Sustained Efficacy and Safety of Adalimumab in Psoriasis Treatment

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of these 2 diseases. Based on our limited findings in this Adalimumab, the third TNF-␣ antagonist, is currently study, we do not recommend a screening eye examina- in phase III trials for psoriasis treatment. As a fully human tion for uveitis in patients with GA. IgG1 monoclonal antibody, it is expected to have less immunogenicity and secondary antibody-mediated loss of ef- Nicole V. Brey, MD ficacy.1,2 Despite clinical reports of antiadalimumab anti- Todd J. Purkiss, MD, PhD bodies, impact on long-term clinical response is unclear.4 Ashok Sehgal, MD One recent study demonstrated adalimumab to be ef- Henry J. Kaplan, MD ficacious for psoriasis treatment of patients with no pre- Jeffrey P. Callen, MD vious exposure to TNF antagonists.5 Since it is uncer- tain whether long-term response to adalimumab (Ն12 Correspondence: Dr Callen, 310 E Broadway, Ste 2A, months) can be sustained in patients for whom other anti- Louisville, KY 40202 ([email protected]). TNF therapy has failed to treat moderate to severe plaque Author Contributions: Drs Kaplan and Callen had full ac- psoriasis, we address this question retrospectively in 49 cess to all the data in the study and take responsibility for patients with and without prior use of TNF-␣ blockade. the integrity of the data and the accuracy of the data analysis. Study concept and design: Brey, Purkiss, and Callen. Methods. This retrospective medical chart review in- Acquisition of data: Brey, Purkiss, and Sehgal. Analysis and cludes 49 patients seen at the Baylor College of Medicine interpretation of data: Purkiss and Kaplan. Drafting of the dermatology clinic. All patients had moderate to severe pso- manuscript: Brey and Purkiss. Critical revision of the manu- riasis based on the physician’s global assessment (PGA) and scriptforimportantintellectualcontent:Purkiss,Sehgal,Kaplan, had started treatment with adalimumab injections at least and Callen. Statistical analysis: Purkiss. Obtained funding: 12 months previously. All were screened for tuberculosis. Kaplan.Administrative,technical,andmaterialsupport:Purkiss Patients who had undergone prior therapy with biological and Kaplan. Study supervision: Kaplan and Callen. agents were switched to adalimumab therapy only after they Financial Disclosure: None reported. had experienced lack or loss of efficacy with their prior treat- Funding/Support: This study was supported by fund- ment. Patients switched from infliximab therapy had a wash- ing from Research to Prevent Blindness, New York, New out period of at least 2 months, and those switched from York (Drs Purkiss, Sehgal, and Kaplan), and the Com- etanercept or efalizumab had a washout period of at least monwealth of Kentucky Research Challenge Trust Fund, 2 weeks. Frankfort (Dr Kaplan). Patientsstartedtreatmentwithadalimumab,40mgweekly, Disclaimer: Dr Callen is the associate editor of Archives for 12 weeks. All were reassessed at 3 months. Patients whose of Dermatology; he was not involved in the editorial evalu- disease was determined to be “clear” or “almost clear” by ation or editorial decision to accept this work for pub- PGA had their doses decreased to once every 2 weeks, while lication. theremaindercontinuedweeklydosingforanother3months. 1. Oz O, Tursen U, Yildirim O, Kaya TI, Ikizoglu G. Uveitis associated with granu- Patients were then reassessed at 3- to 6-month intervals, dur- loma annulare. Eur J Ophthalmol. 2003;13(1):93-95. ing which the dermatologist decreased the dosing frequency 2. Rahimi M, Moinfar N. Granuloma annulare and anterior uveitis. Iranian J Med Sci. 2005;30(3):144-146. to once every 2 weeks or continued the weekly schedule, 3. van Kooij B, van Dijk MC, de Boer J, Sigurdsson V, Rothova A. Is granuloma depending on individual response. annulare related to intermediate uveitis with retinal vasculitis? Br J Ophthalmol. 2003;87(6):763-766. The clinical end point was defined as worsening PGA 4. Jabs DA, Nussenblatt RB, Rosenbaum JT; The Standardization of Uveitis No- despite continuous adalimumab treatment or the occur- menclature (SUN) Working Group. Standardization of uveitis nomenclature rence of adverse events necessitating discontinuation of for reporting clinical data: results of the first international workshop. Am J Ophthalmol. 2005;140(3):509-516. adalimumab treatment. Treatment failure was differen- 5. Gritz DC, Wong IG. Incidence and prevalence of uveitis in Northern Cali- tiated into primary lack of efficacy (no clinical response fornia: the Northern California epidemiology of uveitis study. Ophthalmology. seen), secondary loss of efficacy (PGA degrades to lower 2004;111(3):491-500. 6. Durrani OM, Meads CA, Murray PI. Uveitis: a potentially blinding disease. than clear or almost clear after an initial response), and Ophthalmologica. 2004;218(4):223-236. limited efficacy (clinical response seen, but patient never achieves clear or almost clear status).

