TNF-alpha inhibitors for ankylosing spondylitis and non-radiographic axial spondyloarthritis

Evidence-based recommendations on adalimumab (Humira), certolizumab pegol (Cimzia), etanercept (Enbrel), golimumab (Simponi) and infliximab (Remicade, Remsima, Inflectra). These drugs are for people with severe active ankylosing spondylitis or severe non-radiographic axial spondyloarthritis who have tried non-steroidal anti-inflammatory drugs (NSAIDs), but they have not worked.

# Recommendations
Adalimumab, certolizumab pegol, etanercept, golimumab and infliximab are recommended, within their marketing authorisations, as options for treating severe active ankylosing spondylitis in adults whose disease has responded inadequately to, or who cannot tolerate, nonsteroidal antiinflammatory drugs. Infliximab is recommended only if treatment is started with the least expensive infliximab product. People currently receiving infliximab should be able to continue treatment with the same infliximab product until they and their NHS clinician consider it appropriate to stop.
Adalimumab, certolizumab pegol and etanercept are recommended, within their marketing authorisations, as options for treating severe nonradiographic axial spondyloarthritis in adults whose disease has responded inadequately to, or who cannot tolerate, nonsteroidal antiinflammatory drugs.
The choice of treatment should be made after discussion between the clinician and the patient about the advantages and disadvantages of the treatments available. This may include considering associated conditions such as extraarticular manifestations. If more than 1 treatment is suitable, the least expensive (taking into account administration costs and patient access schemes) should be chosen.
The response to adalimumab, certolizumab pegol, etanercept, golimumab or infliximab treatment should be assessed 12 weeks after the start of treatment. Treatment should only be continued if there is clear evidence of response, defined as:
a reduction in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score to 50% of the pretreatment value or by 2 or more units and
a reduction in the spinal pain visual analogue scale (VAS) by 2 cm or more.
Treatment with another tumour necrosis factor (TNF) alpha inhibitor is recommended for people who cannot tolerate, or whose disease has not responded to, treatment with the first TNFalpha inhibitor, or whose disease has stopped responding after an initial response.
When using BASDAI and spinal pain VAS scores, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect the responses to the questionnaires, and make any adjustments they consider appropriate.# Clinical need and practice
Ankylosing spondylitis and nonradiographic axial spondyloarthritis are part of a group of clinically heterogeneous inflammatory rheumatologic diseases known as spondyloarthritis. Spondyloarthritis can be categorised as having either predominantly axial (sacroiliac joints or spine) or peripheral involvement. In people with axial spondyloarthritis, the predominant symptom is back pain with inflammation of the sacroiliac joints (sacroiliitis) or the spine, or both. The onset of symptoms typically occurs in the third decade of life. Damage is progressive and irreversible and there is increased risk of spinal fracture later in life. There may also be peripheral joint involvement or extraarticular manifestations such as uveitis, inflammatory bowel disease and psoriasis.
Disease is classified as ankylosing spondylitis if changes to the sacroiliac joints or the spine, or both, can be seen on Xray. These include erosions, sclerosis (thickening of the bone), and partial or total ankylosis (fusion of joints). The prevalence of ankylosing spondylitis is thought to range from 0.05% to 0.23% and it is about 3 times more common in men than in women.
Not everyone with symptoms of axial spondyloarthritis will have changes that can be seen on Xray. Disease is then classified as axial spondyloarthritis without radiographic evidence of ankylosing spondylitis (nonradiographic axial spondyloarthritis). Sacroiliitis or inflammation of the spine may be visible on MRI. Limited epidemiological data are available for nonradiographic axial spondyloarthritis, but it affects about equal numbers of men and women.
Conventional therapy for ankylosing spondylitis and nonradiographic axial spondyloarthritis includes nonsteroidal antiinflammatory drugs and physiotherapy. Tumour necrosis factor (TNF) alpha inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab and infliximab) are typically used when the disease has not responded adequately to conventional therapy.
In clinical trials of ankylosing spondylitis and nonradiographic axial spondyloarthritis, 3 key disease components are assessed: disease activity, physical function and structural damage. Several assessment tools have been developed to measure these:
Disease activity is most commonly assessed using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). BASDAI is a validated, composite index that records patients' responses to 6 questions relating to 5 major symptoms: fatigue, axial pain, peripheral pain, stiffness and enthesitis. Responses are recorded on 10 cm visual analogue scales (VAS). An instrument commonly used to assess spinal mobility is the Bath Ankylosing Spondylitis Metrology Index (BASMI). This uses clinical measurements such as the amount of movement achieved when the patient rotates their head (cervical rotation) or reaches towards the floor (lumbar side flexion).
Physical function is often assessed using the Bath Ankylosing Spondylitis Functional Index (BASFI). BASFI is a patientassessed, validated, composite index made up of 10 questions that address function and the patient's ability to manage their disease. As with BASDAI, responses are recorded on a 10 cm VAS.
Structural damage and disease progression in ankylosing spondylitis are usually evaluated by radiography, using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS).
Studies of the natural history of ankylosing spondylitis and nonradiographic axial spondyloarthritis show that disease activity (measured by BASDAI) is fairly stable over time and does not change. Physical function (assessed by BASFI) does deteriorate ('progress') over time, but the rate of progression is not constant or predictable. Changes in BASFI scores over time may be partially driven by progression of spinal damage as assessed by mSASSS.
The Assessment of Spondyloarthritis International Society (ASAS) has developed a set of response criteria that are commonly used in ankylosing spondylitis clinical trials. The ASAS criteria relate to improvement across a set of 4 domains:
patient global assessment (measured on a 10 cm VAS)
physical function (measured using BASFI)
inflammation (using the mean of 2 questions from BASDAI relating to severity and duration of morning stiffness)
spinal pain (measured on a 10 cm VAS).An ASAS 20 response (a common primary efficacy outcome in clinical trials) is defined as an improvement of more than 20% and an absolute change of 1 or more points on the 010 cm VAS in at least 3 of the 4 domains. In the fourth domain, there must be no worsening by a similar amount. Other definitions of ASAS response (ASAS 40, 50 and 70, based on improvements of 40%, 50% and 70% respectively) and an improvement of 50% or more in BASDAI score (BASDAI 50) are also used to measure outcomes in clinical studies.# The technologies
Adalimumab (Humira, AbbVie), certolizumab pegol (Cimzia, UCB Pharma), etanercept (Enbrel, Pfizer), golimumab (Simponi, Merck Sharp & Dohme), and infliximab (Remicade, Merck Sharp & Dohme; Inflectra, Hospira; Remsima,Napp) inhibit the proinflammatory cytokine, tumour necrosis factor (TNF) alpha. TNFalpha inhibitors may modify the inflammatory process of the disease. Adalimumab, certolizumab pegol, golimumab and infliximab are monoclonal antibodies, and etanercept is a recombinant human TNFreceptor fusion protein.
Adalimumab, etanercept, golimumab and infliximab have marketing authorisations in the UK for the treatment of adults with severe active ankylosing spondylitis that has responded inadequately to conventional therapy. Certolizumab pegol has a marketing authorisation in the UK for the treatment of 'adults with severe active ankylosing spondylitis who have had an inadequate response to, or are intolerant to, nonsteroidal antiinflammatory drugs (NSAIDs)'.
Adalimumab, certolizumab pegol and etanercept are also licensed for the treatment of adults with severe axial spondyloarthritis without radiographic evidence of ankylosing spondylitis (nonradiographic axial spondyloarthritis) but with objective signs of inflammation by elevated Creactive protein and/or magnetic resonance imaging, whose disease has responded inadequately to, or who cannot tolerate, NSAIDs. Golimumab has a marketing authorisation for nonradiographic axial spondyloarthritis. However, regulatory approval was received at a late stage in the appraisal process so golimumab was not included for this indication. Infliximab does not currently have a marketing authorisation in the UK for nonradiographic axial spondyloarthritis.

