The strength of recommendations (A-D and D[GPP]) and levels of evidence (1++, 1+, 1-, 2++, 2+, 2-, 3, and 4) are defined at the end of the "Major Recommendations" field.
Which Patients Should be Considered for Biological Therapy?
Eligibility Criteria
To be considered eligible for treatment, patients must have severe disease as defined in (a) and fulfil one of the clinical categories outlined in (b):
- Severe disease is defined as a Psoriasis Area and Severity Index (PASI) score of 10 or more (or a body surface area [BSA] of 10% or greater where PASI is not applicable) and a Dermatology Life Quality Index (DLQI)>10. Disease should have been severe for 6 months, resistant to treatment and the patient should be a candidate for systemic therapy. In exceptional circumstances (for example, disabling acral disease), patients with severe disease may fall outside this definition but may be considered for treatment. (Strength of recommendation D, level of evidence 3).
AND
- Fulfil at least one of the following clinical categories (Strength of recommendation B, level of evidence 1++ and formal consensus):
- Have developed or are at higher than average risk of developing clinically important drug-related toxicity and where alternative standard therapya cannot be used
- Are or have become intolerant to or cannot receive standard systemic therapy
- Are or have become unresponsive to standard therapyb
- Have disease that is only controlled by repeated inpatient management
- Have significant, coexistent, unrelated comorbidity which precludes use of systemic agents such as ciclosporin or methotrexate
- Have severe, unstable, life-threatening disease (erythrodermic or pustular psoriasis)
- Have psoriatic arthritis fulfilling the British Society for Rheumatology (BSR) eligibility criteria for treatment with anti-tumor necrosis factor (TNF) agents, (Kyle, et. al. 2005) in association with skin disease
aStandard systemic therapy includes acitretin, ciclosporin, methotrexate, narrowband ultraviolet (UV) B and psoralen + UVA photochemotherapy (PUVA)
bUnresponsive to standard therapy is defined as an unsatisfactory clinical response (a less than 50% improvement in baseline PASI score or percentage BSA where the PASI is not applicable, and a less than 5-point improvement in DLQI) to at least 3 months of treatment in the therapeutic dose range to the following treatments: ciclosporin 2.2 to 5 mg kg-1 daily; methotrexate single weekly dose (oral, subcutaneous, intramuscular) 15 mg, max 25 to 30 mg; acitretin 25 to 50 mg daily; narrowband UVB or psoralen photochemotherapy (nonresponse, rapid relapse or exceeding recommended maximum doses) 150 to 200 treatments for PUVA, 350 treatments for narrowband UVB (Ibbotson et. al., 2004; Norris, 1994).
Anti-tumor Necrosis Factor Therapies
Etanercept: Clinical Effectiveness
- Etanercept is effective in the treatment of chronic plaque psoriasis, with 38% and 54% of patients clear or nearly clear of disease after 12 weeks of treatment (25 mg twice weekly, 50 mg twice weekly, respectively). (Strength of recommendation A, level of evidence 1++).
- The current license recommends intermittent courses no longer than 24 weeks, with the time to relapse being variable (around 12 weeks) and with similar response rates achieved with repeat dosing.
- Treatment should normally be initiated at 25 mg subcutaneously, twice weekly. However, response is dose dependent and the chances of responding to treatment are greater with 50 mg twice weekly. The choice of the higher dose should be made based on an individual patient basis. (Strength of recommendation B extrapolated from level of evidence 1++).
- Treatment may be continued according to clinical need, although long-term efficacy is only established in psoriasis for up to 2 years. (Strength of recommendation D, level of evidence 3).
Infliximab: Clinical Effectiveness
- Infliximab is effective in the treatment of chronic plaque psoriasis, with 90% of patients becoming clear or minimally affected at 10 weeks following 5 mg kg-1 at weeks 0, 2 and 6. (Strength of recommendation A, level of evidence 1++).