Results. Thirty-nine patients had prior exposure to bio- Sustained Efficacy and Safety logical agents (80%). Thirty-seven had prior anti– of Adalimumab in Psoriasis Treatment: TNF-␣ therapy (76%) (Figure 1). No complications were A Retrospective Study of 49 Patients observed during transitions from prior biological agents. With and Without a History of TNF-␣ Forty-three patients achieved clear to almost clear sta- Antagonist Treatment tus at 3 months (88%), 3 at 6 months, and 1 at 9 months, while 2 continued to received weekly dosing because they f the 3 available tumor necrosis factor ␣ (TNF-␣) did not achieve clear to almost clear status. Two pa- antagonists, infliximab and etanercept are ap- tients, whose dose had been decreased to 1 every 2 weeks proved for treatment of moderate to severe, at 3 months, resumed weekly dosing at 9 months. Sus- O 1,2 chronic, plaque-type psoriasis. Although no standard- tained efficacy at 12 months was observed in 38 patients ized comparison trial exists, infliximab appears to be the (78%). Of the 39 previously treated with biological agents, most rapidly effective, but this initial efficacy is often even- 31 experienced sustained efficacy with adalimumab (79%). tually lost with the development of human antichimeric Of the 37 who had been treated with TNF-␣ antago- antibodies in 15% to 69% of patients.1-3 nists, 29 had a sustained response (78%). Figure 2 sum-

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Patient Treatment Month Infliximab No. Type Event of Occurrence 1 Serious Unexplained fevers 14 20 2 Serious Cellulitis 15 3 Serious Cellulitis 4 4 Serious Back pain 2 2 6 5 Serious Pyelonephritis 6 6 Serious Squamous cell carcinoma 7, 9, and 10 1 7 Minor Influenza 8

2 1 7 a Malignant neoplasms and infections requiring treatment with antibiotics or hospitalization were considered serious adverse events. Patient 4 had back pain that was later found to be due to metastatic adenocarcinoma from an unknown primary tumor; patient 6 had multiple squamous cell carcinomas. Efalizumab Etanercept

proximately 78% of adalimumab patients treated with etanercept, infliximab, or both continued to have almost clear to clear PGA status at 12 months. Figure 1. Distribution of patients using biological agents prior to adalimumab therapy. Safety. In the multicenter trial conducted by Gordon et al,5 9% of patients discontinued therapy owing to an adverse event (AE). The numbers of patients in the placebo and treatment groups who experienced any AE dur-