# Adalimumab
Adalimumab is administered by subcutaneous injection. The recommended dose regimen for patients with ankylosing spondylitis, and for patients with nonradiographic axial spondyloarthritis, is 40 mg (given as 1 injection) every other week. The summary of product characteristics recommends that continued adalimumab therapy should be carefully reconsidered in patients whose disease does not respond within 12 weeks after starting treatment.
The summary of product characteristics lists the following adverse reactions for adalimumab: infections (such as nasopharyngitis, upper respiratory tract infection and sinusitis), injection site reactions (erythema, itching, haemorrhage, pain or swelling), headache, musculoskeletal pain, hepatitis B reactivation, various malignancies and serious haematological, neurological and autoimmune reactions. For full details of adverse reactions and contraindications, see the summary of product characteristics.
The price of adalimumab is 352.14 for a 40 mg prefilled pen or prefilled syringe, or a 40 mg/0.8 ml vial (excluding VAT; 'British National Formulary'  edition 68). The annual cost of treatment with adalimumab is estimated at 9156, assuming the patient has 40 mg every other week (see section 3.4). Costs may vary in different settings because of negotiated procurement discounts.

# Certolizumab pegol
Certolizumab pegol is administered by subcutaneous injection. The recommended loading dosage for patients with ankylosing spondylitis, and for patients with nonradiographic axial spondyloarthritis, is 400 mg (given as 2 injections of 200 mg each) at weeks 0, 2 and 4. The recommended maintenance dose regimen is 200 mg every other week or 400 mg every 4 weeks. The summary of product characteristics recommends that continued certolizumab pegol therapy should be carefully reconsidered if there is no evidence of therapeutic benefit within 12 weeks of starting treatment.
The summary of product characteristics lists the following adverse reactions for certolizumab pegol: infections (including sepsis, pneumonia, tuberculosis, invasive fungal and opportunistic infections), blood and lymphatic system malignancies (including lymphoma and leukaemia), lupuslike syndrome, injection site reactions (erythema, itching, haematoma, pain or swelling), and hepatitis B reactivation. For full details of adverse reactions and contraindications, see the summary of product characteristics.
The price of certolizumab pegol is 357.50 for a 200mg prefilled syringe (excluding VAT; BNF edition 68). UCB Pharma has agreed a patient access scheme with the Department of Health. UCB Pharma will provide the first 12 weeks of certolizumab pegol free of charge, which is equivalent to 10 vials. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. Assuming the recommended dosage is followed (see section 3.7), the annual cost for first year of treatment with certolizumab pegol is estimated at 10,368 (or with the patient access scheme, 6793). Costs may vary in different settings because of negotiated procurement discounts.

# Etanercept
Etanercept is administered by subcutaneous injection. The recommended dosage for patients with ankylosing spondylitis, and for patients with nonradiographic axial spondyloarthritis, is 25 mg administered twice weekly or 50 mg administered once weekly. The summary of product characteristics recommends that continued etanercept therapy should be carefully reconsidered in patients whose disease does not respond within 12 weeks of starting treatment.
The summary of product characteristics lists the following adverse reactions for etanercept: infections (including upper respiratory infections, bronchitis, bladder infections and skin infections, as well as serious infections such as sepsis), injection site reactions (such as pain, swelling, itching, reddening and bleeding at the puncture site), allergic reactions, development of autoantibodies, itching, fever, various malignancies and serious haematological, neurological and autoimmune reactions. For full details of adverse reactions and contraindications, see the summary of product characteristics.
The price of etanercept is 89.38 for a 25mg prefilled syringe or a 25mg vial containing powder for reconstitution (with solvent), and 178.75 for a 50mg prefilled pen or prefilled syringe (excluding VAT; BNF edition 68). The annual cost of treatment with etanercept, using either twice weekly or once weekly dosage frequency (see section 3.10), is estimated at 9296. Costs may vary in different settings because of negotiated procurement discounts.

# Golimumab
Golimumab is administered by subcutaneous injection. The recommended dose regimen for patients with ankylosing spondylitis is 50 mg once a month, on the same date each month. The summary of product characteristics recommends that continued golimumab therapy should be carefully reconsidered if there is no evidence of therapeutic benefit within 1214 weeks of starting treatment (that is, after 34 doses). For patients with a body weight greater than 100 kg whose disease does not respond adequately after 4 doses (50 mg each), the summary of product characteristics states that increasing the dosage of golimumab to 100 mg once a month may be considered. If there is still no evidence of therapeutic benefit after 34 additional doses of 100 mg, continued golimumab therapy should be carefully reconsidered.
The summary of product characteristics lists the following adverse reactions for golimumab: infections (including sepsis, pneumonia, tuberculosis, and invasive fungal and opportunistic infections), demyelinating disorders, lymphoma, hepatitis B reactivation, congestive heart failure, autoimmune processes (lupuslike syndrome) and haematological reactions. For full details of adverse reactions and contraindications, see the summary of product characteristics.
The price of golimumab is 762.97 for a 50mg prefilled pen or prefilled syringe and 1525.94 for a 100mg prefilled pen (excluding VAT; BNF edition 68). Merck Sharp & Dohme has agreed a patient access scheme with the Department of Health. This will make the 100mg dose of golimumab available to the NHS at the same cost as the 50mg dose. The Department of Health considered that this patient access scheme does not constitute an excessive administrative burden on the NHS. Assuming the patient has 50 mg every month, the annual cost of treatment with golimumab is estimated at 9156. Because of the patient access scheme, this cost would remain the same for patients with a body weight greater than 100 kg whose disease does not respond adequately to the 50 mg per month dosage and who subsequently have monthly doses of 100 mg (see section 3.13).