- Infliximab therapy may be initiated at a dose of 5 mg kg-1 at weeks 0, 2, and 6 and subsequent maintenance infusions (either 5 mg kg-1 or 3 mg kg-1) given at 8-week intervals depending on clinical need and circumstances. (Strength of recommendation A, level of evidence 1++).
- In those patients who respond to therapy, regular maintenance infusions may avoid the risk of loss of efficacy seen in some patients receiving intermittent as-required repeat infusions on disease relapse. (Strength of recommendation D, level of evidence 3).
- Infliximab may also be of value in recalcitrant or unstable disease and in generalized pustular psoriasis. (Strength of recommendation D, level of evidence 3).
- Concomitant systemic therapies may be indicated for some patients with very severe or unstable psoriasis, although doses of these should be minimized. (Strength of recommendation D, level of evidence 3).
Adverse Effects and Toxicity: Anti-TNF Therapies
Infection and Anti-TNF Agents
- Actual risks of serious infections are unknown, particularly in those with psoriasis. Concomitant treatment with immunosuppressants or human immunodeficiency virus (HIV) infection may increase any risk. (Strength of recommendation D, level of evidence 3).
- Reactivation of tuberculosis may occur following treatment with anti-TNF agents, and the risks are greatest with infliximab. There appears to be a disproportionate risk of nonpulmonary and disseminated infection. (Strength of recommendation D, level of evidence 3).
- Patients with evidence of either active tuberculosis or previous, inadequately treated tuberculosis should receive antituberculous treatment prior to anti-TNF therapy (Ormerod, 2004; Ormerod and Joint Tuberculosis Committee of the British Thoracic Society, 2005) (Strength of recommendation D, level of evidence 4).
Heart Disease and Anti-TNF Agents
- Anti-TNF agents should be avoided in patients with severe (New York Heart Association [NYHA] class III or IV) congestive heart failure. (Strength of recommendation D, level of evidence 4).
- Those with milder disease should be carefully assessed prior to treatment, and treatment withdrawn at the onset of new symptoms or worsening of pre-existing heart failure. (Strength of recommendation D, level of evidence 4).
Demyelination and Anti-TNF Agents
- Infliximab and etanercept should not be given to people with a history of demyelinating disease or optic neuritis and treatment should be withdrawn if neurological symptoms develop. (Strength of recommendation D, level of evidence 4).
Hepatitis and Anti-TNF Agents
- The safety of TNF blockers in patients with chronic hepatitis B and C is not known. For patients known to be hepatitis B or C positive, advice from a hepatologist should be sought prior to initiation of therapy. (Strength of recommendation D, level of evidence 4).
Efalizumab
Clinical Effectiveness
- Efalizumab is effective in the treatment of moderate to severe chronic plaque psoriasis, with approximately one third of patients treated becoming clear or almost clear after 12 weeks. (Strength of recommendation A, level of evidence 1++).
- Duration of remission is variable on discontinuing therapy and may be associated with disease rebound. (Strength of recommendation D, level of evidence 4).
- The licensed weekly dose (1 mg kg-1) should be used and treatment discontinued after 12 weeks in those who do not respond. (Strength of recommendation A, level of evidence 1++).
- Therapy may be continued according to clinical need although data on long-term efficacy are limited to 27 months. (Strength of recommendation D, level of evidence 4).
Choice of Agent to Use
- Choice of agent efalizumab, etanercept, or infliximab, will depend on the clinical pattern of psoriasis, pre-existing comorbidity, patient preference, prescriber preference and local facilities.
- Etanercept should be considered first choice for patients with significant, uncontrolled psoriatic arthritis (refer to BSR guidelines here [Kyle et. al., 2004] but for this guideline skin disease identifies patient need). (Strength of recommendation D, level of evidence 4).
- For patients with stable psoriasis where a decision has been made to treat with an anti-TNF agent, etanercept should be used unless there are clear reasons not to do so. (Strength of recommendation D, level of evidence 4).