49 Patients ing the first 12 weeks were comparable, but no serious AEs occurred in the placebo group. The investigators ques- tioned whether the reported AEs were directly attribut- able to treatment.5 40 Treated for ≥12 mo 9 Discontinued treatment The incidence of AEs in our study was 14%. Five pain <12 mo tients developed serious AEs (2 cellulitis and 1 each unexplained fevers, back pain, and pyelonephritis) that re- sulted in treatment termination (10%) (Table). One 38 Sustained 2 Limited 1 Pyelonephritis patient developed a serious AE (squamous cell carci- efficacy efficacy 1 Cellulitis 1 Back pain noma) but opted to continue treatment. 3 Primary lack of efficacy 1 Insurance difficulties Conclusion. Results from this study support the idea that 2 Secondary loss of efficacy ␣ at 9 mo patients with psoriasis who have received prior TNF- antagonists can expect sustained clinical response to adalimumab. Although our study is limited by retrospec- Figure 2. Results of adalimumab treatment for psoriasis in the 49 study tive design and small sample size, it adds to the collec- patients. tive understanding of the therapeutic role of adalimumab in the treatment of psoriasis. marizes reasons for discontinuation of adalimumab treatment in 9 patients prior to 12 months. Livia Van, MD Sapna V. Modi, MD Comment. Efficacy. In a multicenter study of adali- Deborah J. Yang, MD mumab in patients with psoriasis who had never been ex- Sylvia Hsu, MD posed to TNF-␣ antagonists, PGA measurements in the weekly treatment group showed a decline in the number Correspondence: Dr Hsu, Department of Dermatology- of patients with clear or almost clear status from 76% at Baylor College of Medicine, 6620 Main St, Ste 1425, Hous- week 12 to 52% at week 60.5 The PGA of clear or almost ton, TX 77030 ([email protected]). clear was comparable at 12 (49%) and 60 (44%) weeks in Author Contributions: Dr Hsu had full access to all the the group receiving 1 dose every 2 weeks. Fourteen pa- data in the study and takes responsibility for the integ- tients (11%) withdrew from the study between weeks 24 rity of the data and the accuracy of the data analysis. Study and 60 secondary to lack of efficacy.5 Our patients’ dosing concept and disign: Van and Hsu. Acquisition of data: Van regimen was based on this study’s dosage arms. and Modi. Analysis and interpretation of data: Ban, Modi, Our study contributes further evidence that most pa- Yang, and Hsu. Drafting of the manuscript: Van, Modi, and tients with moderate to severe psoriasis who initially re- Yang. Critical revision of the manuscript for important in- spond to adalimumab continue to experience efficacy at tellectual content: Van, Modi, Yang, and Hsu. Statistical 1 year (88%). In addition, our study demonstrates that analysis: Van. Study supervision: Yang and Hsu. psoriasis in most patients previously treated with other Financial Disclosure: Dr Hsu has served on advisory TNF-␣ antagonists will respond to adalimumab. Ap- boards for Abbott, Amgen, Biogen Idec, Centocor, Ge-

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 nentech, and Medicis. She has also been an investigator for Centocor and Genentech. Additional Information: This article was accepted for pub- lication prior to January 18, 2008, the date the US Food and Drug Administration approved the use of adalimumab for the treatment of moderate to severe chronic plague-type psoriasis in adults.

1. Graves JE, Nunley K, Heffernan MP. Off-label uses of biologics in dermatology: rituximab, omalizumab, infliximab, etanercept, adalimumab, efalizumab, and alefacept (part 2 of 2). J Am Acad Dermatol. 2007;56(1):e55-e79. 2. Boehncke WH, Prinz J, Gottlieb AB. Biologic therapies for psoriasis: a sys- tematic review. J Rheumatol. 2006;33(7):1447-1451. 3. Baert F, Noman M, Vermeire S, et al. Influence of immunogenicity on the long- term efficacy of infliximab in Crohn’s disease. NEnglJMed. 2003;348(7):601- 608. 4. HUMIRA (adalimumab) [package insert]. North Chicago, IL: Abbott Labo- ratories; 2004. 5. Gordon KB, Langley RG, Leonardi C, et al. Clinical response to adalimumab treatment in patients with moderate to severe psoriasis: double-blind, ran- domized controlled trial and open-label extension study. J Am Acad Dermatol. 2006;55(4):598-606.