# Infliximab
Infliximab is administered by intravenous infusion. The recommended dosage for patients with ankylosing spondylitis is a 5 mg/kg infusion at weeks 0, 2 and 6, then every 68 weeks. The summary of product characteristics states that if there is no response by 6 weeks (that is, after 2 doses), no additional treatment with infliximab should be given.
The summary of product characteristics lists the following adverse reactions for infliximab: infections (including upper respiratory tract infections, sepsis, opportunistic infections and tuberculosis), hepatitis B reactivation, congestive heart failure, serum sickness (delayed hypersensitivity reactions), haematological reactions, systemic lupus erythematosus/lupuslike syndrome, demyelinating disorders, hepatobiliary events, lymphoma, hepatosplenic Tcell lymphoma, and serious infusion reactions. For full details of adverse reactions and contraindications, see the summary of product characteristics.
The NHS list price of the infliximab originator (Remicade) is 419.62 for a 100mg vial containing powder for reconstitution (excluding VAT; BNF edition 68). For a patient with a body weight of 73 kg, the annual cost for first year of treatment with infliximab therapy (including 3 induction doses) is estimated at between 16,785 and 13,428 (depending on whether the maintenance infusions are repeated every 6 or 8 weeks).
Biosimilar versions of infliximab (Inflectra, Hospira; Remsima, Celltrion/Napp) have a marketing authorisation in the UK for the same indications. The therapeutic indications, dosage and method of administration for Inflectra and Remsima are identical to those for Remicade. The NHS list price of Inflectra and Remsima is 377.66 for a 100 mg vial. For a patient with a body weight of 73 kg, the annual cost for first year of treatment with Inflectra or Remsima therapy is estimated at between 15,106 and 12,085 (depending on whether the maintenance infusions are repeated every 6 or 8 weeks). The contraindications, adverse reactions and administration schedule of the biosimilars are the same as for infliximab (see sections 3.16 and 3.17), but both biosimilars are subject to additional monitoring in line with standard European Medicines Agency recommendations.
Infliximab is available to the NHS at contract prices negotiated through the Commercial Medicines Unit. These prices are lower than the list prices but are commercial in confidence.# Committee discussion
The Appraisal Committee (section 7) considered evidence from a number of sources (section 8).

# Clinical effectiveness
The Assessment Group conducted a systematic review and identified 24 relevant randomised controlled trials (RCTs): 19 recruited people with ankylosing spondylitis, 4 recruited people with axial spondyloarthritis without radiographic evidence of ankylosing spondylitis (nonradiographic axial spondyloarthritis), and 1 recruited both populations. All except 2 of the trials were placebocontrolled. Of the 24 RCTs, 17 had openlabel extension studies, with 11 studies having a total duration of at least a year.
Patients whose disease responded inadequately to, or who could not tolerate, nonsteroidal antiinflammatory drugs (NSAIDs) were included in 12 RCTs. However, in 7 of these, between 80% and 100% of patients had NSAIDs during the trial. In the trials that did not require failure of NSAIDs as an inclusion criterion, a similar proportion of patients had NSAIDs during the trial. A baseline Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of greater than or equal to 4 was used as an inclusion criterion in most trials; however, the Assessment Group commented that average BASDAI scores were high, mostly between 5.5 and 6.6 (on a scale from 010, 10 being most severe). Bath Ankylosing Spondylitis Functional Index (BASFI) scores and the level of Creactive protein at baseline also varied across the RCTs, and so did the thresholds used to define elevated Creactive protein in the trials in nonradiographic axial spondyloarthritis. The Assessment Group noted that higher Creactive protein levels are associated with an increased likelihood of an improvement of 50% or more in BASDAI score (BASDAI 50) response.
Of the 20 RCTs in ankylosing spondylitis, 4 were for adalimumab, 1 for certolizumab pegol, 7 for etanercept, 3 for golimumab and 5 for infliximab. Most were conducted in Europe or North America; 4 were conducted in China. Among patients in the included RCTs, 65% to 97% were male, the average age ranged from 27 years to 48 years, and the average duration of disease was 6.8 years to 19.0 years.
Of the 5 RCTs in nonradiographic axial spondyloarthritis, 2 were for adalimumab, 1 for certolizumab pegol and 1 for etanercept. The Assessment Group also included a trial for infliximab, even though infliximab does not have a marketing authorisation in the UK for nonradiographic axial spondyloarthritis. The Assessment Group stated that this was to inform the relative efficacy of tumour necrosis factor (TNF) alpha inhibitors in this indication because the dose used in the identified trial was the same as that licensed for ankylosing spondylitis. Three RCTs were multicentre conducted worldwide, 1 was conducted in Germany and 1 was UK based. Among patients in the included RCTs, 45% to 75% were male, the average age ranged from 28.2 years to 38.3 years, and the average duration of disease was 2.4 years to 17.2 years. The Assessment Group noted substantial heterogeneity in the baseline characteristics across the trials, such as variations in Creactive protein levels and the proportion of patients with MRI changes.
The Assessment Group synthesised the data on clinical effectiveness using a Bayesian metaanalysis. For both indications, it included RCTs reporting results between 10 and 16 weeks after starting treatment. The Assessment Group excluded 2 studies because they were redundant in a class effect model (a study by Giardina et al.) or did not include any of the relevant comparators needed for metaanalysis (PLANETAS). The Assessment Group analysed the TNFalpha inhibitors both individually and as a group, assuming a class effect. The Assessment Group chose to use a fixedeffect model for both analyses (this assumes that all the studies estimated exactly the same treatment effect and that the variability between individual study results occurred by chance). Peripheral symptoms were not included as outcomes in the metaanalysis (except for enthesitis) because few data were available.

## Ankylosing spondylitis
The results of the metaanalysis showed a consistent beneficial effect across all 5 TNFalpha inhibitors at 1016 weeks, compared with placebo. The pooled relative risk (RR) of an Assessment of Spondyloarthritis International Society (ASAS) of 20 (a common primary efficacy outcome in clinical trials) response ranged from 1.80 (certolizumab pegol) to 2.45 (infliximab). For an ASAS 40 (based on improvements of 40% response), the RRs ranged from 2.53 (certolizumab pegol) to 3.42 (adalimumab). For BASDAI 50 the RRs of a response were 3.16 with adalimumab, 3.17 with etanercept, 3.57 with golimumab, 3.60 with certolizumab pegol, and 4.86 with infliximab. The additional reduction in BASDAI and BASFI scores achieved with adalimumab, certolizumab pegol, etanercept and infliximab compared with placebo were all statistically significant and clinically important. Additional reductions in BASDAI scores compared with placebo were 1.46 units with certolizumab pegol, 1.55 units with adalimumab, 1.75 units with etanercept and 2.28 units with infliximab. Additional BASFI reductions were 1.1 units with certolizumab pegol, 1.25 units with adalimumab, 1.43 units with etanercept, 1.45 units with golimumab and 2.16 units with infliximab.
When TNFalpha inhibitors were considered as a class, with 1 treatment effect, the metaanalysis showed statistically significant improvements compared with placebo at 1016 weeks for all outcomes (table 1). The Assessment Group reported little evidence of statistical heterogeneity for the key outcomes (ASAS outcomes, BASFI, BASDAI and BASDAI 50) but substantial heterogeneity for other outcomes.

