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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Background

There is limited information on systemic and biological treatment optimization and transitioning in routine clinical practice.

Objective

To provide practical guidance on treatment optimization and transitioning for moderate-to-severe plaque psoriasis.

Methods

Dermatologists from 33 countries contributed to the Transitioning Therapies programme. Fourteen questions were identified. Answers were drafted based on systematic literature reviews (7/14 questions) and expert opinion (7/14 questions). Using a modified Delphi procedure, dermatologists from 30 countries voted on their level of agreement with each draft answer (scale: 1–9, strong disagreement to strong agreement). Consensus was defined as ≥75% of participants scoring within the 7–9 range.

Results

Consensus was achieved on the answers to all questions. Recommendations for the use of cyclosporine and methotrexate were agreed. Transitioning from a conventional systemic therapy to a biological agent may be done directly or with an overlap (if transitioning is required because of lack of efficacy) or potentially with a treatment-free interval (if transitioning is required for safety reasons). Combination therapy may be beneficial. Continuous therapy for patients on biologicals is strongly recommended. However, during successful maintenance with biological monotherapy, a dosage reduction may be considered to limit drug exposure, although this may carry the risk of decreased efficacy. Switching biologicals for reasons of efficacy should be done without a washout period, but switching for reasons of safety may require a treatment-free interval.

Conclusion

This consensus provides practical guidance on treatment optimization and transitioning for moderate-to-severe plaque psoriasis, based on literature reviews and the expert opinion of dermatologists from across the globe.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Patients with psoriasis remain undertreated, as illustrated in a survey of dermatological practices in Germany, which showed that 29.5% of 1341 patients with psoriasis had moderate disease [Psoriasis Area Severity Index (PASI): 11–20] and 19.4% had severe disease (PASI: >20), but only 31% received systemic treatment.[1]

Treatment goals, which supplement existing guidelines,[2-5] have been developed by a European Consensus Group to promote the consistent use of available therapies to improve patient care.[6] However, while treatment goals provide guidance on when to modify treatment, there are few data in the literature, and limited information in guidelines, to guide physicians on treatment optimization of conventional systemic and biological therapies and how and when to transition from one treatment to another in routine clinical practice.[7] Furthermore, there is ongoing debate on whether a successful therapy should be continued and, if so, for how long. Criteria on which to base the decision to terminate or interrupt treatment have not been elaborated but are of significant clinical importance.

Here, we report on the Transitioning Therapies programme, which was established to provide practical, evidence-based, expert-agreed guidance on appropriate treatment optimization and transitioning in the management of moderate-to-severe plaque psoriasis.

Materials and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Thirty-three countries were involved in the Transitioning Therapies programme. The programme took place between May 2011 and June 2012 and was overseen by a Steering Committee (SC) of nine dermatologists from Europe and Canada (the authors of this article). The programme was conducted as a modified Delphi procedure and consisted of several stages (Fig. 1). Similar methodology has been employed in development of other consensus-based guidelines.[8, 9]

image

Figure 1. Workflow of Transitioning Therapies programme.

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The participating dermatologists were asked to suggest clinically relevant questions, covering optimization of conventional systemic therapies, transitioning from conventional systemic therapies to biological therapy and transitioning from one biological agent to another. These suggestions were assembled into a list of 93 questions. The questions were sent back to the participating dermatologists with a question prioritization form. The group consisted of a total of 147 dermatologists (referred to as the national faculty members), who were selected based on their expertise in treating patients with moderate-to-severe psoriasis.

The results from the question prioritization stage enabled questions to be ranked and critical clinical questions to be identified. Fourteen key questions (some of which had several sub-sections, resulting in 25 components) were agreed at a face-to-face meeting of the SC in October 2011 to be taken forward to the next stage.

Draft answers to the 14 questions were developed by the SC. The feasibility of answering the questions based on a systematic literature search was assessed by the SC and, when possible, draft answers were developed for 7/14 questions (questions 1B, 2B, 7, 8, 11, 13, 14) based on the results of systematic literature review. For the systematic literature search each question was rephrased according to the PICO method.[10] Details of the systematic searches, which were conducted with pre-defined search strings, are listed in Table 1, with the outcomes listed in Table 2. The evidence was graded using the classification of the Oxford Centre for Evidence-Based Medicine: Level 1 (highest level of evidence based on randomized controlled trials); Level 2 (high quality cohort studies and poor quality randomized controlled trials); Level 3 (high quality case-control studies); Level 4 (case series or poor quality cohort or case-control studies); Level 5 (lowest evidence based on expert opinion) (see http://www.cebm.net/index.aspx?o=1025). The remaining seven questions were answered based on non-systematic literature review and expert opinion; these draft answers were not assigned an evidence level.

Table 1. Summary of the systematic literature searches
Databases searched

Medline (search date: 28.10.2011)

Medline in Process (search date: 28.10.2011)

Embase (search date: 28.10.2011)

Cochrane Library (search date: 31.10.2011)

Limits

2000 – present

Humans

English, French or German

Hand searches (2007 onwards)

Journals:

J Invest Dermatol

Brit J Dermatol

J Am Acad Dermatol

Arch Dermatol

J Eur Acad Dermatol Venereol

Abstracts:

German Dermatological Society meetings 2007, 2009 and 2011

American Academy of Dermatology meetings 2009–2011

European Academy of Dermatology and Venereology meetings 2005–2011

From Gene to Clinic meeting London 2005 and 2008

Congress of the Psoriasis International network, Paris 2010

Inclusion criteria

Randomized controlled studies

Case-control studies

Case series

Prospective and retrospective studies

Studies with >5 patients treated with the same medication

Exclusion criteria

False topics

No original data

No relevant outcome data

Fewer than 5 patients

Table 2. Summary of references retrieved in systematic literature searches
QuestionNumber of references retrieved by systematic searchesFinal number of articles included in the systematic reviewsAdditional abstracts/articles identified by hand searches
Q1B/2B150

17 in total:

10 cyclosporine

7 methotrexate

0
Q780920
Q881
Q1182
Q1380
Q14130

Using a structured, iterative process draft answers were sent to the national faculties to be discussed during national meetings. Feedback was returned to the SC and was consolidated into revised answers, taking into account consistency between countries, alternative views and the opinions of the SC.

The revised answers were discussed again (and amended when this was thought to be necessary) at an international meeting of 103 participants from 30 of 33 invited countries which was held in Frankfurt, Germany on 21 and 22 June 2012. Each country had between 1 and 5 dermatologists participating in the international meeting with the exception of Canada (9 participants) and Italy (10 participants). Two thirds of the participants at the international meeting had previously participated in both the question prioritization phase of the programme and the national meetings. The participants were reminded that the recommendations refer to plaque psoriasis unless otherwise stated.

Voting was performed using hand-held electronic voting devices. Each participant had one vote per component or question. Participants indicated their level of agreement with each draft answer using a voting scale of 1–9 (where 1 = strong disagreement and 9 = strong agreement). Each voting score was allocated to one of three ranges: 1–3, 4–6 and 7–9. Consensus was defined as ≥75% of participants scoring within the 7–9 range. If <75% of participants scored within this range, the answer was debated and revised, and a second vote took place, with consensus based on the criteria above.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

At the question prioritization stage, 110 of 147 invited dermatologists responded (with at least 1 valid form from each participating country), with 107 completed valid forms (73% response rate). In total, 14 key questions were identified, some of which had several sub-sections, resulting in 25 components.

