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Figure 1 Clinical aspect of severe LSR after IM application: clinical course over 29 days of follow-up. Digital photographs of the treated areas have been taken pretreatment (a), and 3 (b), 15 (c), 29 (d) days post-treatment.

Acknowledgement This study has been partially funded with an unrestricted grant to Dr Luca Neri by Leo Pharma Italia. C. Longo,1 L. Neri,2 G. Argenziano,1 S. Calvieri,3,4 ,6 P.G. Calzavara-Pinton,5 C. Cantisani,3 C. Catricala K. Peris,7 A. Peserico,8 N. Pimpinelli,9 G. Pellacani10,* 1

Dermatology and Skin Cancer Unit, Arcispedale S. Maria Nuova, IRCCS, , Reggio Emilia Italy, 2Dipartimento di Scienze Cliniche e di Comunita  di Milano, Milano, Italy 3Clinica Dermatologica, Policlinico Universita  di Roma, Rome, Italy 4EmatologiaUmberto I, “Sapienza” Universita oncologia Anatomia Patologica e Medicina Rigenerativa, Policlinico  di Roma, Rome, Italy 5Clinica Umberto I, “Sapienza” Universita  di Brescia, Brescia, Dermatologica, Spedali Civili di Brescia, Universita Italy 6IFO-Istituto Dermatologico, IRCCS Santa Maria e San Gallicano, Rome, Italy, 7Dermatology Institute, Policlinico Gemelli, Catholic University of Rome, Rome, Italy 8Clinica Dermatologica, Dipartimento di MedicinaDIMED, Universit a di Padova, Padova, Italy 9Department of Surgery and Translational Medicine - Division Dermatology, University of Florence Medical School, Florence, Italy 10Department of Dermatology, University of Modena and Reggio Emilia, Modena, Italy *Correspondence: G. Pellacani. E-mail: [email protected] Dr Longo and Dr Neri equally contributed to the production of this manuscript.

References 1 Schmitt AR, Bordeaux JS. Actinic neoplasia syndrome and an update on the epidemiology of basal cell carcinoma, squamous cell carcinoma, and actinic keratosis. Curr Dermatol Rep 2013; 2: 42–47. 2 Stockfleth E, Kerl H, Guideline Subcommittee of the European Dermatology Forum. Guidelines for the management of actinic keratosis. Eur J Dermatol 2006; 16: 599–606.

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3 Werner RN, Sammain A, Erdmann R, Hartmann V, Stockfleth E, Nast A. The natural history of actinic keratosis: a systematic review. Br J Dermatol 2013; 169: 502–518. doi: 10.1111/bjd.12420. 4 Peserico A, Neri L, Calzavara Pinton P et al. Key opinion leader (KOL) consensus for actinic keratosis management in Italy: the AKTUAL Workshop. G Ital Dermatol Venereol 2013; 148: 515–524. 5 Cantisani C, De Gado F, Ulrich M et al. Actinic keratosis: review of the literature and new patents. Recent Pat Inflamm Allergy Drug Discov 2013; 7: 168–175. 6 Lebwohl M, Swanson N, Anderson LL, Melgaard A, Xu Z, Berman B. Ingenol mebutate gel for actinic keratosis. N Engl J Med 2012; 366: 1010–1019. 7 Horne R, Chapman SC, Parham R et al. Understanding patients’ adherence-related beliefs about medicines prescribed for long-term conditions: a meta-analytic review of the necessity-concerns framework. PLoS ONE 2013; 8: e80633. DOI: 10.1111/jdv.12714

Defining effective approaches to the reduction or elimination of biologic therapy immunogenicity and loss of response Editor I have read with great interest the excellent and timely review by Carrascosa et al.1 on the topic of drug immunogenicity in psoriasis. It adds to a recently published systematic review with a similar scope2 and a systematic review and meta-analysis on the