## Table 1 Estimated class effect of TNFalpha inhibitors compared with placebo in ankylosing spondylitis: metaanalysis of outcomes at 1016 weeks (main analysis)
Outcome
% CI
ASAS 20 (RR)
to 2.43
ASAS 40 (RR)
to 3.76
BASDAI 50 (RR)
to 4.16
BASDAI (additional change from baseline)1
1.88 to 1.43
BASFI (additional change from baseline)1
1.59 to 1.18
BASMI (additional change from baseline)1
0.36 to 0.18
SF36 PCS (additional change from baseline)2
to 5.21
SF36 MCS (additional change from baseline)2
to 3.72
MASES
0.89 to 0.19
Negative changes in BASDAI, BASFI and BASMI represent improvement (that is, a health benefit).
Positive changes in SF36 represent improvement (that is, a health benefit).
Abbreviations: ASAS, Assessment in Spondyloarthritis International Society; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; BASFI, Bath Ankylosing Spondylitis Functional Index; BASMI, Bath Ankylosing Spondylitis Metrology Index; CI, confidence interval; MASES, Maastricht Ankylosing Spondylitis Enthesitis Score; RR, relative risk; SF36 MCS, Short Form 36 mental component summary; SF36 PCS, Short Form 36 physical component summary.
The metaanalysis showed no statistically significant differences between the 5 TNFalpha inhibitors for efficacy outcomes at 1016 weeks. The Assessment Group noted that the metaanalysis results for infliximab at 1016 weeks appeared slightly better than results for the other TNFalpha inhibitors (although the credible intervals are wide). It suggested that this apparent superiority could be because of infliximab producing a more rapid clinical improvement than the other treatments (but having similar effectiveness in the long term). This conclusion was based on results from a trial by Giardina et al. that compared infliximab with etanercept. In the Giardina et al. trial, the BASDAI and BASFI outcomes at week 12 favoured treatment with infliximab, but by week 48 the results for infliximab and etanercept were almost identical.
Analysis of longterm efficacy results from openlabel extension studies showed that, after about 2 years of treatment, ankylosing spondylitis continues to respond well to TNFalpha inhibitors in around half of people with the disease. Mean changes from baseline for BASDAI, BASFI and Bath Ankylosing Spondylitis Metrology Index (BASMI, if reported) were generally maintained at clinically meaningful levels during longterm followup. However, the Assessment Group stated that the openlabel extension studies produced less reliable data than the RCTs. Results may not reflect clinical practice because some people continued treatment even though their disease did not respond to therapy (contrary to the UK marketing authorisations). Also, some people took the higher dose of golimumab (100 mg) even though their body weight was less than 100 kg (the summary of product characteristics recommends that increasing the dose to 100 mg once a month should only be considered in patients with body weight greater than 100 kg). The Assessment Group also suggested that differences in outcomes may have been because of differences in followup protocols rather than true treatment effects. The Assessment Group concluded that the longterm benefit of TNFalpha inhibitors appears similar across treatments.
The impact of TNFalpha inhibitors on spinal damage (that is, radiographic progression assessed by the modified Stoke Ankylosing Spondylitis Spinal Score ) is unclear. There are some data that suggest a benefit from TNFalpha inhibitors after about 4 years of treatment. The Assessment Group suggested that the uncertainty may be because of a lack of longterm followup data and the insensitivity of Xrays as a tool for evaluating disease progression in ankylosing spondylitis.
The Assessment Group used results from 11 patient registry studies (identified in a separate screening of the systematic review results) to assess the efficacy of sequential treatment with TNFalpha inhibitors in ankylosing spondylitis. Most of the studies provided data on infliximab, etanercept and adalimumab; less evidence was available for certolizumab pegol and golimumab. The proportion of patients who continued to take their first TNFalpha inhibitor was around 7080% after 1 year, 6575% after 2 years, 70% after 3 years and 55% after 5 years. Only 3 studies provided efficacy results for people who had switched to a second or third TNFalpha inhibitor; results showed about a 30% proportional reduction (10% absolute reduction) in the number of people with a BASDAI 50 response to sequential TNFalpha inhibitors (table 2). In addition, improvements in BASDAI and BASFI reported after a second and third TNFalpha inhibitor were not as good the improvements achieved with the first TNFalpha inhibitor, as seen in the largest registry (DANBIO; table 2). Despite a reduction in efficacy with sequential treatment, the Assessment Group highlighted that, on average, people having a third TNFalpha inhibitor continued treatment for as long as people having their second (table 2).

## Table 2 Efficacy of sequential TNFalpha inhibitors in ankylosing spondylitis, based on results from the DANBIO registry
First TNFalpha inhibitor (n=1436)
Second TNFalpha inhibitor (n=432)
Third TNFalpha inhibitor (n=137)
BASDAI 50 at 3 months
BASDAI: median change after 3 months of treatment
BASFI: median change after 3 months of treatment
Median time to drug discontinuation (95% CI)
years(2.6 to 3.7)
years(1.0 to 2.2)
years(0.9 to 2.7)
Abbreviations: BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; BASFI, Bath Ankylosing Spondylitis Functional Index; CI, confidence interval; TNF, tumour necrosis factor.
The Assessment Group concluded that, despite a decrease in response rates, sequential treatment with TNFalpha inhibitors can be beneficial for people with ankylosing spondylitis.

## Nonradiographic axial spondyloarthritis
Outcomes for 3 of the 4 treatments in the metaanalysis (certolizumab pegol, etanercept and infliximab) were based on results from single trials of each drug. The RRs, compared with placebo, of an ASAS 20 response were similar for adalimumab, certolizumab pegol and etanercept (ASAS 20 was not reported in the trial of infliximab), ranging from 1.46 to 1.92. The RRs of a BASDAI 50 response (compared with placebo) was 1.92 with etanercept, 2.52 with adalimumab and 2.80 with certolizumab pegol. A greater variation in results was seen in the ASAS 40 response and reductions in BASDAI and BASFI. For ASAS 40 the RRs ranged from 2.07 (etanercept) to 3.63 (infliximab). Additional reductions in BASDAI compared with placebo were 0.70 units with etanercept, 1.23 with adalimumab, 1.85 with certolizumab pegol, and 2.67 units with infliximab. Additional BASFI reductions were 0.60 units with etanercept, 0.90 units with adalimumab, 1.90 units with certolizumab pegol and 2.24 units with infliximab. Infliximab appeared to be the most effective, but this trial was judged to have a high risk of bias.
When TNFalpha inhibitors were considered as a class, with 1 treatment effect, the metaanalysis showed statistically significant improvements compared with placebo at 1016 weeks for all outcomes (table 3). The Assessment Group reported that statistical heterogeneity was apparent in the analyses, and therefore the reliability of the pooled estimates, and their true relevance to people seen in clinical practice, is questionable. Estimates of the class effect of TNFalpha inhibitors were consistently smaller in nonradiographic axial spondyloarthritis compared with those seen in ankylosing spondylitis trials (most noticeably for BASFI and BASDAI 50).

## Table 3 Estimated class effect of TNFalpha inhibitors compared with placebo in nonradiographic axial spondyloarthritis: metaanalysis of outcomes at 1016 weeks (main analysis)
Outcome
% CI
ASAS 20 (RR)
to 2.04
ASAS 40 (RR)
to 3.62
BASDAI 50 (RR)
to 3.10
BASDAI (additional reduction from baseline)
1.74 to 0.90
BASFI (additional reduction from baseline)
1.34 to 0.64
BASMI (additional reduction from baseline)
0.32 to 0.02
SF36 PCS (additional reduction from baseline)
to 5.81
SF36 MCS (additional reduction from baseline)
to 4.62
Abbreviations: ASAS, Assessment in Spondyloarthritis international Society; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; BASFI, Bath Ankylosing Spondylitis Functional Index; BASMI, Bath Ankylosing Spondylitis Metrology Index; CI, confidence interval; RR, relative risk; SF36 MCS, Short Form 36 mental component summary; SF36 PCS Short Form 36 physical component summary.
The Assessment Group did indirect comparisons of the TNFalpha inhibitors. There were no statistically significant differences between the 5 TNFalpha inhibitors for efficacy outcomes at 1016 weeks.
Analysis of longterm efficacy results from openlabel extension studies showed that, after 1 year of treatment, nonradiographic axial spondyloarthritis continues to respond well to TNFalpha inhibitors in around half of people with the disease. This level of response is maintained up to 2 years with certolizumab pegol and up to 3 years with adalimumab. Mean change from baseline for BASDAI, BASFI and BASMI (if reported) were generally maintained at clinically meaningful levels during longterm followup (data available up to 1 year). However, the openlabel extension studies produced less reliable data than the RCTs. Results may not reflect clinical practice, because some people continued treatment even though their disease did not respond to therapy (contrary to the UK marketing authorisations). The Assessment Group concluded that the longterm benefits of TNFalpha inhibitors appear similar across treatments.
The Assessment Group did not identify any efficacy data for people with nonradiographic axial spondyloarthritis who had switched to a second or third TNFalpha inhibitor.