Following development of the draft answers, feedback was generated at national meetings of the national faculty members from 32 of the 33 participating countries, and consolidated into revised answers as described above.

The revised answers were discussed and voted upon at the international meeting. Consensus was achieved on all 25 components at the international meeting with only one component (Q13) requiring a second vote. The consensus-agreed answers are presented in Tables 3.

Table 3. Recommendations on optimizing conventional systemic therapies: cyclosporine
  1. PASI, Psoriasis Area Severity Index; PUVA, psoralen plus ultraviolet A; clinically meaningful response, a 50% reduction in the mean PASI in a population of patients.

Q1A

What is the maximum period for which conventional systemic therapies should be given to patients responding to treatment?

  1. Treatment with cyclosporine is generally used intermittently for inducing a clinical response with one or several courses over 3–6 months.
  2. When necessary, cyclosporine may be given to patients responding to treatment continuously for up to 2 years. In exceptional cases, where no other treatment options are available, treatment with cyclosporine can be extended for longer than 2 years with adequate monitoring. However, changes in the risk-benefit profile for cyclosporine can already occur from an early stage of treatment and this should be borne in mind when considering treatment options.[25, 26]
  3. The long-term use of cyclosporine should be considered with caution because of the significant risk of renal toxicity, the development of arterial hypertension and the increased risk of skin cancer[24] especially in patients with extensive previous phototherapy (e.g. >200 PUVA treatments). Long-term cyclosporine use should be considered with particular caution in patients with a history of cancer or who are immunosuppressed.
  4. Regular monitoring should be performed according to the existing guidelines; skin examination to check for skin cancer is also recommended.

99% consensus agreement on first vote; median score = 8

Q1B

Following treatment with conventional systemic therapy, during what time period should we expect to see a clinical response? At what time points should we monitor patients for treatment response, for example, with PASI 75?

  1. In clinical trials with cyclosporine starting dosages of 2.5–3 mg/kg/day, clinically meaningful responses (50% reduction in the mean PASI) have been observed after 4–6 weeks.[11-17] (Level of evidence 2)
  2. Higher starting dosages (≥5 mg/kg/day) lead to a more rapid onset of response (50% reduction in mean PASI within a mean time of 3–4 weeks)[17-20] (Level of evidence 2) although this may be associated with greater toxicity than starting at a lower dosage.
  3. The clinical response to cyclosporine in a patient population with dosages of 2.5–5 mg/kg/day can be expected to reach a maximum within 5–12 weeks.[13-23] (Level of evidence 2)

100% consensus agreement on first vote; median score = 9

Optimization of conventional systemic therapies

Cyclosporine

Consensus recommendations on optimizing therapy with cyclosporine are presented in Table 3. Treatment with cyclosporine should generally only be used for short periods to induce a clinical response. Clinically meaningful responses (50% reduction in mean PASI in a population of patients) have been observed after 4–6 weeks of cyclosporine (starting dosages of 2.5–3 mg/kg/day) (Level of evidence 2),[11-17] with a more rapid onset of response (within 3–4 weeks) with higher starting dosages (≥5 mg/kg/day) (Level of evidence 2),[17-20] although this may be associated with greater toxicity. Clinical response to cyclosporine 2.5–5 mg/kg/day can be expected to reach a maximum within 5–12 weeks (Level of evidence 2).[13-23]

When necessary for medical reasons, cyclosporine may be given to responding patients for up to 2 years. In exceptional cases, where no other treatment options are available, cyclosporine may be given for longer than 2 years but caution is advised because of the significant risk of renal toxicity, the development of arterial hypertension and the increased risk of skin cancer (especially in patients with extensive previous phototherapy, e.g. >200 PUVA treatments).[24] Special caution is also recommended for patients with a history of cancer or in those who are immunosuppressed. Changes in the risk-benefit profile for cyclosporine can occur early after treatment onset and this should be taken into account when considering treatment options.[25, 26] Patients on cyclosporine therapy should be monitored regularly according to the existing guidelines and examination for skin cancer should be undertaken.

Methotrexate

There is no evidence-based study directly addressing the question of how long methotrexate can be administered to patients. However, there is a wealth of expert experience suggesting that methotrexate therapy is effective for long periods of time (10–15 years) in appropriate patients and with regular safety monitoring. Therefore, methotrexate may be given to patients for as long as it remains effective and well tolerated (Table 4).

Table 4. Recommendations on optimizing conventional systemic therapies: methotrexate
  1. HBV, hepatitis B virus; HCV, hepatitis C virus; PASI, Psoriasis Area Severity Index; PASI 75, a 75% reduction in PASI; PIIINP, procollagen III N-terminal peptide; clinically meaningful response, a 50% reduction in the mean PASI in a population of patients.

Q2A

What is the maximum period for which conventional systemic therapies should be given to patients responding to treatment?

  1. Methotrexate may be given to patients for as long as it remains effective and well-tolerated.
  2. Screening and monitoring of patients according to the existing guidelines is required.
  3. In most cases, the risk of liver toxicity with methotrexate therapy is low; however, the impact of additional risk factors such as baseline liver disease (including HBV or HCV), alcohol intake, obesity and type 2 diabetes and the use of concomitant medications should be taken into account.[36, 39, 40] The risk of liver toxicity may increase with cumulative doses of methotrexate.
  4. There is no clear evidence for or against increased risk of malignancies[82] or serious infections with methotrexate therapy in patients with psoriasis.

97% consensus agreement on first vote; median score = 9

Q2B

Following treatment with conventional systemic therapy, during what time period should we expect to see a clinical response? At what time points should we monitor patients for treatment response, for example, with PASI 75?

  1. In clinical trials with oral methotrexate (5–7.5 mg weekly starting dose, escalating), clinically meaningful responses (50% reduction in the mean PASI) have been observed after 7–13 weeks.[11, 27-31] A reduction of the mean PASI by 75% has been observed within 14 weeks.[27] (Level of evidence 2)
  2. Higher oral starting doses (15–22.5 mg weekly) lead to more rapid onset of response (50% reduction in the mean PASI within a mean time of 3–4 weeks[12, 32] and 75% reduction in the mean PASI within 7 weeks).[32] (Level of evidence 2)
  3. The clinical response to oral methotrexate in a patient population can be expected to reach a maximum within 12–20 weeks.[12, 27-29, 32, 33] (Level of evidence 2)

98% consensus agreement on first vote; median score = 9

Q3

If a patient does not respond to methotrexate within 16–24 weeks, should we increase the dose? What is the maximum dose we should use before considering treatment failure?