- Infliximab is useful in clinical circumstances requiring rapid disease control (e.g. in unstable erythrodermic or pustular psoriasis) due to its very rapid onset of action and high response rate. (Strength of recommendation D, level of evidence 4).
- For patients with a high risk of latent tuberculosis (and therefore requiring tuberculosis prophylaxis) or with evidence of demyelinating disease, efalizumab should be considered first choice. (Strength of recommendation D, level of evidence 4).
How to Prescribe Biological Therapies
Role of Specialist Nurse
Safe prescribing of biological therapies requires good infrastructure and specialist nursing personnel. With additional training a nurse may take responsibility for a number of the tasks outlined in the patient pathway including screening, treatment administration, patient education, prescription coordination for home drug delivery, patient support, monitoring, and data collection (e.g. PASI). A list of core competencies including cannulation skills is suggested by the Royal College of Nursing for rheumatology nurses involved in biological therapies.
Patient Information and Consent
Patients should be fully informed of the risks and benefits of biological therapies through detailed, collaborative discussion with the supervising consultant and clinical nurse specialist. Written information should be provided (available on the British Association of Dermatologists [BAD] website) and patients given adequate time to consider their decision. In clinical circumstances where these therapies are being used outside their licensed indications, written consent should be obtained.
Registration
In the interest of acquiring long-term safety data a comprehensive national register is proposed. Once this is operative (expected in early 2006), all patients should be registered and followed up through this register.
Pretreatment Assessment
All patients should undergo a full clinical history, physical examination and further investigations as required, with particular reference to the known toxicity profile of the agent being considered.
Specific exclusion criteria and recommended pretreatment investigations are listed in the tables below. Assessment for risk of tuberculosis in patients considered for anti-TNF therapy is detailed in Figure 1 of the original guideline document.
Exclusion Criteria for Anti-tumor Necrosis Factor (TNF) Agents and Efalizumab
Pregnant or breast feeding
Active infections. High risk include:
- Chronic leg ulcers
- Persistent or recurrent chest infections
- Indwelling urinary catheter
Latent tuberculosisa* (see Figure 1 of the original guideline document)
Malignancy or premalignancy states excluding:
- Adequately treated non-melanoma skin cancer
- Malignancies diagnosed and treated more than 10 years previously (where the probability of total cure is very high)
Demyelinating diseasea
Congestive cardiac failurea
(New York Heart Association grade III or IV, see Table 1 of the original guideline document)
Relative contraindications:
- Psoralen + ultraviolet A therapy > 200 treatments, especially when followed by ciclosporin therapy
- Human immunodeficiency virus-positive or Acquired Immunodeficiency Syndrome (AIDS)
- Hepatitis B or C virus-positive
|
aThese apply to anti-TNF agents only.
Recommended Pretreatment and Monitoring Investigations
| |
|
Pretreatmenta |
Monitoringa |
| Disease severity assessment |
|
|
|
Skin |
PASI
DLQI
|
Yes |
At 3 months, then every 6 months |
Joints (Where applicable) |
Follow recommended BSR guidelines for psoriatic arthritis |
Yes |
At 3 months, then every 6 months |
| General health (symptom enquiry and clinical examination) |
Infection
Demyelinationb
Heart failureb
Malignancy (including skin)
|
Yes |
At 3-6 month intervals |
| Assessment for latent tuberculosisb |
See Figure 1 of the original guideline document |
|
|
| Blood tests |
Full blood count |
Yes |
Efalizumab: monthly for the first 3 months, then every 3 months
Tumour necrosis factor blockers: at 3 months, then every 6 months
|
| Creatinine, urea and electrolytes, liver function tests |
Yes |
At 3 months, then every 6 months |
| Hepatitis B and C |
Yes |
- |
| Human immunodeficiency virus |
Consider testing in those at risk |
- |
| Autoantibodiesb (antinuclear antibodies, antidouble-stranded DNA antibodies) |
Yes |
- |
| Urine |
Urine analysis |
Yes |
At 3 months, then every 6 months |
| Radiology |
Chest X-ray |
Yes |
- |
PASI, Psoriasis Area and Severity Index; DLQI, Dermatology Life Quality Index; BSR, British Society for Rheumatology.
aAdditional assessment and monitoring may be required in patients on concomitant therapy or in certain clinical circumstances.
bApplies to tumour necrosis factor blockers only.