# Adverse events
The identified RCTs did not allow for a meaningful analysis of adverse events because of limitations in the number and size of RCTs and the short duration of the placebocontrolled periods. The Assessment Group evaluated adverse event rates from a Cochrane Review and from network metaanalysis of 9 biological interventions (abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab and tocilizumab) in adults with any disease, except HIV/AIDS. The Cochrane Review included 160 RCTs (including 48,676 people); 115 of these RCTs (72%) included the TNFalpha inhibitors under consideration in this appraisal.
Analysis of the Cochrane Review showed that, as a group, TNFalpha inhibitors are associated with significantly higher rates of serious infections, tuberculosis reactivation, nonmelanoma skin cancer, total adverse events, and withdrawals because of adverse events, when compared with control treatments in the shortterm (median treatment duration of the RCTs was 6 months).
When individual TNFalpha inhibitors were analysed separately, only infliximab and certolizumab pegol were associated with statistically significant increases in adverse events compared with control treatments:
infliximab was associated with higher rates of total adverse events (number needed to harm  13, 95% credible interval  8 to 505) and withdrawals because of adverse events (NNH 10, 95% CrI 5 to 30)
certolizumab pegol was associated with higher rates of serious infections (NNH 12, 95% CrI 4 to 79) and serious adverse events (NNH 18, 95% CrI 9 to 162).
Cancer risk was not analysed as part of the Cochrane Review. Because TNFalpha inhibitors are known to have a possible association with cancer, the Assessment Group identified an individual patientdata metaanalysis (including 22,904 people from 74 RCTs) that assessed the cancer risk associated with 3 of the TNFalpha inhibitors under consideration in this appraisal (adalimumab, etanercept and infliximab). When considering the class effect of the 3 TNFalpha inhibitors, there was no increase in risk of cancers excluding nonmelanoma skin cancer (RR 0.99, 95% confidence interval  0.61 to 1.68). However TNFalpha inhibitors were associated with a doubling in the risk of nonmelanoma skin cancer (RR 2.02, 95% CI 1.11 to 3.95).

# Evidence from patient experts
Patient experts discussed the 2 conditions together, reporting that the key symptom is inflammatory back pain which becomes increasingly severe over time. Up to 25% of people with ankylosing spondylitis or nonradiographic axial spondyloarthritis eventually develop complete fusion of the spine, which leads to substantial disability. Patient experts noted that, because the conditions present at an early age when people are beginning their career (average age of onset is 24 years), disease progression leads to substantial loss in work productivity. Onethird of people give up work before normal retirement age and another 15% reduce or change their work because of their disease. Being unable to work has important consequences both for the individual and for their family; people with ankylosing spondylitis or nonradiographic axial spondyloarthritis are more likely to divorce or to never marry and women are less likely to have children. Many people with the conditions report depression and fatigue. Patient experts reported that, in addition to local spinal symptoms, 50% of people suffer from associated disorders elsewhere. For example, 40% experience eye inflammation, 16% develop psoriasis and 10% have inflammatory bowel disease. Patient experts also highlighted the issue of underdiagnosis  symptoms are often present for 710 years before a diagnosis is made.
Comments from patient experts indicated the outcome most important to people with axial spondyloarthritis was the prevention of further damage to their spine and joints. A reduction in pain and fatigue was also important. The patient experts stated that people having TNFalpha inhibitors have reported substantial improvements in pain and stiffness, leading to improvements in mobility and an improved quality of life. People reported that they were able to independently manage activities of daily living that were previously problematic. However, patient experts estimated that 2 in 10 cases of axial spondyloarthritis do not respond to treatment with a TNFalpha inhibitor. Based on previous NICE guidance, these people would not be offered an alternative TNFalpha inhibitor. This knowledge leads to high levels of anxiety in people with axial spondyloarthritis. The option to switch to a second TNFalpha inhibitor would reduce fears and anxiety. There is also anecdotal evidence suggesting that a second or third TNFalpha inhibitor can be clinically effective if the first has failed.
The patient experts reported that when people were asked about infliximab specifically, some people preferred its mode of administration (an infusion administered by a healthcare professional) to the method of selfinjection. This might benefit people with memory problems, learning disabilities, dexterity problems, or a fear of needles. However, some people were worried about the potential for postponed appointments (leading to a return of symptoms) and the need to take time off work and the need to travel for treatment with infliximab.

# Cost effectiveness

## Published evidence
The Assessment Group's systematic review of costeffectiveness evidence identified 5 published economic evaluations of TNFalpha inhibitors in patients with ankylosing spondylitis. No published economic evaluations were identified for patients with nonradiographic axial spondyloarthritis. The Assessment Group considered that the published models lacked evidencebased justifications for parameter estimates and structural assumptions.

## Company submissions
For ankylosing spondylitis, the companies compared the 5 TNFalpha inhibitors that have a marketing authorisation for this indication (adalimumab, certolizumab pegol, etanercept, golimumab and infliximab) with each other, and with conventional care. For nonradiographic axial spondyloarthritis, the companies compared the 3 TNFalpha inhibitors that have a marketing authorisation in this indication (adalimumab, certolizumab pegol and etanercept) with each other and with conventional therapy (except for AbbVie, which did not include etanercept in its model). All evaluations adopted an NHS perspective. Costs and benefits in all cases were discounted at 3.5%.
The companies used a lifetime horizon for their models, except AbbVie (adalimumab) which used a 40year time horizon. Based on recommendations in NICE's technology appraisal guidance on adalimumab, etanercept and infliximab for ankylosing spondylitis, all models included response criteria to decide whether TNFalpha inhibitors were continued or stopped. The criteria were ASAS 20, ASAS 40 or BASDAI 50 at week 12, except for UCB Pharma which used response criteria at week 24, in its basecase model for the ankylosing spondylitis population. In common with previously published models, the models were based on the estimation of BASDAI and BASFI scores over time. All models assumed that, after initial improvements in BASDAI for people whose disease responds to treatment, BASDAI scores remain relatively constant over the longer term. However, there were differences in assumptions about longterm disease progression (that is, changes in physical function measured by BASFI) and the rebound effect after treatment withdrawal (in patients whose disease initially responded but then stopped responding to therapy). The models assumed 1 of 2 scenarios; 'optimistic' or 'pessimistic'. The optimistic scenario assumed an ongoing benefit of TNFalpha inhibitors after withdrawal (known as 'rebound equal to gain' or 'rebound to baseline'). In this scenario, physical function (measured by BASFI) deteriorates ('rebounds') to the patient's baseline level. The pessimistic scenario assumed a greater deterioration in physical function after treatment withdrawal, to the level that it would have been if the disease had not initially responded to therapy (known as 'rebound to natural history' or 'rebound to conventional care'). In both scenarios, the subsequent trajectory of disease progression after rebound (measured by BASFI) mirrors the natural history of the disease. Differences in assumptions are presented in table 4 and table 5, along with other key structural assumptions.

