Correspondence
Systematic review and meta-analysis of ustekinumab for moderate to severe psoriasis: comment doi: 10.1111/ced.12614 We read the article by Meng et al.1 in Clinical and Experimental Dermatology with interest. We agree that a system-
atic assessment of the evidence with respect to efficacy and safety of ustekinumab is valuable to guide physicians in the treatment of patients with psoriasis. However, we are concerned about one major error in the review by Meng et al.1 The authors reported that they included nine randomized controlled trials (RCTs) with a total of 11 381 patients, but the included patients were not derived from 9 independent RCT populations; these 9
Table 1 Publications and study populations included in the review Meng et al.1 Publication
Phase
Study population
Study conditions
Study population also reported in
Igarashi et al.2
2/3
Japanese patients
–
Krueger et al.3
2
Global study
Leonardi et al.6 (Phoenix 1, NCT00267969)
3
USA, Canada, Belgium
Ustekinumab 45 mg (n = 64); ustekinumab 90 mg (n = 62); placebo (n = 32) Ustekinumab 45 mg (n = 64); ustekinumab 90 mg (n = 64); placebo (n = 64). Study groups with a single dose of 45 or 90 mg were not considered Ustekinumab 45 mg (n = 255); ustekinumab 90 mg (n = 256); placebo (n = 255)
Papp et al.9 (Phoenix 2)
3
Tsai et al.10 (PEARL)
3
Europe and North America (Austria, Canada, France, Germany, Switzerland, UK, USA) Taiwanese/Chinese and Korean patients
Ustekinumab 45 mg (n = 409); ustekinumab 90 mg (n = 411); placebo (n = 410) Ustekinumab 45 mg (n = 61); placebo (n = 60)
Lebwohl et al.4 Papp et al.5
Guenther et al.7 Kimball et al.8 Lebwohl et al.4 Papp et al.5 Guenther et al.7 Lebwohl et al.4 Papp et al.5 –
Figure 1 Meta-analysis of serious adverse events at week 12: infections.
810
Clinical and Experimental Dermatology (2015) 40, pp807–815
ª 2015 British Association of Dermatologists
Correspondence
publications provided data from only 5 placebo-controlled RCT populations covering 2467 patients (see Table 1 of that paper1). Although multiple counting of study populations does not influence the conclusion of the review, the calculated confidence interval of the pooled effect estimates became smaller due to the (false) inclusion of a higher number of patients. Moreover, the review gives the impression that ustekinumab is supported by more evidence than it actually is (Table 1). The multiple counting affects the evaluation of the safety of ustekinumab. For example, the review1 reported the inclusion of six publications in the meta-analysis of ustekinumab with respect to the risk of infections at the end of 12 weeks of treatment. In these six publications, the study populations of Phoenix 1 and Phoenix 2 are included four and three times, respectively. Correctly, data from the publications of Igarashi et al.,2 Leonardi et al.6 and Papp et al.8 should be considered for this meta-analysis, as should two further references that were missing from the review (Table 2; Fig. 1). In 2011, Tsai et al. provided data from a study of ustekinumab 45 mg compared with placebo,1 while in 2013, Zhu et al. reported data from an RCT (the LOTUS study) investigating ustekinumab 45 mg compared with placebo, which provided efficacy and safety data for 321 Chinese patients. If we use these studies, the risk ratios for ustekinumab 45 and 90 mg are 1.17 (95% CI 1.00–1.38) and 1.06 (95% CI 0.88–1.29), respectively. Similarly, the effect estimates for serious infections and other adverse events are affected by multiple inclusion of the same study population. In conclusion, review authors should be aware of multiple reporting of RCT data in different contexts, and should carefully check the inclusion of study populations. A. Jacobs and S. Rosumeck Division of Evidence Based Medicine, Klinik f€ur Dermatologie, Venerologie und Allergologie, Charite–Universit€atsmedizin Berlin, Chariteplatz 1, 10117 Berlin, Germany E-mail: [email protected] Conflict of interest: the authors declare that they have no conflicts of interest. Accepted for publication 22 September 2014
References 1 Meng Y, Dongmei L, Yanbin P et al. Systematic review and meta-analysis of ustekinumab for moderate to severe psoriasis. Clin Exp Dermatol 2014; 39: 696–707. 2 Igarashi A, Kato T, Kato M et al. Efficacy and safety of ustekinumab in Japanese patients with moderate-tosevere plaque-type psoriasis: long-term results from a phase 2/3 clinical trial. J Dermatol 2012; 39: 242–52. 3 Krueger GG, Langley RG, Leonardi C et al. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl J Med 2007; 356: 580–92.