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immunogenicity of anti-TNF therapy in immune-mediated inflammatory diseases3 highlighting the clinical relevance and implications of the development of anti-drug antibodies (ADAs), especially as regards their role behind treatment failure.4 The European Medicines Agency and Food & Drug Administration define the assessment of immunogenicity as mandatory for the approval of biopharmaceuticals; however, clinical trials may not reflect true immunogenicity induced by long-term treatment and in real-life circumstances. ADAs against adalimumab have been detected in up to 45% of patients with psoriasis treated according to the label during 24 weeks, and their presence has been associated with lower serum trough concentrations and with non-response or loss of response.5 A follow-up study of this cohort6 has shown that patients with no ADA formation in the first 24 weeks of treatment have little chance of it in the following 24 weeks. In the presence of ADAs and loss of effectiveness, dose intensification carries a significant increase in cost with limited probability of success.5 Another study7 has provided independent confirmation that formation of ADAs usually occurs early in patients with psoriasis treated according to the label, and the presence of ADAs and low drug levels after 4 weeks of treatment predicts response at 6 months. In a systematic review including 25 studies involving 7969 patients with psoriasis who had laboratory tests to determine the presence of ADAs, 950 patients tested positive.2 ADAs against infliximab, etanercept, adalimumab and ustekinumab were detected in 5.4–43.6%, 0–18.3%, 6–45% and 3.8–6% of patients, respectively. The variability in the rate of detection of ADAs in psoriasis has also been observed in other systemic inflammatory diseases such as rheumatoid arthritis (RA), Crohn’s disease and ankylosing spondylitis, but in many post-marketing studies the rates have been higher than those published in the data sheets.3 Furthermore, the methodology used to detect drug and ADA levels is not unified, even though there have been important advances with the addition of commercial kits, usually based on ELISA techniques. The time point of ADA assessment is also important. The majority of studies included in a recent metaanalysis assessed ADA at 12 months, showing a lower ADA frequency in patients receiving concomitant immunosuppression.1 This reduction was more apparent when RIA was used compared with ELISA methods (64% reduction vs. 34%), which may be explained by the increased specificity and lesser drug interference of RIA over ELISA. Factors believed to contribute to the formation of ADAs include the type of treatment (i.e. etanercept, adalimumab, infliximab or ustekinumab), the intrinsic immunogenicity of each drug (generally chimeric > humanized > fully human, but there are significant variations within each category), patient-related factors, including genetic background, the overall individual’s ability to produce antibodies and immune responses and drug pharmacokinetics, dosing intervals and

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patterns of induction, the route of administration, the association or not with immunosuppressive medication and methotrexate in particular, as well as the type, severity, activity and duration of the disease.1,3 In addition to their neutralizing capacity, ADAs lead to increased clearance of the drug (even in the case of non-neutralizing ADAs) through formation and eventual clearance of immunocomplexes.The trough levels of adalimumab and infliximab in psoriasis patients are positively associated with clinical response and significantly lower in cases having anti-adalimumab or anti-infliximab antibodies.8 The consequences are loss of effectiveness (for which dose intensification carries a significant increase in cost with limited probability of success5), and increased risk of infusion reactions in the case of infliximab and intravenously administered drugs in general. Moreover, when ADA levels are high (serum levels of the drug are usually undetectable in these cases) dose increase is generally ineffective and switching should be considered.4,5 When loss of response is due to the formation of ADAs, intraclass drug switching can be considered, because immunogenicity is drug specific,9 even though those patients often develop ADAs against new drugs as they are introduced.10 On the other hand, when loss of response (or lack of primary response) is not due to neutralization or increased clearance by ADAs, switching to another therapeutic class may be the best option.9 Factors able to modulate the clinical impact of immunogenicity need to be identified. In some trials, initial higher doses of infliximab or adalimumab appear to be less immunogenic.11 Some reports show that dose escalation decreases ADA detection, improving drug response, but others show that the procedure can indeed boost the immune response with serious consequences, such as infusion-related adverse events.1 Concomitant immunosuppression (particularly with methotrexate) seems to attenuate the impact of ADAs on drug response, but the exact mechanism remains unknown. Concomitant methotrexate has been shown to be efficient in reducing immunogenicity in a dose-dependent manner,12 either by reducing the frequency of detectable ADAs or by delaying their detection. Combination treatment with methotrexate has been reported to affect infliximab pharmacokinetics in patients with RA.13 Nevertheless, a recent study failed to demonstrate the patients with influence of methotrexate on infliximab pharmacokinetics in ankylosing spondylitis.14,15 The pharmacokinetics of antibodies is complex. Antibody clearance is increased when antigen burden (i.e. the amount of target to be neutralized) is high.15 Interestingly, for infliximab, the antigen burden (i.e. the concentration of circulating TNF-a) is lower in ankylosing spondylitis than in RA, and this is consistent with the reported differences in elimination half-life in both diseases (16 vs. 10 days, respectively).15 Methotrexate might decrease TNF-a levels, leading to a decrease in target-related clearance of inflix-

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imab, which could be less significant in diseases with lower antigen burden. Further research is required to establish the potential advantages of patient stratification based on genetic or serum biomarkers,16 and the best strategies for prevention and reversion of immunogenicity. These might include combination treatment with methotrexate (dose, time to be started and duration of treatment), the effect of dosage individualization and changes in the frequency of administration of the biological drugs. In addition, longitudinal studies are required to provide more information regarding the clinical relevance for therapeutic decisions of trough serum drug and ADA level determinations, as well as the duration and potential reversibility of ADAs once they have appeared. L. Puig*