## Table 4 Model structure and key assumptions: ankylosing spondylitis
Parameter
Infliximab, Golimumab
(MSD)
Adalimumab
(AbbVie)
Certolizumab pegol
(UCB Pharma)
Etanercept
(Pfizer)
Model type
Decision tree followed by Markov model
Markov model
Decision tree followed by Markov model
Patientlevel simulation model
Response criteria (12 or 24 weeks)
BASDAI 50 response
ASAS 20 response
ASAS 20 response
BASDAI 50 response
Response criteria justification
GORAISE outcome
ATLAS primary endpoint
RAPIDaxSpA primary endpoint
NICE definition of response (TA143)
Annual rate of withdrawal (longterm)
% (GORAISE)*
<15.0% on treatment at year 40(ATLAS)*
%(NICE TA143)*
% for etanercept
BASFI progression: disease responds to TNFalpha inhibitor 'responders'
Constant after week 108; 0.035 after week 256
Constant after week 260
Constant after week 24
Constant after week 48
BASFI progression: TNFalpha inhibitor 'nonresponders'
BASFI progression: Conventional care
after week 24
after week 12
Rebound assumption
Rebound to baseline(6 months)
Rebound to baseline(immediately)
Rebound to conventional therapy(6 months)
Rebound to baseline(6 months)
Abbreviations: ASAS, Assessment in Spondyloarthritis international Society; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; BASFI, Bath Ankylosing Spondylitis Functional Index; MSD, Merck Sharp & Dohme; TA, technology appraisal; TNF, tumour necrosis factor.
*Applied to all TNFalpha inhibitors in the model.

## Table 5 Model structure and key assumptions: nonradiographic axial spondyloarthritis
Parameter
Adalimumab
(AbbVie)
Certolizumab pegol
(UCB Pharma)
Etanercept
(Pfizer)
Model type
Markov model
Decision tree followed by Markov model
Patientlevel simulation model
Response criteria (12 or 24 weeks)
ASAS 40 response
ASAS 20 response
BASDAI 50 response
Response criteria justification
ABILITY1 primary endpoint
RAPIDaxSpA primary endpoint
NICE definition of response (TA143)
Annual rate of withdrawal (longterm)
<10% on treatment at year 40 (ATLAS)
%(NICE technology appraisal guidance on adalimumab, etanercept and infliximab for ankylosing spondylitis)
% for etanercept
BASFI progression: TNFalpha inhibitor 'responders'
Constant after week 140
Constant after week 12
Constant after week 48
BASFI progression: TNFalpha inhibitor 'nonresponders'
(ABILITY1 study)
(Kobelt 2007)
Constant: 0.070
(Kobelt 2007)
BASFI progression: Conventional care
after week 12
Rebound assumption
Rebound to baseline(immediately)
Rebound to conventional therapy(6 months)
Rebound to baseline(6 months)
Abbreviations: ASAS, Assessment in Spondyloarthritis International Society; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; BASFI, Bath Ankylosing Spondylitis Functional Index; TA, technology appraisal; TNF, tumour necrosis factor.

## Comparison of company models
A comparison of the basecase incremental costeffectiveness ratio (ICER) estimates compared with conventional therapy submitted by each company is provided in table 6 (ankylosing spondylitis) and table 7 (nonradiographic axial spondyloarthritis).

## Table 6 Ankylosing spondylitis: comparisons of company ICER estimates ( per qualityadjusted life year  gained) compared with conventional therapy
AbbVie (adalimumab)
UCB Pharma
(certolizumab pegol)
Pfizer (etanercept)
MSD (golimumab, infliximab)
Conventional care
Adalimumab
Certolizumab pegol
Etanercept
Golimumab
Infliximab
Abbreviations: MSD, Merck Sharp & Dohme.
Based on list price for certolizumab pegol.
Based on patient access scheme for certolizumab pegol.

## Table 7 Nonradiographic axial spondyloarthritis: comparisons of company ICER estimates ( per qualityadjusted life year  gained) compared with conventional therapy
AbbVie (adalimumab)
UCB Pharma
(certolizumab pegol)
Pfizer (etanercept)
Conventional care
Adalimumab
Certolizumab pegol
Etanercept
Not Assessed
Based on list price for certolizumab pegol.
Based on patient access scheme for certolizumab pegol.
The Assessment Group commented that, in general, the companies submitted good quality models. Despite the different model structures and assumptions used across the company submissions, similar ICERs were reported for each of the TNFalpha inhibitors compared with conventional care in ankylosing spondylitis. There were greater differences between company submissions in the ICERs reported for nonradiographic axial spondyloarthritis'. The Assessment Group suggested that the variation in ICER estimates reported across the submissions (both within and between populations) might be explained by differences in the following parameters and underlying assumptions:
the response criteria and time when response was measured
the magnitude of improvement in outcomes and the time when these were assumed to 'level off' (that is, plateau)
the underlying rate of disease progression, measured by change in BASFI scores, without treatment ('natural history' of disease) and the impact of TNFalpha inhibitors on this rate
disease progression after treatment stopped (the 'rebound' assumption) and the timing of this.
Although there was consistency across the companies' ICER estimates for the ankylosing spondylitis population, the Assessment Group considered them (and the ICERs reported for people with nonradiographic axial spondyloarthritis) to be both speculative and uncertain. The uncertainty is because of unresolved issues with parameter estimates and structural assumptions used in published costeffectiveness evaluations (highlighted in the Assessment Group's review). For example, several company models used data from openlabel extension studies without any formal consideration of the selection bias inherent in these studies. The Assessment Group was also concerned about the appropriateness of the sources of natural history data, and subsequent assumptions made about the trajectories of BASDAI and BASFI progression. Related to this are assumptions about the effect of TNFalpha inhibitors on disease progression, and a lack of consensus on whether TNFalpha inhibitors are primarily symptomcontrol treatments or whether they are also disease modifiers. The Assessment Group noted that identical assumptions for the impact of treatment on progression were applied across both populations, without consideration of how generalisable these assumptions were. Finally, the Assessment Group suggested that BASDAI and BASFI may not be the most appropriate conceptual basis for modelling progression of these diseases. But, in the absence of data linking other disease measures to costs and utilities, it concluded that there were no other options.

## Sequential treatment
The Assessment Group did not believe that the company submissions provided a robust basis for informing the cost effectiveness of intermittent and sequential use of TNFalpha inhibitors. Only Pfizer submitted evidence for the cost effectiveness of sequential treatment. In its basecase analysis, only people who stopped treatment because of adverse events were eligible to receive a second TNFalpha inhibitor. The model assumed that the second treatment had equal efficacy to the first. In a sensitivity analysis, people who stopped treatment because of loss of response also switched to a second TNFalpha inhibitor, which was assumed to have a reduced effect. In the sensitivity analysis, pairwise comparison of the TNFalpha inhibitors with conventional care showed that, in a mixed population of people who had and who had not previously received TNFalpha inhibitors, the ICERs for treatment were about 1000 higher than the ICERs for a population only of people who had not previously received treatment (for all treatments except infliximab). This was the case for both ankylosing spondylitis and nonradiographic axial spondyloarthritis. Excluding infliximab, the ICERs for the other TNFalpha inhibitors in ankylosing spondylitis were similar (ranging from 21,823 to 22,641 per qualityadjusted life year  gained). The ICER for infliximab for the mixed population was 35,766 per QALY gained (lower than the ICER for infliximab for a population of people who had not received treatment). The ICERs for the 3 treatments for nonradiographic axial spondyloarthritis ranged from 23,877 to 24,041 per QALY gained. The company used evidence from the DANBIO patient registry to estimate the efficacy of the second TNFalpha inhibitor. The Assessment Group commented that registries are unreliable because of their selection bias. The company also stated that the results of this analysis should be interpreted with caution because of the lack of robust clinical data showing the efficacy of sequential treatment.