ª 2015 British Association of Dermatologists
4 Lebwohl M, Leonardi C, Griffiths CE et al. Long-term safety experience of ustekinumab in patients with moderate-tosevere psoriasis (Part I of II): results from analyses of general safety parameters from pooled Phase 2 and 3 clinical trials. J Am Acad Dermatol 2012; 66: 731–41. 5 Papp KA, Griffiths CE, Gordon K et al. Long-term safety of ustekinumab in patients with moderate-to-severe psoriasis: final results from 5 years of follow-up. Br J Dermatol 2013; 168: 844–54. 6 Leonardi CL, Kimball AB, Papp KA et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76week results from a randomised, double-blind, placebocontrolled trial (PHOENIX 1). Lancet 2008; 371: 1665– 74 (erratum appears in Lancet 2008; 371: 1838). 7 Guenther L, Han C, Szapary P et al. Impact of ustekinumab on health-related quality of life and sexual difficulties associated with psoriasis: results from two phase III clinical trials. J Eur Acad Dermatol 2011; 25: 851–7. 8 Kimball AB, Papp KA, Wasfi Y, et al. Long-term efficacy of ustekinumab in patients with moderate-to-severe psoriasis treated for up to 5 years in the PHOENIX 1 study. J Eur Acad Dermatol Venereol 2013; 27: 1535–45. 9 Papp KA, Langley RG, Lebwohl M et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet 2008; 371: 1675–84. 10 Tsai TF, Ho JC, Song M et al. Efficacy and safety of ustekinumab for the treatment of moderate-to-severe psoriasis: a phase III, randomized, placebo-controlled trial in Taiwanese and Korean patients (PEARL). J Dermatol Sci 2011; 63: 154–63. 11 Zhu X, Zheng M, Song M et al. Efficacy and safety of ustekinumab in Chinese patients with moderate to severe plaque-type psoriasis: results from a phase 3 clinical trial (LOTUS). J Drugs Dermatol 2013; 12: 166–74.
Necrobiotic xanthogranuloma with multiple myeloma doi: 10.1111/ced.12620 A 75-year-old man presented with a 2-year history of slowly progressive, well-defined, erythematous and indurated plaques involving the inguinal region, popliteal fossa, arms, forearms and trunk. The plaques showed central atrophy and yellowish discolouration, along with loose redundant skin in the centre of the plaques (Fig. 1a–d). The patient reported marked weight loss (11 kg) over a period of 6 months. He did not have any other systemic problems.
Clinical and Experimental Dermatology (2015) 40, pp807–815
811
Systematic review and meta-analysis of ustekinumab for moderate to severe psoriasis: comment doi: 10.1111/ced.12614 We read the article by Meng et al.1 in Clinical and Experimental Dermatology with interest. We agree that a system-
atic assessment of the evidence with respect to efficacy and safety of ustekinumab is valuable to guide physicians in the treatment of patients with psoriasis. However, we are concerned about one major error in the review by Meng et al.1 The authors reported that they included nine randomized controlled trials (RCTs) with a total of 11 381 patients, but the included patients were not derived from 9 independent RCT populations; these 9
Table 1 Publications and study populations included in the review Meng et al.1 Publication
Phase
Study population
Study conditions
Study population also reported in
Igarashi et al.2
2/3
Japanese patients
–
Krueger et al.3
2
Global study
Leonardi et al.6 (Phoenix 1, NCT00267969)
3
USA, Canada, Belgium
Ustekinumab 45 mg (n = 64); ustekinumab 90 mg (n = 62); placebo (n = 32) Ustekinumab 45 mg (n = 64); ustekinumab 90 mg (n = 64); placebo (n = 64). Study groups with a single dose of 45 or 90 mg were not considered Ustekinumab 45 mg (n = 255); ustekinumab 90 mg (n = 256); placebo (n = 255)
Papp et al.9 (Phoenix 2)
3
Tsai et al.10 (PEARL)
3
Europe and North America (Austria, Canada, France, Germany, Switzerland, UK, USA) Taiwanese/Chinese and Korean patients
Ustekinumab 45 mg (n = 409); ustekinumab 90 mg (n = 411); placebo (n = 410) Ustekinumab 45 mg (n = 61); placebo (n = 60)
Lebwohl et al.4 Papp et al.5
Guenther et al.7 Kimball et al.8 Lebwohl et al.4 Papp et al.5 Guenther et al.7 Lebwohl et al.4 Papp et al.5 –
Figure 1 Meta-analysis of serious adverse events at week 12: infections.
