Optimising adalimumab treatment in psoriasis with concomitant methotrexate.

Psoriasis is a chronic, inflammatory skin disease affecting 2*3% of the
Caucasian population in Western countries. It is associated with several
comorbidities, psychosocial impairment and markedly reduced quality of life1.
Psoriasis is an immune-mediated inflammatory disorder involving Tcell
activation, epidermal hyperplasia and cytokine production. Biologics, like
adalimumab, are used for the treatment of psoriasis when traditional treatments
such as topical agents, phototherapy and systemic agents (methotrexate,
cyclosporine e.g.) have failed or are contra-indicated.

Adalimumab is a fully human monoclonal antibody, which binds to free
circulating TNF*, preventing it from activating TNF receptors. It has been
proven effective for the treatment of psoriasis 2;3. However in some patients
with moderate to severe plaque psoriasis, the efficacy of adalimumab
monotherapy is insufficient or declines over time and median drug survival is
about 2-2.5 years4;5.
In rheumatoid arthritis (RA) and inflammatory bowel disease a clear
relationship has been established between biologic drug serum trough
concentrations, the presence of antidrug antibodies (ADA), and efficacy. In
psoriasis, one relatively small study has investigated and confirmed the
relationship between serum trough concentrations of adalimumab, neutralizing
antibodies and effectiveness6. In this study, 45% of patients developed ADA
within 12 weeks of starting treatment, and many of these patients had no or an
insufficient improvement of psoriasis disease activity. This percentage appears
to be higher than in other immune mediated inflammatory disorders, possibly due
to the use of a biologic without concomitant methotrexate. In contrast,
additional immunosuppressive agents such as methothrexate (MTX) are commonly
used in rheumatoid arthritis on biologic therapy. MTX is a systemic therapy
that has demonstrated clinical efficacy as monotherapy in patients with
psoriasis 3 7;8.

Adding MTX to treatment adalimumab treatment in patients with RA has shown to
have a synergistic effect. Efficacy increased and immunogenicity decreased
without loss of tolerability in several studies in patients with RA 9-16. At
this moment, addition of MTX to adalimumab treatment is standard of care in
patients with RA according to the European guidelines. 17
In psoriasis, only two clinical trials investigating a biologic (etanercept) in
combination with MTX have been conducted on short term (12 to 24 weeks). For
adalimumab in combination with MTX several clinical trials no RCT evidence is
available, evidence is based on small observational cohort studies and case
reports. The clinical trials, observational studies and case series reports
that have been conducted demonstrated an increased clinical efficacy for the
combination therapy of TNF* inhibitors plus MTX. Short term adverse events were
not different from what would have been expected when using monotherapy. Long
term efficacy and safety data are not available although the majority of
patients that start on TNF* inhibitors continue treatment for several years.4
Therefore, in order to guide usage of biologic combination treatment in
clinical practice it is important to gain long-term efficacy and safety data
for TNF* inhibitors plus MTX versus TNF* inhibitor monotherapy. 18-22 With
these data guidance and recommendations for treatment with a combination of
adalimumab and MTX could be initiated in future clinical guidelines. 23

Adalimumab has a large inter-individual variability in plasma concentrations
(trough concentration range 0-150 mg/l), particularly due to the development of
ADA6;20;21;24;25. Some patients initially do not respond well to a specific
biologic drug (primary non-responders), or lose response during maintenance
treatment (secondary non-responders)6;25-30. Both primary and secondary
non-response may be due to pathophysiological, pharmacokinetic (PK) and
pharmacodynamic (PD) variability between patients.6;25-30. The most important
factor causing inter-individual variability in response to adalimumab appears
to be immunogenicity, resulting in ADA, which bind to adalimumab forming small
immune complexes, in this way neutralizing the drug. These immune complexes are
thought to clear slowly. 31
According to rheumatology data, the early combination of adalimumab and MTX
could prevent the decline in efficacy by reducing ADA formation. Therefore,
combination therapy could be a valuable strategy to optimize adalimumab
treatment of severe or recalcitrant psoriasis. Randomised studies on the use of
combination therapies in moderate to severe chronic plaque psoriasis with
longer follow-up and larger patient populations are needed24;26;27.