  1. Oral methotrexate therapy can be initiated at dosages between 5 and 15 mg/week with early monitoring (before the second dose). If a low starting dose is selected, rapid dosage escalation to 15 mg/week by week 3 can be considered.
  2. If at week 8 the response is insufficient, an increase in the dosage to 20 mg/week can be considered.
  3. For patients who are non-responders to 20 mg oral methotrexate treatment at 16–24 weeks the effect of further increasing the dose remains unclear.[29, 31, 34]
  4. There is evidence for oral methotrexate only; increased efficacy and tolerability may be achievable by subcutaneous administration.

95% consensus agreement on first vote; median score = 9

Q4

What is the optimal safety monitoring (clinical, laboratory) of patients receiving methotrexate? How often?

  1. Current guidelines provide monitoring recommendations for screening, initiation and maintenance with methotrexate therapy.[2, 3] For methotrexate-naive patients, it is particularly important to assess for early signs of toxicity before administering the second dose of methotrexate.
  2. In addition to guideline recommendations, monitoring for liver toxicity may include measurement of PIIINP every 3–6 months in the same laboratory and assessment of the liver using transient elastography, if these tests are available.
  3. Liver biopsy is not routinely indicated but may be considered in specific clinical circumstances following discussion with a hepatologist.

88% consensus agreement on first vote; median score = 8

In clinical trials, clinically meaningful responses (50% reduction in mean PASI in a population of patients) have been observed after 7–13 weeks of oral methotrexate (5–7.5 mg weekly starting dose, escalating),[11, 27-31] with a reduction in mean PASI by 75% occurring within 14 weeks (Level of evidence 2).[27] Higher oral starting doses (15–22.5 mg weekly) produce a more rapid onset of response (50% reduction in mean PASI within a mean of 3–4 weeks[12, 32]; and 75% reduction in mean PASI within 7 weeks[32]) (Level of evidence 2). The clinical response to oral methotrexate can be expected to reach a maximum within 12–20 weeks (Level of evidence 2).[12, 27-29, 32, 33]

There are few evidence-based studies on the pattern of treatment of psoriasis with methotrexate and treatment decisions have often been a matter of judgement and best practice. Nonetheless, we recommend that oral methotrexate can be initiated at dosages of 5–15 mg/week with early monitoring (before the second dose) (Table 4). If a low starting dose is selected, rapid dosage escalation to 15 mg/week by week 3 can be considered. A further increase in dosage to 20 mg/week is an option if response is insufficient at week 8. In non-responders to 20 mg oral methotrexate at 16–24 weeks (the timeframe established in the European treatment goals) the effect of further dose increases remains unclear,[29, 31, 33] although a formal dose escalation study to establish an upper dose limit has not been performed. Furthermore, there is no evidence that splitting the dose provides an increase in efficacy. Increased efficacy and tolerability may be achievable with subcutaneous administration, as shown in patients with rheumatoid arthritis;[35] however, to date, no study data comparing oral vs. subcutaneous methotrexate have been published for psoriasis.[36] Although supplementation with folic acid is often recommended,[36] there is little evidence about its pharmacological effects on tolerability of methotrexate.

There was some debate at the international meeting on the monitoring recommendations for methotrexate therapy which reflected the inter-country variation in access to specific tests. Despite this, consensus was achieved on monitoring recommendations for screening, initiation and maintenance with methotrexate therapy. Patients for whom methotrexate is considered should be monitored according to existing guidelines.[2, 3] In methotrexate-naïve patients, it is important to assess for early signs of bone marrow toxicity before administering the second dose.[37, 38] In addition, it is important to take account of the impact of risk factors for liver toxicity (e.g. baseline liver disease [including HBV or HCV], alcohol intake, obesity, type 2 diabetes and the use of concomitant medications).[36, 39, 40] In most cases, the risk of liver toxicity with methotrexate is low, although risk may increase with cumulative doses; it is not possible to provide an absolute threshold value for cumulative dose as there is limited evidence in the literature. Physicians may also perform the PIIINP test every 3–6 months (using the same laboratory), which is considered the best non-invasive test for liver fibrosis; however, PIIINP levels can be difficult to interpret in patients with active psoriatic arthritis or lung fibrosis or in other situations in which fibroneogenesis occurs. Assessment of the liver using transient elastography may also be considered, if available, but further studies are required to fully evaluate the diagnostic properties of this test. Liver biopsy is not routinely indicated[2] but may be considered in specific clinical circumstances following discussion with a hepatologist.

There was considerable debate at the international meeting on whether testing for tuberculosis (including chest X-ray, skin and/or blood tests) should be performed prior to initiating methotrexate therapy as recommended in guidelines[2, 5] as there is no evidence for an increased risk of latent TB reactivation by the drug. In the case of a positive history of TB substantiated by positive skin or blood testing (interferon gamma release assay) and/or positive chest X-ray, therapy for latent TB with drugs such as isoniazide may increase the risk of liver toxicity when given together with methotrexate.

Stopping conventional therapy

In most patients with moderate-to-severe psoriasis, continuous therapy is required to achieve long-term disease control and stopping therapy is not generally recommended (Table 5). Nonetheless, stopping therapy (either abruptly or by tapering) with careful follow-up may be considered in patients with prolonged clinical and quality of life (QoL) response. There is little evidence to suggest the subgroups of patients in which therapy can be interrupted or stopped, with the exception of patients with guttate psoriasis. The course of the disease is important when considering treatment interruption. In many patients who do discontinue therapy, disease recurrence can be expected within 2–6 months.

Table 5. Recommendations on stopping conventional therapy
  1. DLQI, Dermatology Life Quality Index; PASI 50, a 50% reduction on the Psoriasis Area Severity Index; PASI 75, a 75% reduction in PASI; PGA, Physician's Global Assessment; PsA, psoriatic arthritis; QoL, quality of life.

Q5

Can conventional systemic therapy be stopped in cases of sustained response/clearance using monotherapy? If so, how many months of sustained clearance should we see before stopping therapy?In which patient groups can we stop conventional systemic therapies (e.g. all patients, only those with previous slow relapses following discontinuation)?

  • 1.
    Continuous therapy is required to achieve long-term disease control. Therefore, stopping therapy is not generally recommended. However, if agreed with the patient, and after achieving a clinical response of clear or almost clear with good QoL for a prolonged period of time, for example, a minimum of 1 year, stopping conventional systemic therapy can be considered with careful follow-up.
  • 2.
    Consideration of stopping therapy in patients with well-controlled psoriasis should be based on:
  • Patient preference
  • Presence of individual risk factors with an impact on the long-term benefit-risk profile
  • Prior course of disease including pattern of flares/rebound
  • Presence of comorbidity
  • Presence of PsA
  • Disease phenotype, severity and impact on QoL
  • Availability of treatment options in case of disease recurrence
  • Type of treatment
  • 3.
    Recurrence of the disease can be expected within 2–6 months in many patients discontinuing therapy.
  • 4.
    There is little evidence to suggest the subgroups of patients in which therapy can be interrupted or stopped.

98% consensus agreement on first vote; median score = 9

Q6

In patients who have stopped conventional systemic therapy, what criteria should we use to determine when therapy should be reintroduced (e.g. loss of PASI 75, loss of PASI 50 (relapse), loss of DLQI<5 response, loss of PGA <2, loss of PGA <3)?