810
Clinical and Experimental Dermatology (2015) 40, pp807–815
ª 2015 British Association of Dermatologists
Correspondence
publications provided data from only 5 placebo-controlled RCT populations covering 2467 patients (see Table 1 of that paper1). Although multiple counting of study populations does not influence the conclusion of the review, the calculated confidence interval of the pooled effect estimates became smaller due to the (false) inclusion of a higher number of patients. Moreover, the review gives the impression that ustekinumab is supported by more evidence than it actually is (Table 1). The multiple counting affects the evaluation of the safety of ustekinumab. For example, the review1 reported the inclusion of six publications in the meta-analysis of ustekinumab with respect to the risk of infections at the end of 12 weeks of treatment. In these six publications, the study populations of Phoenix 1 and Phoenix 2 are included four and three times, respectively. Correctly, data from the publications of Igarashi et al.,2 Leonardi et al.6 and Papp et al.8 should be considered for this meta-analysis, as should two further references that were missing from the review (Table 2; Fig. 1). In 2011, Tsai et al. provided data from a study of ustekinumab 45 mg compared with placebo,1 while in 2013, Zhu et al. reported data from an RCT (the LOTUS study) investigating ustekinumab 45 mg compared with placebo, which provided efficacy and safety data for 321 Chinese patients. If we use these studies, the risk ratios for ustekinumab 45 and 90 mg are 1.17 (95% CI 1.00–1.38) and 1.06 (95% CI 0.88–1.29), respectively. Similarly, the effect estimates for serious infections and other adverse events are affected by multiple inclusion of the same study population. In conclusion, review authors should be aware of multiple reporting of RCT data in different contexts, and should carefully check the inclusion of study populations. A. Jacobs and S. Rosumeck Division of Evidence Based Medicine, Klinik f€ur Dermatologie, Venerologie und Allergologie, Charite–Universit€atsmedizin Berlin, Chariteplatz 1, 10117 Berlin, Germany E-mail: [email protected] Conflict of interest: the authors declare that they have no conflicts of interest. Accepted for publication 22 September 2014
References 1 Meng Y, Dongmei L, Yanbin P et al. Systematic review and meta-analysis of ustekinumab for moderate to severe psoriasis. Clin Exp Dermatol 2014; 39: 696–707. 2 Igarashi A, Kato T, Kato M et al. Efficacy and safety of ustekinumab in Japanese patients with moderate-tosevere plaque-type psoriasis: long-term results from a phase 2/3 clinical trial. J Dermatol 2012; 39: 242–52. 3 Krueger GG, Langley RG, Leonardi C et al. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl J Med 2007; 356: 580–92.
ª 2015 British Association of Dermatologists
4 Lebwohl M, Leonardi C, Griffiths CE et al. Long-term safety experience of ustekinumab in patients with moderate-tosevere psoriasis (Part I of II): results from analyses of general safety parameters from pooled Phase 2 and 3 clinical trials. J Am Acad Dermatol 2012; 66: 731–41. 5 Papp KA, Griffiths CE, Gordon K et al. Long-term safety of ustekinumab in patients with moderate-to-severe psoriasis: final results from 5 years of follow-up. Br J Dermatol 2013; 168: 844–54. 6 Leonardi CL, Kimball AB, Papp KA et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76week results from a randomised, double-blind, placebocontrolled trial (PHOENIX 1). Lancet 2008; 371: 1665– 74 (erratum appears in Lancet 2008; 371: 1838). 7 Guenther L, Han C, Szapary P et al. Impact of ustekinumab on health-related quality of life and sexual difficulties associated with psoriasis: results from two phase III clinical trials. J Eur Acad Dermatol 2011; 25: 851–7. 8 Kimball AB, Papp KA, Wasfi Y, et al. Long-term efficacy of ustekinumab in patients with moderate-to-severe psoriasis treated for up to 5 years in the PHOENIX 1 study. J Eur Acad Dermatol Venereol 2013; 27: 1535–45. 9 Papp KA, Langley RG, Lebwohl M et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet 2008; 371: 1675–84. 10 Tsai TF, Ho JC, Song M et al. Efficacy and safety of ustekinumab for the treatment of moderate-to-severe psoriasis: a phase III, randomized, placebo-controlled trial in Taiwanese and Korean patients (PEARL). J Dermatol Sci 2011; 63: 154–63. 11 Zhu X, Zheng M, Song M et al. Efficacy and safety of ustekinumab in Chinese patients with moderate to severe plaque-type psoriasis: results from a phase 3 clinical trial (LOTUS). J Drugs Dermatol 2013; 12: 166–74.
Necrobiotic xanthogranuloma with multiple myeloma doi: 10.1111/ced.12620 A 75-year-old man presented with a 2-year history of slowly progressive, well-defined, erythematous and indurated plaques involving the inguinal region, popliteal fossa, arms, forearms and trunk. The plaques showed central atrophy and yellowish discolouration, along with loose redundant skin in the centre of the plaques (Fig. 1a–d). The patient reported marked weight loss (11 kg) over a period of 6 months. He did not have any other systemic problems.
Clinical and Experimental Dermatology (2015) 40, pp807–815
811