12 Krieckaert CL, Nurmohamed MT, Wolbink GJ. Methotrexate reduces immunogenicity in adalimumab treated rheumatoid arthritis patients in a dose dependent manner. Ann Rheum Dis 2012; 71: 1914–1915. 13 Maini RN, Breedveld FC, Kalden JR et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 1998; 41: 1552–1563. 14 Mulleman D, Lauferon F, Wendling D et al. Infliximab in ankylosing spondylitis: alone or in combination with methotrexate? A pharmacokinetic comparative study. Arthritis Res Ther 2011; 13: R82. 15 Ternant D, Mulleman D, Lauferon F et al. Influence of methotrexate on infliximab pharmacokinetics and pharmacodynamics in ankylosing spondylitis. Br J Clin Pharmacol 2012; 73: 55–65. 16 Hoffmann JH, Hartmann M, Enk AH, Hadaschik EN. Autoantibodies in psoriasis as predictors for loss of response and anti-infliximab antibody induction. Br J Dermatol 2011; 165: 1355–1358. DOI: 10.1111/jdv.12716

Department of Dermatology, Hospital de la Santa Creu i Sant Pau, noma de Barcelona, Barcelona, Catalonia, Spain Universiat Auto *Correspondence: L. Puig. E-mail: [email protected]

References 1 Carrascosa JM, van Doorn MB, Lahfa M, Nestle FO, Jullien D, Prinz JC. Clinical relevance of immunogenicity of biologics in psoriasis: implications for treatment strategies. J Eur Acad Dermatol Venereol 2014. doi:10. 1111/jdv.12549 [Epub ahead of print]. 2 Hsu L, Snodgrass BT, Armstrong AW. Antidrug antibodies in psoriasis: a systematic review. Br J Dermatol 2014; 170: 261–273. 3 Garc^es S, Demengeot J, Benito-Garcia E. The immunogenicity of antiTNF therapy in immune-mediated inflammatory diseases: a systematic review of the literature with a meta-analysis. Ann Rheum Dis 2013; 72: 1947–1955. 4 Bartelds GM, Krieckaert CL, Nurmohamed MT et al. Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up. JAMA 2011; 305: 1460–1468. 5 Lecluse LL, Driessen RJ, Spuls PI et al. Extent and clinical consequences of antibody formation against adalimumab in patients with plaque psoriasis. Arch Dermatol 2010; 146: 127–132. 6 Menting SP, van L€ umig PP, de Vries AC et al. Extent and consequences of antibody formation against adalimumab in patients with psoriasis: one-year follow-up. JAMA Dermatol 2014; 150: 130–136. 7 Mahil SK, Arkir Z, Richards G, Lewis CM, Barker JN, Smith CH. Predicting treatment response in psoriasis using serum levels of adalimumab and etanercept: a single-centre, cohort study. Br J Dermatol 2013; 169: 306–313. 8 Takahashi H, Tsuji H, Ishida-Yamamoto A, Iizuka H. Plasma trough levels of adalimumab and infliximab in terms of clinical efficacy during the treatment of psoriasis. J Dermatol 2013; 40: 39–42. 9 Jamnitski A, Bartelds GM, Nurmohamed MT et al. The presence or absence of antibodies to infliximab or adalimumab determines the outcome of switching to etanercept. Ann Rheum Dis 2011; 70: 284– 288. 10 Bartelds GM, Wijbrandts CA, Nurmohamed MT et al. Anti-infliximab and anti-adalimumab antibodies in relation to response to adalimumab in infliximab switchers and anti-tumour necrosis factor naive patients: a cohort study. Ann Rheum Dis 2010; 69: 817–821. 11 Karmiris K, Paintaud G, Noman M et al. Influence of trough serum levels and immunogenicity on long-term outcome of adalimumab therapy in Crohn’s disease. Gastroenterology 2009; 137: 1628–1640.

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An unusual linear hypermelanosis reflecting lyonization in women with € rjeson–Forssman–Lehmann Bo syndrome Editor B€ orjeson–Forssman–Lehmann syndrome (BFLS) is an X-linked multisystem birth defect characterized by intellectual deficiency, epilepsy, hypogonadism, obesity, narrow palpebral fissures and large ears.1,2 The syndrome is caused by mutations in the PHF6 gene being localized on Xq26.2.3 The complete disorder is observed in males, whereas female carriers tend to be rather mildly affected or, by way of exception, clinically healthy. During recent years, a more thorough examination of female carriers provided evidence that they display a distinct phenotype including mild intellectual deficiency, frontotemporal hypotrichosis, prominent supraorbital ridges, broad and highly arched eyebrows, a broad nasal tip, dental anomalies, tapering fingers and clinodactyly or brachydactyly.4 Moreover, affected females often show hyperpigmented macules arranged along Blaschko’s lines (Fig. 1).4–6 Remarkably, male BFLS patients do not show any pigmentary disturbance, which renders the Blaschko-linear hypermelanosis of affected women even more interesting. This uncommon pigmentary disorder has so far not been mentioned in dermatological journals or textbooks. It can now be added to the list of nevoid hypermelanotic lesions reflecting functional X-chromosome mosaicism.7 BFLS should be borne in mind when dermatologists see Blaschko-linear melanotic macules in a female patient.

© 2014 European Academy of Dermatology and Venereology

Defining effective approaches to the reduction or elimination of biologic therapy immunogenicity and loss of response.

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