1. Rapp SR, Feldman SR, Exum ML et al. Psoriasis causes as much disability as
other major medical diseases. J Am Acad Dermatol 1999; 41: 401-7.
2. Croom KF, McCormack PL. Adalimumab: in plaque psoriasis. Am J Clin Dermatol
2009; 10: 43-50.
3. Saurat JH, Stingl G, Dubertret L et al. Efficacy and safety results from the
randomized controlled comparative study of adalimumab vs. methotrexate vs.
placebo in patients with psoriasis (CHAMPION). Br J Dermatol 2008; 158: 558-66.
4. Gniadecki R, Kragballe K, Dam TN et al. Comparison of drug survival rates
for adalimumab, etanercept and infliximab in patients with psoriasis vulgaris.
Br J Dermatol 2011; 164: 1091-6.
5. Esposito M, Gisondi P, Cassano N et al. Survival rate of anti-TNF alpha
treatments for psoriasis in routine dermatological practice: a multicenter
observational study. Br J Dermatol 2013.
6. 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: 127-32.
7. Griffiths CE, Clark CM, Chalmers RJ et al. A systematic review of treatments
for severe psoriasis. Health Technol Assess 2000; 4: 1-125.
8. Heydendael VM, Spuls PI, Opmeer BC et al. Methotrexate versus cyclosporine
in moderate-to-severe chronic plaque psoriasis. N Engl J Med 2003; 349: 658-65.
9. Emery P, Breedveld FC, Hall S et al. Comparison of methotrexate monotherapy
with a combination of methotrexate and etanercept in active, early, moderate to
severe rheumatoid arthritis (COMET): a randomised, double-blind, parallel
treatment trial. Lancet 2008; 372: 375-82.
10. Klareskog L, van der Heijde D, de Jager JP et al. Therapeutic effect of the
combination of etanercept and methotrexate compared with each treatment alone
in patients with rheumatoid arthritis: double-blind randomised controlled
trial. Lancet 2004; 363: 675-81.
11. van der Heijde D, Klareskog L, Rodriguez-Valverde V et al. Comparison of
etanercept and methotrexate, alone and combined, in the treatment of rheumatoid
arthritis: two-year clinical and radiographic results from the TEMPO study, a
double-blind, randomized trial. Arthritis Rheum 2006; 54: 1063-74.
12. van Riel PL, Taggart AJ, Sany J et al. Efficacy and safety of combination
etanercept and methotrexate versus etanercept alone in patients with rheumatoid
arthritis with an inadequate response to methotrexate: the ADORE study. Ann
Rheum Dis 2006; 65: 1478-83.
13. Weinblatt ME, Kremer JM, Bankhurst AD et al. A trial of etanercept, a
recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with
rheumatoid arthritis receiving methotrexate. N Engl J Med 1999; 340: 253-9.
14. Weisman MH, Moreland LW, Furst DE et al. Efficacy, pharmacokinetic, and
safety assessment of adalimumab, a fully human anti-tumor necrosis factor-alpha
monoclonal antibody, in adults with rheumatoid arthritis receiving concomitant
methotrexate: a pilot study. Clin Ther 2003; 25: 1700-21.
15. Weinblatt ME, Keystone EC, Furst DE et al. Adalimumab, a fully human
anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of
rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA
trial. Arthritis Rheum 2003; 48: 35-45.
16. Bang LM, Keating GM. Adalimumab: a review of its use in rheumatoid
arthritis. BioDrugs 2004; 18: 121-39.
17. Smolen JS, Landewe R, Breedveld FC et al. EULAR recommendations for the
management of rheumatoid arthritis with synthetic and biological
disease-modifying antirheumatic drugs. Ann Rheum Dis 2010; 69: 964-75.
18. Gottlieb AB, Langley RG, Strober BE et al. A randomized, double-blind,
placebo-controlled study to evaluate the addition of methotrexate to etanercept
in patients with moderate to severe plaque psoriasis. Br J Dermatol 2012; 167:
649-57.
19. Philipp S, Wilsmann-Theis D, Weyergraf A et al. Combination of adalimumab
with traditional systemic antipsoriatic drugs - a report of 39 cases. J Dtsch
Dermatol Ges 2012; 10: 821-37.
20. Zachariae C, Mork NJ, Reunala T et al. The combination of etanercept and
methotrexate increases the effectiveness of treatment in active psoriasis
despite inadequate effect of methotrexate therapy. Acta Derm Venereol 2008; 88:
495-501.
21. Driessen RJ, van de Kerkhof PC, de Jong EM. Etanercept combined with
methotrexate for high-need psoriasis. Br J Dermatol 2008; 159: 460-3.
22. van den Reek JM, van Lumig PP, Kievit W et al. Effectiveness of adalimumab
dose escalation, combination therapy of adalimumab with methotrexate, or both
in patients with psoriasis in daily practice. J Dermatolog Treat 2013.
23. Nast A, Boehncke WH, Mrowietz U et al. S3 - Guidelines on the treatment of
psoriasis vulgaris (English version). Update. J Dtsch Dermatol Ges 2012; 10
Suppl 2: S1-95.
24. 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: 1914-5.
25. West RL, Zelinkova Z, Wolbink GJ et al. Immunogenicity negatively
influences the outcome of adalimumab treatment in Crohn's disease. Aliment
Pharmacol Ther 2008; 28: 1122-6.
26. Bartelds GM, Wijbrandts CA, Nurmohamed MT et al. Clinical response to
adalimumab: relationship to anti-adalimumab antibodies and serum adalimumab
concentrations in rheumatoid arthritis. Ann Rheum Dis 2007; 66: 921-6.
27. 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: 1460-8.