## Assessment Group's model
The Assessment Group developed a de novo economic model to assess the cost effectiveness of all 5 TNFalpha inhibitors that have a marketing authorisation for ankylosing spondylitis and the 3 that are licensed for nonradiographic axial spondyloarthritis. The Assessment Group developed a cohort model in the form of a modified decision tree. The model used a lifetime horizon, assuming that patients enter the model at the age of 40 years and have an average body weight of 73 kg. BASDAI 50 response at 12 weeks determined whether patients continued having a TNFalpha inhibitor or withdrew from treatment. For those whose disease responded, there was an ongoing risk of treatment withdrawal at any time point. Patients who stopped treatment (at 12 weeks or later) were assumed to move on to conventional care. The analysis was done from the perspective of the NHS and personal social services, and costs and health effects were discounted at an annual rate of 3.5%. The mean costs and QALYs reported are derived from probabilistic sensitivity analysis (that is, produced by varying the input parameters simultaneously with values from a probability distribution).
To address some of the uncertainties identified in published economic evaluations and company submissions, and to generate more appropriate parameter estimates (and associated uncertainties) for its de novo model, the Assessment Group performed an extended evidence synthesis of the available clinical data. The evidence synthesis was used to estimate baseline BASDAI/BASFI scores, the effect of treatment on these scores, and the probability of a response (BASDAI 50) at 12 weeks. The Assessment Group also used a new approach to model longterm disease progression and the impact of treatment on the natural history of disease, by relating the assumptions more explicitly to the existing clinical data for TNFalpha inhibitors. Specifically, the Assessment Group accounted for the independent effects of symptomatic improvements (that is, a reduction in disease activity according to BASDAI) on BASFI scores. It also considered the effect of changes in radiographic progression (measured by mSASSS) on BASFI. Because of these analyses, the model assumed that patients who continued to have, and whose disease responded to ('responders'), a TNFalpha inhibitor after week 12 had a slower progression rate (according to BASFI scores) compared with the natural history of the disease (this effect was delayed until year 4). For 'responders' who subsequently stopped taking TNFalpha inhibitors, there was some rebound in BASFI and BASDAI scores (this is also relevant for patients who stop at 12 weeks). Because trial data could not accurately characterise the extent of this rebound, the Assessment Group presented 2 scenarios in their base case; 1 assuming rebound to baseline and 1 assuming rebound to natural history (representing the bestcase and worstcase scenarios respectively). The Assessment Group's model used different baseline BASDAI/BASFI scores for 'responders' and for patients whose disease did not respond ('nonresponders'). Therefore, in the rebound to baseline scenario, 'responders' and 'nonresponders' reverted to different baseline scores after treatment was stopped. This assumption was based on results from the extended synthesis, which estimated that 'nonresponders' had higher baseline BASDAI and BASFI scores than 'responders' (that is, response is unlikely to be independent of baseline patient characteristics).
Healthrelated quality of life was estimated using BASDAI and BASFI data, using the approach submitted by Pfizer. Separate algorithms were used for each population, using data from the 1031 study and the 314EU study (both mapped to EQ5D).
The only adverseevent costs included in the model were serious infections and tuberculosis reactivation. All other costs were assumed to vary according to the BASFI score (data were derived from the OASIS database). The Assessment Group's model used both the list price for certolizumab pegol and the patient access scheme, so that the list price ICERs could be considered until the patient access scheme is agreed by the Department of Health.
The Assessment Group did 6 sensitivity analyses:
Scenario 1 assumed no placebo effect; that is, no patients having conventional care had a BASDAI 50 response at week 12. By contrast, the basecase model incorporated a probability of response to conventional care at 12 weeks.
Scenario 2 reduced the difference in baseline BASDAI/BASFI scores between 'responders' and 'nonresponders'. As in the base case, a difference still exists (conditional on response). But while the base case used estimates from the Assessment Group's extended synthesis, the sensitivity analysis was informed by data from company submissions. This scenario also used data pooled from company submissions (instead of the extended synthesis) to estimate the change in BASDAI and BASFI scores for 'responder's and 'nonresponders'.
Scenario 3 assumed that TNFalpha inhibitors have no effect on BASFI progression (in the base case, BASFI progression is slowed in 'responders').
Scenario 4 assumed that the treatment effect of TNFalpha inhibitors (measured by BASFI) was reached immediately. By contrast, in the basecase model, disease modification was delayed until year 4.
Scenario 5 mapped utilities using a linear model (consistent with previous NICE technology appraisal guidance on adalimumab, etanercept and infliximab and on golimumab for treating ankylosing spondylitis). The base case used a nonlinear mapping algorithm.
Scenario 6 used results from ankylosing spondylitis trials in the model for nonradiographic axial spondyloarthritis.
In both the basecase model and the sensitivity analyses, the Assessment Group assumed a class effect of TNFalpha inhibitors (that is, the QALYs gained are the same for each) based on their review of the clinical evidence. Therefore, the difference in the ICERs between the individual TNFalpha inhibitors is driven entirely by different acquisition and administration costs. In a fully incremental comparison of cost effectiveness, using the class effect assumption, the TNFalpha inhibitor with the lowest cost would dominate the other treatments (that is, provide the same QALYs at a lower cost). Therefore, the Assessment Group presented pairwise ICERs comparing each TNFalpha inhibitor with conventional therapy.
In the rebound to baseline scenario (table 8), pairwise comparison of the TNFalpha inhibitors with conventional care showed that infliximab had the highest ICER (40,576 per QALY gained) and the lowest probability of being cost effective at a 20,000 and 30,000 per QALY threshold (0% and 9% respectively). The ICER for infliximab using the biosimilar price was 36,751 per QALY gained. Excluding infliximab, the ICERs of the other TNFalpha inhibitors were similar, ranging from 19,240 (certolizumab pegol with the PAS) to 21,577 (etanercept). At a maximum acceptable ICER of 20,000 per QALY gained, certolizumab pegol with the patient access scheme had a 55% probability of being cost effective compared with conventional therapy. Its probability of being cost effective compared with conventional therapy at a maximum acceptable ICER of 30,000 per QALY gained was about 90%.