  1. There are no standard criteria for treatment reintroduction.
  2. Shared decision making between physician and patient is important.
  3. Patient management should take into account that after having experienced disease control for some time, patients may become less tolerant of disease recurrence.
  4. Recurrence of limited disease may be controlled with topical therapy or phototherapy.
  5. As a practical guide, consider reintroducing systemic therapy if there is a PGA >2 and/or PASI ≥5 and/or DLQI ≥5 or if there is rapid disease recurrence.

98% consensus agreement on first vote; median score = 9

Following cessation of conventional systemic therapy, there are no standard criteria for treatment reintroduction. Therefore, it is important that decision making is shared between the physician and patient, taking into account that patients who have experienced prolonged disease control may become less tolerant of disease recurrence. It should also be noted that more rapid loss and more severe recurrence of disease is likely to limit the probability of re-establishing effective disease control when treatment is reintroduced. As a practical guide, the reintroduction of conventional systemic therapy may be considered if there is a PGA >2 and/or PASI ≥5 and/or DLQI ≥5 or if there is rapid disease recurrence. Furthermore, the early reintroduction of therapy is required if a patient develops psoriatic arthritis after stopping conventional systemic therapy.

Transitioning from conventional systemic therapy to biological therapy

There is limited evidence in the literature on the effect of overlapping the different treatments or the methods of transitioning. However, the possibility of overlapping therapies during transitioning can be implied from studies that report on combination therapy. Recommendations for transitioning will differ depending on the reason for transitioning, for example, in the case of safety, a treatment-free interval may be necessary, whereas in response to lack of efficacy, transitioning directly or with an overlap period can be considered (Table 6). Importantly, if a patient develops psoriatic arthritis, transitioning to an agent that is efficacious in both psoriasis and psoriatic arthritis is required. Irrespective of the reason for transitioning, the new drug should be given at the approved induction dosage.

Table 6. Recommendations for transitioning from conventional systemic therapy to biological therapy
  1. TNF, tumour necrosis factor; partial responder (or intermediate responder), defined in the European treatment goals as achievement of an intermediate response of change in PASI ≥50 but <75 (as compared with disease severity at the time of treatment initiation), where DLQI ≤5 has not been achieved or where DLQI<5 has been achieved.

Q7

In cases of non-response to conventional systemic therapies, should transitioning to a biological agent be done sequentially without a washout period, sequentially with a washout period, or should treatments be overlapped? What is the appropriate dosing schedule in each of these scenarios?

General

  1. Recommendations for transitioning therapies will differ depending on the reason for transitioning. When transitioning from conventional systemic therapy to another drug for safety reasons, a treatment-free interval may be necessary until the safety parameter has normalized or stabilized.
  2. When transitioning due to lack of efficacy, transitioning directly or with an overlap period can be considered.
  3. When transitioning from conventional systemic treatments to biological treatments, approved induction dosages should be used.

99% consensus agreement on first vote; median score = 9

Acitretin to a biological agent

  1. Treatment transitioning from acitretin to TNF antagonists can be performed without a washout period or with an overlap.[48, 83] (Level of evidence 3)
  2. Treatment transitioning from acitretin to ustekinumab can be performed without a washout period or with an overlap. (Level of evidence 5)
  3. However, women of child-bearing age should continue with contraception for 2 years as recommended for the use of acitretin.

94% consensus agreement on first vote; median score = 9

Cyclosporine to a biological agent

  1. Treatment transitioning from cyclosporine to TNF antagonists can be performed without a washout period.[84, 85] (Level of evidence 4)
  2. Treatment transitioning from cyclosporine to ustekinumab may be performed without a washout period. (Level of evidence 5)
  3. A short overlap period (e.g. 2–8 weeks) of cyclosporine with TNF antagonists or ustekinumab can be considered in order to reduce the risk of rebound in partial responders but the overlap period should be minimized and the dose of cyclosporine tapered down as soon as possible. (Level of evidence 5)

92% consensus agreement on first vote; median score = 9

Methotrexate to a biological agent

  1. Treatment transitioning from methotrexate to TNF antagonists can be performed without a washout period.[33, 74] (Level of evidence 2)
  2. Treatment transitioning from methotrexate to ustekinumab can be performed without a washout period. (Level of evidence 5)
  3. Methotrexate can be overlapped or used concurrently with TNF antagonists[41-45, 86] (level of evidence 2) or ustekinumab (level of evidence 5).[87, 88]

98% consensus agreement on first vote; median score = 9

Guidance on transitioning (with overlap and washout period recommendations) from specific conventional systemic therapies to each of the TNF antagonists or ustekinumab is provided in Table 6.

Combining conventional systemic therapy with biological therapy

There is no approved indication for any combination of a biological with conventional systemic therapies in psoriasis (Table 7). However, combination therapy is often used to improve efficacy, optimize the risk-benefit profile, reduce the risk of immunogenicity (with methotrexate) and improve long-term disease management.

Table 7. Recommendations on combining conventional systemic therapy with biological therapy
  1. TNF, tumour necrosis factor.

Q8

Is it efficacious to combine biological therapy with conventional systemic therapy? Is it safe to combine biological therapy with conventional systemic therapy?

  1. There is no approved indication for any combination of a biological with conventional systemic therapies in psoriasis.
  2. A conventional systemic therapy can be added to biological monotherapy with the intention to improve efficacy, optimize the risk-benefit profile, reduce the risk of immunogenicity (with methotrexate) and enhance long-term disease management.
  3. For the TNF antagonists, combination with methotrexate (5–15 mg/week) is safe (Level of evidence 4) and increases the long-term efficacy of the treatment regimen.[41-45] (Level of evidence 3)
  4. Due to the lack of evidence and the potentially increased toxicity, for example, an increased skin cancer risk, the combination of TNF antagonists or ustekinumab with cyclosporine should be used with caution. (Level of evidence 5)
  5. The combination of etanercept 25 mg/week with acitretin showed similar efficacy as 2x25 mg/week etanercept monotherapy.[48] (Level of evidence 2) The combination of acitretin with lower doses of etanercept 25 mg/week has a safety profile comparable to the monotherapy.[48] (Level of evidence 3)
  6. The combination of adalimumab with acitretin may be considered. (Level of evidence 4)
  7. A treatment combination of methotrexate with ustekinumab may be used, but there is limited data on safety and efficacy (Level of evidence 5).
  8. Data for the combination of acitretin with infliximab or ustekinumab are not currently available but an increased clinical response might also be expected. (Level of evidence 5)

97% consensus agreement on first vote; median score = 9

Q9

What is the optimal safety monitoring (clinical, laboratory) of patients receiving combination therapy with a conventional systemic agent and a biological therapy? How often?

  1. The optimal safety monitoring for combination therapy has not been determined.
  2. All parameters recommended to be monitored for each drug as monotherapy should be assessed.
  3. As a practical guide, the monitoring interval should be defined by the drug with the most stringent monitoring criteria.
  4. If synergistic toxicity is suspected, monitoring intervals may need to be reduced and additional parameters may need to be added.