Whole-Body Cryotherapy in Atopic Dermatitis

Figure 1. Sketch of the Univers Cryo-Combi whole-body cryotherapy device topic dermatitis (AD) is a chronic inflammatory (Oy MJG Univers Ab, Helsinki, Finland) showing the 3 chambers. skin disease with dry and itchy skin causing re- A markable adverse impact on quality of life. Some and Rehabilitation Center, Porvoo, Finland, followed by an patients do not tolerate treatments, or in some cases the treat- 8-week follow-up period. The whole-body cryotherapy de- ments are ineffective. Effective combination therapies for vice (Univers Cryo-Combi; Oy MJG Univers Ab, Helsinki, moderate or severe AD are lacking or scarce. Very cold air Finland) consists of 3 chambers set at different tempera- has been reported to increase the body’s antioxidative ca- tures (Figure 1). The first 2 chambers are meant for pre- pacity. The cold has also been shown to reduce the conduc- cooling (−30°C and −60°C), and the patient remains in these tion velocity of peripheral nerves1 and the nerve ganglia ca- for a very short time. The third chamber temperature reaches pacity to synthesize acetylcholine,2 which is considered a –110°C, and the patient remains inside for 1 to 3 minutes neurotransmitter in atopic pruritus.3 People who regularly wearing a bathing suit or trunks, acral parts covered. swiminice-coldwaterhaveincreasedconcentrationsofanti- The primary end point was the change in the Scoring inflammatory cytokines in their peripheral blood. Thus, cold of Atopic Dermatitis index (SCORAD) (scale, 0-103) dur- air or water is suggested to have local and systemic anti- ing the treatment period. Secondary end points in- inflammatory effect and also to relieve itch. cluded changes in transepidermal water loss (TEWL) mea- Locally applied cryotherapy has been used in experi- sured by Vapometer (Delfin Technologies Oy, Kuopio, mental treatments of inflammatory and substantially itch- Finland) and self-assessed visual analog scale (VAS) (0- ing skin diseases such as psoriasis and prurigo nodularis. 100) for pruritus and sleep disturbances. Changes in qual- Whole-body cryotherapy has been developed and used in ity of life were assessed with the Dermatology Life Qual- treating rheumatic inflammation and pain since the 1970s.4 ity Index (DLQI). The main outcome measures were based In a cryotherapy chamber, the whole body is exposed to on assessments made before and after the treatment pe- temperatures between –100°C and –180°C. The rationale riod. The SCORAD evaluations were performed weekly for this study was to assess the effect of whole-body cryo- during the treatment period and every 2 weeks thereafter. therapy on the signs and symptoms of AD. Statistical analysis was performed with SPSS 13.01 for Windows (SPSS Inc, Chicago, Illinois) using the Wil- Methods. Eighteen healthy adults (10 men and 8 wom- coxon signed rank nonparametric test. P values less than en) with mild to moderate AD were enrolled (the criteria .05 were regarded as significant. The patient data were of Rajka and Langeland5). Patients with cardiovascular dis- evaluated on intention-to-treat and last-observation- ease, uncontrolled asthma, other remarkable skin dis- carried-forward bases. eases, or cold urticaria were excluded. The participants gave written informed consent. The study was approved by the Results. Sixteen of 18 patients completed the treatment scientific ethics committee for Helsinki University Hospital. period. On average, 11 treatment sessions were com- Topical anti-inflammatory preparations (ie, corticoste- pleted (range, 9-12); omitted sessions could not be sub- roids or topical calcineurin inhibitors [TCIs]) or systemic stituted. Of the patients who left the study, 1 patient dis- antihistamines were not allowed for 1 week before or at continued owing to worsening dermatitis, the other owing any time during the study. The washout period for systemic to work schedule. The mean SCORAD index decreased therapy and phototherapy was 6 weeks. Whole-body cryo- from 38.7 to 31.1 (−19.6%) (P=.03).The mean TEWL im- therapy was given 3 times a week for 4 weeks in Haikko Spa proved from 58.8 g/m2/h to 47.4 g/m2/h (−19.4%) (P=.03).

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