an observation period of approximately four years, the discontinuation rate of anti-TNF treatment ranges between 30-60%14
and 19–41%.15 The rates of
discontinuation for the individual anti-TNF treatments differ between studies, however, both studies indicate a reduction in drug survival over time.
Ustekinumab seems to have a higher drug survival rate,16
but the size of the
dataset and the observation period are limited. Interestingly, the OLE ustekinumab study documented a very low dropout rate (6% per year) and a 75% retention through year 4,12
the study of Clemmensen et al.16 Taken together, the available data suggest a significant long-term loss of efficacy ranging from just below 10% per year for ustekinumab to 20% for the anti-TNFa agents.
Predictors of the long-term efficacy Taking into account the gradual loss of the clinical response in patients, it would be helpful to be able to identify those factors that determine the long-term success. This is unfortunately not the case. The production of anti-drug autoantibodies is often blamed,17
supporting evidence is lacking in psoriasis. The best predictor of treatment response is the drug serum level,9
these assays are not routinely available. Male patients seem to have a significantly better drug survival rate than do women, irrespective of either the biologic used or the indication (psoriasis, PsA, rheumatoid arthritis)14,15,18
The reason for this very
puzzling but reproducible finding has not been elucidated. As could be expected, obesity (weight >100kg) is a negative predictor of the response.19
failure of the anti-TNFa agent predicts a very poor clinical outcome,14
been used as an argument to switch the mechanism of action of the biologic in patients who lose the efficacy. It is controversial whether concomitant methotrexate treatment prevents the loss of efficacy.14,15
affect the long-term efficacy of biologics are given in Table 1.
How to optimise the efficacy of biologics?
Biologics are usually used in
monotherapy and in fixed doses; possible optimisation schemes have not been thoroughly tested. As discussed above, obesity negatively affects treatment outcome and dose increase should be
contemplated in heavy patients.17
from clinical studies document the benefit of dose increase in case of etanercept (from 25mg to 50mg weekly) and ustekinumab (from 45mg for patients with a body weight ≤100kg to 90mg for patients with a body weight >100kg). Our own retrospective analysis shows that dose adjustment (decreased interval or increased dose) is necessary to maintain efficacy in approximately 25% of patients treated with infliximab.20 would also be beneficial.21
Weight loss Efficacy may
also be improved by adding conventional therapy. In particular, the narrow-band UVB is an especially useful modality,22 whereas the long-term benefit of acitretin or topical therapy is more dubious.
The efficacy of biologic agents surpasses most of the conventional treatments and offers an excellent benefit–risk ratio. The major drawback is a gradual loss of efficacy during the long-term treatment (reaching 10–20% annually). The causes of this phenomenon are not known, but in a large proportion of patients the treatment effect can be rescued by dose optimisation and combination with conventional modalities. l
References 1. Reich K et al. Comparative effects of biological therapies on the severity of skin symptoms and health-related quality of life in patients with plaque-type psoriasis: a meta-analysis. Curr Med Res Opin 2008;24:1237–54.
2. Reich K et al. Efficacy of biologics in the treatment of moderate to severe psoriasis: a network meta-analysis of randomized controlled trials. Br J Dermatol 2012;166:179–88.
3. Ash Z et al. A systematic literature review of drug therapies for the treatment of psoriatic arthritis: current evidence and meta-analysis informing the EULAR recommendations for the management of psoriatic arthritis. Ann Rheum Dis 2012;71:319–26.
4. Griffiths CEM et al. Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis. N Engl J Med 2010;362:118–28.
Factors known to negatively
5. De Vries ACQ et al. Interventions for nail psoriasis. The Cochrane database of systematic reviews 2013;1:CD007633.
6. Hongbo Y et al. Translating the science of quality of life into practice: What do dermatology life quality index scores mean? J Invest Dermatol 2005;125(4):659–64.
7. Baker EL et al. Effect of Biologic Agents on Non-PASI Outcomes in Moderate-to-Severe Plaque Psoriasis: Systematic Review and Meta-Analyses. Dermatol Ther 2012;2(1):9.
8. Papp K et al. Assessment of the long-term safety and effectiveness of etanercept for the treatment of
psoriasis in an adult population. J Am Acad Dermatol 2012;66(2):e33–45.
9. Reich K et al. Infliximab induction and maintenance therapy for moderate-to-severe psoriasis: a phase III, multicentre, double-blind trial. Lancet 2005;366:1367–74.
10. Gordon K et al. Long-term efficacy and safety of adalimumab in patients with moderate to severe psoriasis treated continuously over 3 years: Results from an open-label extension study for patients from REVEAL. J Am Acad Dermatol 2012;66:241–51.
11. Papp K A 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.
12. Kimball AB 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(12):1535–45.
13. Boehncke WH Clinical long-term studies: data collection and assessment. J Ger Soc Dermatol 2011:9:479–84.
14. Gniadecki R et al. Comparison of drug survival rates for adalimumab, etanercept and infliximab in patients with psoriasis vulgaris. Br J Dermatol 2011;164:1091–6.
15. Esposito M et al. Survival rate of anti-TNF alpha treatments for psoriasis in routine dermatological practice: a multicenter observational study. Br J Dermatol 2013;169(3):666–72.
16. Clemmensen A et al. Responses to ustekinumab in the anti-TNF agent-naïve vs. anti-TNF agent- exposed patients with psoriasis vulgaris. J Eur Acad Dermatol Venereol 2011;25:1037–40.
17. Krintel SB et al. The frequency of anti-infliximab antibodies in patients with rheumatoid arthritis treated in routine care and the associations with adverse drug reactions and treatment failure. Rheumatology 2013; 52:1245–53.
18. Hetland ML et al. Direct comparison of treatment responses, remission rates, and drug adherence in patients with rheumatoid arthritis treated with adalimumab, etanercept, or infliximab: results from eight years of surveillance of clinical practice in the nationwide Danish DANBIO registry. Arthritis Rheum 2010;62:22–32.
19. Puig L. Obesity and psoriasis: body weight and body mass index influence the response to biological treatment. J Eur Acad Dermatol Venereol 2011;25:1007–11.
20. Mehren CR, Gniadecki R. Dose-creep of Infliximab During Psoriasis Treatment: An Observational Study. Acta Derm Venereol 2012;92(4):355–7.
21. Jensen P et al. Effect of weight loss on the severity of psoriasis: a randomized clinical study. J Amer Med Assoc Dermatol 2013;149:795–801.
22. Mrowietz U et al. A consensus report on appropriate treatment optimization and transitioning in the management of moderate-to- severe plaque psoriasis. J Eur Acad Dermatol Venereol 2013;doi:10.1111/jdv.12118. [Epub ahead of print].
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