95% consensus agreement on first vote; median score = 9

Q10

If there is no response or insufficient response when combining a conventional systemic therapy with a biological agent, should we increase the dose of the conventional systemic therapy? Increase the dose of the biological? Reduce time intervals of the biological? Change to another biological?

  1. The combination of a biological with a conventional systemic therapy is an option in the treatment of psoriasis; however, there is no clinical trial evidence on which to provide answers to these questions.
  2. Conventional systemic therapy with methotrexate or acitretin can be added to a biological monotherapy with the intention to improve efficacy, optimize the risk-benefit profile, reduce the risk of immunogenicity (with methotrexate) and enhance long-term disease management. The conventional systemic therapy should be added beginning with the lowest recommended dosage, for example, 5–10 mg/week for methotrexate. The combined use of cyclosporine and a biological raises safety concerns.
  3. If adequate response is still not achieved:
  • Optimize the current therapy (e.g. increase the dosage of the conventional systemic therapy; increase the dose or decrease the treatment interval of the biological)
  • Consider switching to another biological drug

93% consensus agreement on first vote; median score = 9

The safety (Level of evidence 4) and efficacy (Level of evidence 3) of methotrexate (5–15 mg/week) combined with the TNF antagonists etanercept and infliximab has been demonstrated,[41-45] but data were not identified for methotrexate combined with adalimumab nor ustekinumab. Nonetheless, this latter combination may be considered (Level of evidence 5). Since the systematic search was conducted, a retrospective case note review of ustekinumab use in real-life settings in 10 centres in the United Kingdom and Ireland has been published, which includes information on combination therapy.[46] In addition, a case series of adalimumab with methotrexate has been published very recently.[47]

TNF antagonists or ustekinumab should be used with caution in combination with cyclosporine because of a lack of evidence on efficacy and the potential for increased toxicity (e.g. an increased risk of skin cancer) (Level of evidence 5). Etanercept 25 mg/week in combination with acitretin has a similar efficacy (Level of evidence 2) and safety profile (Level of evidence 3) to etanercept 25 mg twice weekly.[48] Adalimumab may be also considered in combination with acitretin (Level of evidence 4). In contrast, data for acitretin combined with infliximab or ustekinumab are not currently available, although an increased clinical response might also be expected (Level of evidence 5).

The optimal safety monitoring for combination therapy has not been determined. We recommend monitoring as for monotherapy, with the monitoring frequency defined by the drug with the most stringent monitoring criteria. If synergistic toxicity is suspected, more frequent monitoring intervals may be required and additional monitoring parameters added.

When combining therapies, the conventional systemic therapy should be added to a biological beginning with the lowest recommended dosage (e.g. 5–10 mg/week for methotrexate). If adequate response is not achieved with combination therapy, consider optimizing the current therapy or switching to another biological (Table 7).

Adjusting biological therapy

There is no published data addressing dose adjustment protocols in a formal fashion. A dosage reduction to limit drug exposure may be considered during successful maintenance with biological monotherapy, although there is a theoretical risk that this may decrease efficacy and some evidence that extended intervals of administration may increase the risk of anti-drug antibody formation.[49-52] Nonetheless, decreasing the dosage (decreasing the dose or extending the dosing interval) of biological therapy below the recommended range may be considered in patients on combination therapy (see Table 8 for specific recommendations) (Level of evidence 5).

Table 8. Recommendation on adjusting biological therapy
  1. PASI 75, a 75% reduction in Psoriasis Area Severity Index; PsA, psoriatic arthritis; QoL, quality of life; TNF, tumour necrosis factor.

Q11

In a patient who is responding to a biological agent, can the dosing interval be increased or the dosage reduced?

  1. During successful maintenance with biologicals as monotherapy, a dosage reduction can be considered to limit drug exposure. However, long-term efficacy and safety data has only been generated for the approved dosage and there is a theoretical risk of decreased efficacy when using reduced dosages. In addition, there is some evidence to suggest that a lower dosage of a biological drug may increase the risk of anti-drug antibody formation.
  2. Decreasing the dosage of biological therapy below the recommended range may be considered in patients on combination therapy, that is, methotrexate + TNF antagonists. (Level of evidence 5)
  3. In clinical practice, dosing intervals have been increased with adalimumab and etanercept[53-58] while maintaining clinical response. (Level of evidence 5 for adalimumab; Level of evidence 2 for etanercept)
  4. With infliximab monotherapy, dosing intervals should not be increased over the intervals generally recommended.[49] (Level of evidence 2)
  5. The dosage of infliximab may be reduced from 5 mg/kg bodyweight to a minimum of 3 mg/kg bodyweight particularly if combined with methotrexate. (Level of evidence 5)
  6. With ustekinumab, increasing the injection intervals beyond 12 weeks does not appear meaningful, but theoretically, the dose for a responding patient may be reduced from 90 to 45 mg. (Level of evidence 5)

96% consensus agreement on first vote; median score = 9

Q12A

Can biological therapy be stopped or interrupted in cases of sustained response/clearance? If so, how many months of sustained clearance should we see before stopping therapy?

  • 1.
    Stopping biological therapy is not generally recommended. In patients with moderate-to-severe psoriasis, significant therapeutic breaks are difficult to achieve without risk of recurrence or an impact on efficacy following re-initiation of therapy – biological therapy should generally be administered using a continuous uninterrupted treatment regimen.[49, 50, 53, 59-64]
  • 2.
    However, if agreed with the patient, and after achieving a clinical response of clear or almost clear with good QoL for a prolonged period of time, for example, a minimum of 1 year, stopping biological therapy can be considered with careful follow-up.
  • 3.
    There is little evidence to suggest the subgroups of patients in which therapy can be interrupted or stopped. However, subgroups in which this might be considered include patients with:
  • Patient preference
  • Patients with a history of disease-free intervals or previously stable plaque-type psoriasis
  • Absence of significant comorbidities
  • Absence of PsA
  • Low impact of disease on QoL
  • No worsening of disease after previous dose reductions and treatment withdrawals
  • 4.
    However, because biological therapies are typically considered for patients with more severe disease, and come after failed conventional systemic therapy, patients on biologicals are less likely to fulfil these criteria. Furthermore, fewer treatment options are available for these patients during treatment re-introduction following treatment failure.
  • 5.
    Another consideration is that the risk of antibody formation against biological therapies increases with intermittent therapy. This is particularly important for the use of infliximab monotherapy where a higher risk of infusion reactions has been observed with intermittent therapy.[50]

79% consensus agreement on first vote; median score = 8

Q12B

Can efficacy with biological therapy be regained following therapeutic interruption and re-initiation using the same therapy? How long can the therapeutic interruption last without losing efficacy?

  1. Continuous biological therapy generally results in greater improvements in efficacy over time compared with intermittent therapy.[49, 50, 53, 59-64]
  2. In clinical trials with primary responding patients, up to 20% fail to regain a PASI 75 response after the first reintroduction of the same biological monotherapy.[49, 50, 53, 59-64] This decrease in efficacy may be greater with intermittent use of the drug.
  3. In patients receiving biological therapy, there is a high likelihood of disease recurrence within several months of cessation of treatment although some patients may maintain disease control for a prolonged period of time.
  4. Where therapy has been withdrawn and restarted, an induction dosing schedule should be used for re-introduction of the biological agent, with the possible exception of infliximab (because of the increased risk of infusion reactions).