Monitoring and Assessment of Disease Response
Patients should be seen at 12 weeks to determine whether therapy should be continued, and thereafter at 3-6-monthly intervals. The need for monitoring biochemistry and haematology is less than that required for conventional drug therapies (see table above) with the exception of platelet counts for patients on efalizumab. However, regular review of the clinical status of the patient is essential to ensure early detection of adverse effects, particularly infection.
Adequate Response to Treatment
This is defined as a 50% or greater reduction in baseline PASI score (or percentage BSA where the PASI is not applicable) and a 5-point or greater improvement in DLQI within 3 months of initiation of treatment.
Where arthritis has determined eligibility for treatment, please refer to the BSR guideline for psoriatic arthritis for the definition of treatment response.
Withdrawal of Therapy
Therapy should be withdrawn after 3 months if there has not been at least a 50% improvement in baseline PASI score (or percentage BSA where the PASI is not applicable) and a 5-point or greater improvement in DLQI. Withdrawal of therapy is also indicated due to the development of a serious adverse event. Adverse events which may justify the withdrawal of treatment include the following: malignancy (excluding nonmelanoma skin cancer); severe drug-related toxicity; pregnancy (temporary withdrawal); severe intercurrent infection (temporary withdrawal); major surgical procedures (temporary withdrawal in accordance with updated BSR guidelines).
Definitions:
Strength of Recommendations
A At least one meta-analysis, systematic review, or randomized controlled trial (RCT) rated as 1++ , and directly applicable to the target population, or
A systematic review of RCTs or a body of evidence consisting principally of studies rated as 1+ , directly applicable to the target population and demonstrating overall consistency of results
Evidence drawn from a NICE technology appraisal
B A body of evidence including studies rated as 2++, directly applicable to the target population and demonstrating overall consistency of results, or
Extrapolated evidence from studies rated as 1++ or 1+
C A body of evidence including studies rated as 2+ , directly applicable to the target population and demonstrating overall consistency of results, or
Extrapolated evidence from studies rated as 2++
D Evidence level 3 or 4, or
Extrapolated evidence from studies rated as 2+ , or
Formal consensus
D (GPP) A good practice point (GPP) is a recommendation for best practice based on the experience of the guideline development group
Level of Evidence
The published studies selected from the search were assessed for their methodological rigour against a number of criteria as currently recommended by the National Institute for Health and Clinical Excellence (NICE) and the Scottish Intercollegiate Guidelines Network. The overall assessment of each study was graded using a code: '+ +', '+' or '-', based on the extent to which the potential biases have been minimized.
1++ High-quality meta-analyses, systematic reviews of randomized controlled trials (RCTs), or RCTs with a very low risk of bias
1+ Well-conducted meta-analyses, systematic reviews of RCTs, or RCTs with a low risk of bias
1- Meta-analyses, systematic reviews of RCTs, or RCTs with a high risk of bias*
2++ High-quality systematic reviews of case-control or cohort studies
High-quality case-control or cohort studies with a very low risk of confounding, bias or chance and a high probability that the relationship is causal
2+ Well-conducted case-control or cohort studies with a low risk of confounding, bias or chance and a moderate probability that the relationship is causal
2- Case-control or cohort studies with a high risk of confounding, bias or chance and a significant risk that the relationship is not causal*
3 Nonanalytical studies (e.g. case reports, case series)
4 Expert opinion, formal consensus RCT, randomized controlled trial
* Studies with a level of evidence '-' should not be used as a basis for making a recommendation.