Primary:
*To assess if combination therapy of adalimumab and MTX significantly improves
the drug survival at one year compared to adalimumab monotherapy in patients
with moderate-to-severe psoriasis.

Secondary:
*To assess if combination therapy of adalimumab and MTX improves the efficacy
at 13, 25, 37, 49, 61, 73, 85, 97, 109, 121, 133 en 145 weeks compared to
adalimumab monotherapy;
*To assess if combination therapy of adalimumab and MTX leads to a higher
average adalimumab trough concentration and lower ADA titers compared with
adalimumab monotherapy at 13, 25, 37, 49, 61, 73, 85, 97, 109, 121, 133 en 145
weeks;
*To compare Quality of Life between the combination (adalimumab and MTX) and
the monotherapy (adalimumab) group at 13, 25, 37, 49, 61, 73, 85, 97, 109, 121,
133 en 145 weeks;
*To assess the tolerability and safety of the combination therapy compared to
the monotherapy group;
*To determine the correlation of certain patient characteristics like age,
gender, ethnicity, BMI, PsA, smoking, alcohol use, disease duration, disease
severity by PASI, concomitant medication, naïve for biologics versus non-naïve
(perhaps specified per biologic), trial medication and potential other
co-variates (e.g. genetic polymorphisms) with other endpoints.

A prospective randomised open label outcome assessor blinded multicentre study.

Patients will be randomised 1:1 to adalimumab (per label) with concomitant MTX
10 mg/week and folic acid 5 mg/week (combination therapy group) or adalimumab
per label (monotherapy group).

All patients randomised in this study are patients in whom adalimumab therapy
is being initiated. They will be randomised in treatment with adalimumab either
with or without MTX, Therefore, patients must be eligible for adalimumab and
MTX treatment at the time of inclusion. If randomised for the combination
treatment group they will receive adalimumab (per label) and concomitant MTX 10
mg/week and folic acid 5 mg/week. MTX therapy will be initiated 2 weeks prior
to adalimumab therapy. At each visit the PASI score and IGA will be assessed
and patients will be asked for side-effects. The questionnaires PGA, Skindex
29, DLQI need to be filled in and this will require 15 minutes extra time for
the patients. At each visit two (extra) blood sample need to be collected for
determining antidrug antibodies and drug serum level. At the start of the
study, one extra sample will be obtained for pharmacogenetic sampling.
If the patient participates in the extension study (week 49-145) MTX dosing can
be adjusted for efficacy or safety reasons. Adalimumab is provided in a
standard dose that will not be adjusted throughout the entire study.
The burden and risk of use of MTX is associated with potential side-effects
like ulcerative stomatitis, low white blood cell count (and thus predisposition
to infection), nausea, abdominal pain, fatigue, fever and dizziness. Potential
benefits are that the combination therapy group may achieve a better clinical
efficacy and drug survival, resulting in a longer period of optimal response to
adalimumab. Based on the reassuring experience with combined MTX and biologic
treatment in patients with rheumatoid arthritis it is not expected that safety
problems will be an issue during this study.