trial, 30 were observational studies, and 46 were case reports or case series. There is significant heterogeneity among the methods used. We reviewed 1239 patients in total. Of the 197 treated with oral propranolol, 191 (97.0%) achieved complete ulcer healing. Thirty-one patients failed corticosteroid therapy (oral, intralesional, or topical) and were subsequently successfully treated with other therapies. Surgical resections were typically performed for larger hemangiomas and those causing complications. None of the therapies discussed appear to offer significant advantages over others. Therefore, treatment decisions should be individualized based on location of disease, extent, symptoms, feasibility, cost, and parental preference.

Efficacy and Safety of Apremilast Monotherapy for Moderate to Severe Psoriasis: Retrospective Study :

Background: Apremilast is a new oral drug for the treatment of moderate to severe plaque psoriasis that reduces inflammation by inhibiting phosphodiesterase 4. Its efficacy and safety data are limited; hence, real-world outcomes are important for elucidating the full spectrum of its adverse events (AEs) and expanding generalizability of clinical trial findings. Objective: Assess the efficacy and safety of apremilast monotherapy in real-world practice. Methods: A retrospective chart review was conducted in 2 academic dermatology practices. Efficacy was measured as the proportion of patients achieving a ≥75% reduction from baseline Psoriasis Area and Severity Index score (PASI-75) or a Psoriasis Global Assessment (PGA) score of 0 (clear) or 1 (almost clear) at 16 weeks. Safety was measured as the proportion of patients reporting ≥1 AE at 16 weeks. Results: Thirty-four patients were included. Efficacy: 19 patients (55.9%) achieved PASI-75 or PGA 0/1. Safety: 23 patients (67.6%) experienced ≥1 AEs. Five patients (14.7%) withdrew treatment prior to week 16 due to AEs. One patient withdrew treatment due to mood lability and depression. Common AEs included headache (32.4%), nausea (20.6%), diarrhoea (14.7%), weight loss (8.8%), and loose stool (8.8%). Conclusion: Apremilast monotherapy had higher efficacy with similar safety outcomes in the real world compared to clinical trials. There were higher proportions of reported headaches compared to clinical trials. This study supports the apremilast monotherapy clinical trial findings, suggesting that it has an acceptable safety profile and significantly reduces the severity of moderate to severe plaque psoriasis. Limitations include the retrospective nature of the study.

Short- and Long-Term Management of an Acute Pustular Psoriasis Flare: A Case Report:

Background: Generalised pustular psoriasis (GPP) and acrodermatitis continua of Hallopeau (ACH) are chronic, relapsing variants of pustular psoriasis proven to be remarkably challenging to treat. Due to their uncommon presentation, there are few described cases in literature and scarce evidence for management. Further information is needed to help dermatologists formulate treatment plans for patients presenting with such diseases. Case Summary: We report the case of a 68-year-old man with a 3-year history of psoriasis presenting to our clinic with a severe breakout of GPP and associated ACH. The patient underwent treatment with cyclosporine A (200 mg PO twice daily) for a period of 2 weeks. This provided dramatic improvement in disease symptoms, with clearance of pustules, remarkable reduction of ACH lesions, and absence of pain. The patient was transitioned to infliximab (5 mg/kg intravenous) and apremilast (30 mg PO twice daily), displaying minimal GPP relapse and well-controlled onychodystrophy for several months. Conclusion: This case supports the use of cyclosporine as a first-line agent in providing immediate symptomatic relief for pustular psoriasis flares. Transitioning to infliximab and apremilast combination therapy offers a unique treatment regime for long-term GPP and ACH management.

Biologic switching between interleukin 17A antagonists secukinumab and ixekizumab: a 12‐week, multicenter, retrospective study

A recent review by Hu etxa0al. highlights the use of biologic switching in clinical practice to maximize skin clearance and improve clinical outcomes. However, efficacy and safety outcomes of ixekizumab therapy in patients who did not respond to, lost response, or were intolerant to secukinumab was not mentioned in their review and is lacking. As such, dermatologists may be hesitant to switch between interleukin (IL)-17A antagonists, electing to try an alternative biologic with a different mechanism of action. We recently published a series of 17 patients switching between IL-17A antagonists, suggesting ixekizumab is a promising treatment option with good clinical outcome and few adverse events (AE) for plaque psoriasis patients with prior exposure to secukinumab. This article is protected by copyright. All rights reserved.

Maintenance of therapeutic response over one year using apremilast combination therapy compared to monotherapy for the treatment of plaque psoriasis: a multicenter, retrospective study

The skin on the nondominant arm overlying the deltoid was cleaned and anesthetized in the usual fashion. In an effort to limit variables to the effect of the petrolatum, no incision was performed. Two 6-0 fast-absorbing gut sutures were placed, 1 coatedwith petrolatum and 1 not coated with petrolatum (control) in a randomized order blinded to the patient. The suture was tied with a secure knot but loosely tensioned to not contract the skin. The sites were kept protected using sterile film dressings with a nonstick gauze pad and could be evaluated by the participants by rolling cotton tipped applicators over the sutures. No further petrolatumwas applied to the wound. The study participants recorded the time when the suture knot spontaneously fell out of the surface of the skin. We found no statistically significant difference in absorption time between the petrolatum-coated and nonpetrolatumecoated sutures, with coated sutures lasting an average of 223 hours (9.3 days) and plain sutures lasting an average of 208 hours (8.7 days; P 1⁄4 .51). A wide variety of absorption times was observed across both groups (Table I), ranging 66-403 hours (2.8-16.8 days). There was no association between participant age with time to suture absorption. No study participants experienced any scarring or other complications. In conclusion, petrolatum coating did not significantly affect the absorption time. This study might be limited somewhat by sample size and participants self-reporting the data, but of clinical significance was the wide variability of absorption times from person to person, which was likely due to the organic nature of the suture itself. Major Jason R. Susong, MD, and Major James R. Neiner, MD