81% consensus agreement on first vote; median score = 8

Furthermore, dosing intervals may be increased with some biologicals, such as adalimumab (Level of evidence 5) and etanercept (Level of evidence 2),[53-58] but not with infliximab monotherapy (Level of evidence 2).[49] Theoretically, the dose for a patient responding to ustekinumab may be reduced from 90 to 45 mg (Level of evidence 5).

Stopping biological therapy voluntarily (as opposed to stopping for medical reasons which may include elective surgery, pregnancy or serious infection) is generally not recommended and treatment administration should be continuous and uninterrupted.[49, 50, 53, 59-64] These recommendations are based on data that show that greater efficacy occurs with continuous biological therapy than with intermittent therapy,[49, 50, 53, 59-64] up to 20% of patients fail to regain a PASI 75 response after reintroduction of the same biological monotherapy,[49, 50, 53, 59-64] and significant therapeutic breaks are difficult to achieve without a high risk of disease recurrence.

Nonetheless, if agreed with the patient, and after achieving a clinical response of clear or almost clear with good QoL for a prolonged period, stopping biological therapy can be considered with careful follow-up (Table 8).

In cases of temporary interruption of therapy, a major impact on efficacy is not expected, that is, skipping one dose is not generally considered treatment interruption (with the exception of etanercept, due to the dosing schedule). When considering treatment interruption, it is important to be aware that there are fewer treatment options available during treatment re-introduction following biological failure, and the risk of antibody formation against biologicals increases with intermittent therapy, particularly with infliximab monotherapy.[50] There is little evidence to suggest the patient subgroups in which biological therapy can be interrupted or stopped. Where therapy has been withdrawn and restarted, an induction dosing schedule should be used for re-introduction of the biological agent, with the possible exception of infliximab (because of the increased risk of infusion reactions).

There is no established definition of inadequate clinical response to biological therapy, although in published clinical trials, a primary non-response was defined as not achieving PASI 50 (Table 9).[55, 65-71] Strategies for primary and secondary non-responders can include dosage increases or a reduction in dosing intervals (Table 9),[55, 65-71] and combination therapy with conventional treatments, as detailed above (Level of evidence 5). If these approaches are unsuccessful, the patient may be switched to a different biological therapy.

Table 9. Recommendations on transitioning from one biological therapy to another
Q13

In the case of inadequate response to a biological therapy (etanercept, infliximab, adalimumab and ustekinumab), should we increase the dose or reduce treatment intervals before switching? Which is preferable?

  • 1.
    There is no established definition of inadequate clinical response. In published clinical trials with the biological agents a primary non-response was defined as not achieving PASI 50.
  • 2.
    Strategies for primary and secondary non-responders, include:
  • For adalimumab, an increase of the dosage from 40 mg every other week to 40 mg/week.[65, 66] (Level of evidence 3)
  • For etanercept, an increase of the dosage from 50 mg/week to 2 × 50 mg/week.[55, 67, 68] (Level of evidence 4)
  • For ustekinumab, with primary partial responders, the dose can be increased from 45 to 90 mg with 12 week dosing intervals. If this is unsuccessful, the dose can be further increased to 90 mg at 8 week intervals.[69] (Level of evidence 2)
  • For infliximab, a reduction of the dosing intervals from every 8 weeks to every 6 weeks with 5 mg/kg can be considered in secondary non-responders, defined as the loss of at least 50% of the initial improvement.[70, 71] (Level of evidence 4). In special cases an increase of the dosage > 5 mg/kg can be considered (Level of evidence 5).
  • Alternatively, combination strategies with conventional treatments can be considered. (Level of evidence 5)
  • 3.
    If at the end of the induction phase there is an inadequate clinical response (primary inadequate response), or in the case of secondary non-response to biological monotherapy, and if the aforementioned strategies have been considered, it is recommended to switch to another drug.

79% consensus agreement on second vote; median score=8

Q14

When transitioning from one biological therapy to another, for whatever reason, should transitioning to a different biological agent be done:

  • sequentially without a washout period?
  • sequentially with a washout period? If so, how long should we wait before giving the new biological therapy? What factors should influence this decision (dosing interval, elimination half-life, potential for rebound, other)?

What is the appropriate dosing schedule for the second biological?

Should we use the maintenance dose or the loading dose?

General

  1. In the situation where switching biologicals has been decided due to failure of efficacy, switching is advisable without a washout period at the time of the next scheduled dose, using the standard induction dose, followed by the maintenance dose.
  2. If switching is necessary for reasons of safety, a treatment-free interval may be necessary until the safety parameter has normalized or stabilized.

94% consensus agreement on first vote; median score = 9

 

Adalimumab [RIGHTWARDS ARROW] another biological agent

  1. Administer the first treatment with etanercept after a treatment transitioning from adalimumab at the time point of the next scheduled drug dosage (typically 2 weeks).[72] (Level of evidence 3)
  2. Administer the first treatment with infliximab after a treatment transitioning from adalimumab at the time point of the next scheduled drug dosage (typically 2 weeks). (Level of evidence 5)
  3. Administer the first treatment with ustekinumab after a treatment transitioning from adalimumab at the time point of the next scheduled drug dosage (typically 2 weeks).[73] (Level of evidence 4)

97% consensus agreement on first vote; median score = 9

 

Etanercept [RIGHTWARDS ARROW] to another biological agent

  1. Administer the first treatment with adalimumab after a treatment transitioning from etanercept at the time point of the next scheduled drug dosage (typically 1 week).[66, 74, 75] (Level of evidence 3)
  2. Administer the first treatment with infliximab after a treatment transitioning from etanercept at the time point of the next scheduled drug dosage (typically 1 week).[76, 77] (Level of evidence 4)
  3. Administer the first treatment with ustekinumab after a treatment transitioning from etanercept at the time point of the next scheduled drug dosage (typically 1 week).[73, 78] (Level of evidence 2)

99% consensus agreement on first vote; median score = 9

 

Infliximab [RIGHTWARDS ARROW] to another biological agent

  1. Initiation of the first treatment with adalimumab after a treatment transitioning from infliximab can be considered as early as 2–4 weeks after the last infliximab dose, particularly in cases of treatment failure. (Level of evidence 5)
  2. Initiation of the first treatment with etanercept after a treatment transitioning from infliximab can be considered early as 2–4 weeks after the last infliximab dose, particularly in cases of treatment failure.[79] (Level of evidence 4)
  3. Initiation of the first treatment with ustekinumab after a treatment transitioning from infliximab can be considered as early as 2–4 weeks after the last infliximab dose, particularly in cases of treatment failure.[73] (Level of evidence 4)

99% consensus agreement on first vote; median score = 9Ustekinumab [RIGHTWARDS ARROW] to another biological agent

 
  • Initiation of the first treatment with adalimumab, etanercept or infliximab after a treatment transitioning from ustekinumab should be performed at 8–12 weeks but can be considered as early as 2–4 weeks after the initial biological dose in cases of treatment failure. (Level of evidence 5)
  • 89% consensus agreement on first vote; median score = 9
  • Dosing schedule for the second biological
  • The second biological should be used starting with the defined induction dosage and followed by the maintenance dosage.
  • 96% consensus agreement on first vote; median score = 9
 Level of evidence
  1. PASI 50, a 50% reduction in the Psoriasis Area Severity Index; partial responder (or intermediate responder), defined in the European treatment goals as achievement of an intermediate response of change in PASI ≥50 but <75 (as compared with disease severity at the time of treatment initiation), where DLQI ≤5 has not been achieved or where DLQI<5 has been achieved; Treatment failure (or inadequate response), failure to achieve or maintain an improvement of PASI ≥50 (as compared with disease severity at the time of treatment initiation).

Adalimumab [RIGHTWARDS ARROW]etanercept3[72]
Adalimumab [RIGHTWARDS ARROW]infliximab5
Adalimumab [RIGHTWARDS ARROW]ustekinumab4[73]
Etanercept [RIGHTWARDS ARROW]adalimumab3[74]
Etanercept [RIGHTWARDS ARROW]infliximab3[77]
Etanercept [RIGHTWARDS ARROW]ustekinumab2[73, 78]
Infliximab [RIGHTWARDS ARROW]adalimumab5
Infliximab [RIGHTWARDS ARROW]etanercept4[79]
Infliximab [RIGHTWARDS ARROW]ustekinumab4[73]
Ustekinumab [RIGHTWARDS ARROW]adalimumab/etanercept/infliximab5

Transitioning from one biological therapy to another

None of the trials identified in the literature search compared the safety and efficacy of transitioning with or without a washout period. We recommend that switching between biologicals due to failure of efficacy is performed without a washout period at the time of the next scheduled dose, using the standard induction dose, followed by the maintenance dose (Table 9). When switching for reasons of safety, it may be necessary to delay introduction of the new biological until the safety parameter has normalized or stabilized. Switching recommendations for individual biologicals are presented in Table 9.[66, 72-79] The second biological should be used starting with the pharmacokinetically defined induction dosage followed by the maintenance dosage.[72-74, 77-79]

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Evidence-based guidelines provide useful information about systemic anti-psoriatic drugs, but they often provide very little information on key questions that have not been addressed in clinical trials. A number of important questions – including the length of continuous therapy, criteria for treatment cessation and possible re-introduction as well as transitioning from one drug to another for various medical reasons and patient-related factors – are often discussed among clinicians taking care of psoriasis patients. It was therefore the aim of the programme to address these issues by defining key questions and answering these in the best possible way by systematic or non-systematic literature search and expert opinion.

This programme included an academically rigorous process, supported by a large number of dermatologists worldwide, representing a broad range of clinical opinion from diverse geographical regions and a variety of clinical practices.

The programme does have several limitations. Although systematic literature searches were conducted for some questions, this was not possible for other questions. In these instances, recommendations were based on the clinical experience and opinion of the participating dermatologists. It should also be acknowledged that experience with the TNF antagonists is much more extensive than that with the more recently licensed ustekinumab. Despite these limitations, consensus agreement on all of the recommendations (with consensus of at least 90% achieved for most of the 25 components) was gained from a large group of clinicians representing a broad scope of clinical opinion.

This consensus process has highlighted areas requiring further research. There are only limited data in the literature on combinations of conventional systemic therapies and biologicals in patients with moderate-to-severe psoriasis, and recommendations for dosages could not be given on an evidence-based level. In addition, there were insufficient data to comment on the safety of combination therapy or to propose an optimal safety monitoring schema; although data for the safety of methotrexate and TNF antagonists can be derived from studies in patients with psoriatic or rheumatoid arthritis.[80]

Data for combination treatment with ustekinumab are limited, with no evidence for combination therapy with conventional systemic therapies, or for efficacy and safety when overlapped with cyclosporine during treatment transitioning. In addition, the recommendation allowing overlap with ustekinumab and acitretin is based on information from combination trials, which only imply that overlap is allowable.

Although we recommend that continuous systemic treatment for psoriasis should be maintained, treatment interruption may be considered in some circumstances. However, it is important to note that the criteria for defining the duration of sustained response before stopping therapy have not been defined; neither have data on the duration of treatment cessation before reintroduction of the same therapy.

Differing resource settings, reimbursement for long-term management, access to care, the type of treatment centre, concomitant therapies (except where specified) or the co-existence of other disease have not been taken into consideration when formulating these recommendations. As such, it may not be possible for all physicians to apply all aspects of the guidance within their practice. For example, not all tests for monitoring methotrexate therapy are available in all countries, and in some instances, country-specific regulations may not allow off-label approaches to therapy optimization. In addition, the recommendations do not take into account the potential impact of compliance or adherence which should be explored prior to making transitioning decisions.[2, 3]

A recent study by Augustin and colleagues outlined specific issues in psoriasis and suggested goals and actions to address these needs.[81] It specifically highlighted the need for guidance on treatment optimization and treatment switching which is not provided by the current guidelines. The Transitioning Therapies programme addresses this need by providing practical consensus-agreed guidance on appropriate treatment optimization and transitioning in the clinical management of moderate-to-severe plaque psoriasis.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

This article summarizes the results of the International Consensus meeting on Progressive Psoriasis Initiative (PPI) Transitioning Therapies, which was held in Frankfurt, Germany on 21-22 June 2012.

Abbott solely funded the Progressive Psoriasis Initiative programme. The PPI programme and all content was funded by Abbott through an educational grant to the Medical Center Schleswig-Holstein, Campus Kiel, Germany. The PPI programme was led by a Steering Committee whose goal was to define and gain European consensus on treatment goals and gain international consensus on how to optimize treatment transitioning for patients with moderate-to-severe plaque psoriasis.

Abbott provided funding to the medical communications agency Lucid, Burleighfield House, Loudwater, UK, to manage the PPI programme that led to the development of this manuscript. Abbott paid consultancy fees to members of the Steering Committee for their participation at Steering Committee meetings and reimbursed travel costs.

Abbott provided funding to Lucid to manage the international Consensus meeting that also led to the development of this manuscript. Abbott reimbursed travel costs for participants of the International Consensus meeting.

No payments were made to the authors for the writing of this manuscript. Abbott had no influence on the development of the manuscript nor did it review the content of the manuscript. The authors (all of whom are members of the PPI Steering Committee) determined and approved the final content of the manuscript. Elaine Bell of Lucid provided editorial support for the authors in the development of this manuscript. Abbott paid Lucid for this study.

We thank all the participants in the Transitioning Therapies programme. The people listed below have participated at various stages in the programme (suggesting questions and/or question prioritization and/or review of draft answers at national meetings and/or participation at the international consensus meeting):

Bashar Abbasi, Jordan; Hussain Abdel Dayem, UAE; Mohammed Ahmed, UAE; Laith Akkash, Jordan; Melih Akyol, Turkey; Ali Al Amir, Saudi Arabia; Anwar Al Hammadi, UAE; Abdullah AL Khalifa, Saudi Arabia; Amna Al Muhairi, UAE; Maryam Al Obad, UAE; Ali Al Radadi, Saudi Arabia; Abdullah Al Rakban, Saudi Arabia; Hala Al Shaikh Ali, Syria; Mouza Al Suwaidi, UAE; Ali Al-Nahdi, Saudi Arabia; Sibel Alper, Turkey; Mario Amaya-Guerra, Mexico; Paolo Amerio, Italy; Alfred Ammoury, Lebanon; Salem Antaby, Syria; Christina Antoniou, Greece; Petr Arenberger, Czech Republic; Nilgün Atakan, Turkey; Luna Azulay, Brazil; Christopher Baker, Australia; Flora Balieva, Norway; Bo Bang, Denmark; Federico Bardazzi, Italy; Hugues Barthelemy, France; Maria Rita Bongiorno, Italy; Hugo Boonen, Belgium; Marc Bourcier, Canada; Emel Bülbül Baskan, Turkey; Matilda Bylaite, Lithuania; Marzia Caproni, Italy; Andre Carvalho, Brazil; J. Česien≐, Lithuania; Petra Cetkovska, Czech Republic; Arnon Cohen, Israel; Curdin Conrad, Switzerland; Osvaldo Correia, Portugal; Antonio Costanzo, Italy; Tomas Dam, Denmark; Esteban Daudén, Spain; Michael David, Israel; Christa De Cuyper, Belgium; Clara De Simone, Italy; Pierre-Luc Dion, Canada; Jan Dutz, Canada; Cristina Echeverría, Argentina; Claes Enk, Israel; Lorena Estrada-Aguilar, Mexico; Lincoln Fabricio, Brazil; Mohammed Fatani, Saudi Arabia; Carlos Ferrandiz, Spain; Ana Ferreira, Portugal; Paulo Filipe, Portugal; Peter Foley, Australia; Lars French, Switzerland; Humaid Ghanem Khalfan, UAE; Pierre-Dominique Ghislain, Belgium; Samer Ghosn, Lebanon; Paolo Gisondi, Italy; Calin Giurcaneanu, Romania; I. Glazauskiene, Lithuania; Wieslaw Glinski, Poland; Minerva Gómez-Flores, Mexico; Catherine Goujon Henry, France; Esther Guevara-Sanginés, Mexico; Wayne Gulliver, Canada; Mehmet Ali Gürer, Turkey; Rolland Gyulai, Hungary; Ingo Haase, Germany; Dafna Halel-halevy, Israel; Anna Hallander, Sweden; Issam Hamadah, Saudi Arabia; Peter Häusermann, Switzerland; Jose Manuel Hernanz-Hermosa, Spain; Emmilia Hodak, Israel; Péter Holló, Hungary; Chih-ho Hong, Canada; Jamal Ibrahim, UAE; Arieh Ingber, Israel; Dimitrios Ioannidis, Greece; Lars Iversen, Denmark; Fermin Jurado-Santacruz, Mexico; Razan Kadry, UAE; Nouraldeen Kassar, Syria; Norito Katoh, Japan; Andreas Katsambas, Greece; Lajos Kemény, Hungary; Külli Kingo, Estonia; Brian Kirby, Ireland; Erol Koc, Turkey; Martina Kojanova, Czech Republic; Aotonios Kolios, Switzerland; Pille Konno, Estonia; Gertraud Krähn-Senftleben, Germany; Sabine Krueger, Greece; Vesta Kucinskiene, Lithuania; Natalia Kuzmina, Sweden; Morad Lahfa, France; Jo Lambert, Belgium; Elisavet Lazaridou, Greece; Francesco Loconsole, Italy; Adriana Lopeztello-Santillán, Mexico; Charles Lynde, Canada; Francois Maccari, France; Renata Magalhães, Brazil; Sofia Magina, Portugal; Emmanuel Mahe, France; Sameer Mahfoud, Syria; Piergiorgio Malagoli, Italy; César Maldonado-García, Mexico; Tarja Mälkönen, Finland; I. Marciukaitiene, Lithuania; Trevor Markham, Ireland; Gabriela Marques Pinto, Portugal; Hagit Matz, Israel; Sandy McBride, UK; Akimichi Morita, Japan; Cato Mørk, Norway; Nils-Jørgen Mørk, Norway; Michelle Murphy, Ireland; Hidemi Nakagawa, Japan; Joanna Narbutt, Poland; Alex Navarini, Switzerland; Alin Nicolescu, Romania; Mamitaro Ohtsuki, Japan; Nahide Onsun, Turkey; Isam Oumeish, Jordan; Güzin Özarmagan, Turkey; Pantelis Panagakis, Greece; Felix Pavlotsky, Israel; Thanasis Petridis, Greece; Stefano Piaserico, Italy; Yves Poulin, Canada; Errol Prens, the Netherlands; Feras Qarqaz, Jordan; Marc Radtke, Germany; Michal Ramon, Israel; Tapio Rantanen, Finland; Ashraf Reda, UAE; Adam Reich, Poland; Hassan Riad, Qatar; Dimitrios Rigopoulos, Greece; Monica Rivera, Mexico; Norma Rodríguez-Martínez, Mexico; Ricardo Romiti, Brazil; Lidia Rudnicka, Poland; Ousama Sammak, Syria; Jose Luis Sánchez-Carazo, Spain; Shigetoshi Sano, Japan; Hugo Schönenberger de Oliveira, Portugal; Gordon Searles, Canada; Nilgün Şentürk, Turkey; Marieke Seyger, the Netherlands; Nemer Shehadeh, Syria; Dorit Shapiro, Israel; Stephen Shumack, Australia; Shireen Sidhu, Australia; R. Sidlauskiene, Lithuania; Lone Skov, Denmark; Dimitrios Sotiriadi, Greece; Peter Soyer, Australia; Eli Sprecher, Israel; Phyllis Spuls, the Netherlands; D. Staniene, Lithuania; Farid Stephan, Lebanon; Michael Sticherling, Germany; Klaus Strömer, Germany; I. Sutaite, Lithuania; Andrea Szegedi, Hungary; Jacek Szepietowski, Poland; Toomas Talme, Sweden; Diamant Thaci, Germany; Bing Thio, the Netherlands; George Sorin Tiplica, Romania; Anne Marie Tobin, Ireland; Tiago Torres, Portugal; Androniki Toska, Greece; Tsen-Fang Tsai, Taiwan; Skaidra Valiukeviciene, Lithuania; Paulo Varela Fernandes, Portugal; Luis Vega, Mexico; Annie Vermersch Langlin, France; Ralph von Kiedrowski, Germany; Ben Walker, UK; Norbert Wikonkál, Hungary; Fabienne Willaert, Belgium; Birgitta Wilson Claréus, Sweden; Nikhil Yawalkar, Switzerland; Savaş Yaylı, Turkey; Jensen Yeung, Canada; Mouna Yousef, UAE; Bosmat Zamir, Israel; Michael Ziv, Israel

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  3. Introduction
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  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
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