## Table 8 Basecase results for ankylosing spondylitis: rebound to baseline
Costs ()
QALYs
Incremental costs ()
Incremental QALYs
ICER (/QALY)
Conventional therapy
Certolizumab pegol with the PAS
Golimumab
Adalimumab
Etanercept
Infliximab
Abbreviations: ICER, incremental costeffectiveness ratio; PAS, patient access scheme; QALY, qualityadjusted life year.
In the rebound to natural history scenario (table 9), the ICERs for the TNFalpha inhibitors varied between 33,762 (certolizumab pegol with the patient access scheme) and 66,529 (infliximab) per additional QALY gained, compared with conventional care. The ICER using the biosimilar price for infliximab was 60,222 per QALY gained. At a maximum acceptable ICER of 20,000 per QALY gained, certolizumab pegol with the patient access scheme had only a 4% probability of being cost effective compared with conventional therapy. This probability rose to 40% at a maximum acceptable ICER of 30,000 per QALY gained. As before, infliximab had the lowest probability of being cost effective (0% likelihood at both thresholds).

## Table 9 Basecase results for ankylosing spondylitis: rebound to natural history
Costs ()
QALYs
Incremental costs ()
Incremental QALYs
ICER (/QALY)
Conventional therapy
Certolizumab pegol with the PAS
Golimumab
Adalimumab
Etanercept
Infliximab
Abbreviations: ICER, incremental costeffectiveness ratio; PAS, patient access scheme; QALY, qualityadjusted life year.
The ICER estimates appeared to remain relatively stable (compared with the basecase results) across most of the 6 sensitivity analyses. The exception to this was scenario 2, which used company data to inform the baseline BASDAI/BASFI scores (conditional on response) and to estimate the change in BASDAI and BASFI scores for 'responders' and 'nonresponders'. When the company data were used, the ICER estimates became more favourable towards the TNFalpha inhibitors (table 10), driven by smaller differences between the baseline scores of 'responders' and 'nonresponders'.

## Table 10 Results of the Assessment Group's sensitivity analysis (scenario 2) for ankylosing spondylitis ( per QALY gained)
Incremental costeffectiveness ratio (ICER)
Rebound to baseline
Rebound to natural history
Certolizumab pegol with PAS
Golimumab
Adalimumab
Etanercept
Infliximab
Abbreviations: ICER, incremental costeffectiveness ratio; PAS, patient access scheme.
In the reboundtobaseline scenario (table 11), the ICERs of the alternative TNFalpha inhibitors ranged from 28,247 (certolizumab pegol with the patient access scheme) to 29,784 (etanercept) per QALY gained, compared with conventional care. The probability that certolizumab pegol with the patient access scheme was more cost effective than conventional care alone was 14% at a maximum acceptable ICER of 20,000 per QALY threshold and 59% at a maximum acceptable ICER of 30,000 per QALY threshold.

## Table 11 Basecase results for nonradiographic axial spondyloarthritis: rebound to baseline
Costs ()
QALYs
Incremental costs ()
Incremental QALYs
ICER
                  (/QALY)
Conventional therapy
Certolizumab pegol with PAS
Adalimumab
Etanercept
Abbreviations: ICER, incremental costeffectiveness ratio; PAS, patient access scheme; QALY, qualityadjusted life year.
In the reboundtonaturalhistory scenario (table 12), the ICER of the alternative TNFalpha inhibitors varied between 32,528 (certolizumab pegol with the patient access scheme) to 34,232 per additional QALY (etanercept). At a maximum acceptable ICER of 20,000 per QALY gained, certolizumab pegol with the patient access scheme had a 6% probability of being cost effective compared with conventional therapy. The probability of certolizumab pegol with a patient access scheme being cost effective compared with conventional therapy at a maximum acceptable ICER of 30,000 per QALY gained was about 43%.

## Table 12 Basecase results for nonradiographic axial spondyloarthritis: rebound to natural history
Costs ()
QALYs
Incremental costs ()
Incremental QALYs
ICER (/QALY)
Conventional therapy
Certolizumab pegol with PAS
Adalimumab
Etanercept
Abbreviations: ICER, incremental costeffectiveness ratio; PAS, patient access scheme; QALY, qualityadjusted life year.
The ICER estimates remained relatively stable (compared with the basecase results) across the 6 sensitivity analyses. Scenario 2 showed the largest variation compared with the basecase analysis. ICER estimates became more favourable towards the TNFalpha inhibitors (table 13), driven by smaller differences between the baseline scores of 'responders' and 'nonresponders'.

## Table 13 Results of the Assessment Group's sensitivity analysis' (scenario 2) for nonradiographic axial spondyloarthritis ( per QALY)
Incremental costeffectiveness ratio
Rebound to baseline
Rebound to natural history
Certolizumab pegol with patient access scheme
Adalimumab
Etanercept
The Assessment Group listed the following as the main limitations in its model:
BASDAI and BASFI may not be the most appropriate tools for modelling disease progression, but they were used because of a lack of data linking costs and QALYs to other disease measures
uncertainty remains in longterm projections of BASDAI and BASFI scores
there are potential benefits that have not been formally captured and quantified, such as potential impact on productivity costs and benefits that TNFalpha inhibitors may confer for extraarticular manifestations
the model could not address important clinical questions on the sequential use of TNFalpha inhibitors
the model is based on an assumption that 12week continuation rules are adhered to in clinical practice, which does not necessarily reflect how TNFalpha inhibitors are currently used within the NHS.
The Assessment Group acknowledged that BASDAI and BASFI may not be the most appropriate measures to use in the model. However, it considered that its approach captured the potential impact of TNFalpha inhibitors on longterm disease progression (BASFI changes) more explicitly than existing models. The de novo model included changes in different clinical/biological processes (in addition to disease activity according to BASDAI) that independently affect BASFI. The Assessment Group considered that the effect of symptomatic improvements (that is, changes in BASDAI scores) on BASFI was captured in the conditional scores applied to 'responders'. In addition, because longterm BASDAI was assumed to be constant after the shortterm response period, longterm changes in BASFI were modelled as a function of mSASSS scores.
Following consultation on the preliminary guidance, the companies that market biosimilar infliximab presented updated economic analyses using a range of prices for infliximab to reflect the tendering process that was ongoing at the time of the consultation. Ranges, rather than single prices, were necessary because the process is regional rather than national and may differ between organisations. After the Committee meeting at which these analyses were discussed, NICE was able to confirm with the Commercial Medicines Unit that the tendering process was complete and that the prices presented in the companies' submissions were now available within the NHS. The Assessment Group then recalculated their basecase ICERs for infliximab in ankylosing spondylitis using an acquisition cost of infliximab to reflect the highest price the NHS would need to pay for infliximab (that is, the upper end of the range of acquisition costs for the cheapest product) and the Committee's preferred infusion cost (see section 4.65). Because the contract prices resulting from the tendering process are commercially confidential, the results of this analysis are not presented here (because this could allow the contract prices to be estimated from the ICERs).

# Consideration of the evidence
The Appraisal Committee reviewed the data available on the clinical and cost effectiveness of TNFalpha inhibitors, having considered evidence on the nature of ankylosing spondylitis and nonradiographic axial spondyloarthritis and the value placed on the benefits of TNFalpha inhibitors by people with the conditions, those who represent them, and clinical experts. It also took into account the effective use of NHS resources.

## Clinical management
The Committee discussed the diagnosis of ankylosing spondylitis or nonradiographic axial spondyloarthritis. It heard that differentiation between the two is based on radiological changes on Xrays. The Committee understood that to diagnose ankylosing spondylitis, definitive radiographic change on Xray is needed. The Committee heard from the clinical experts that diagnosing nonradiographic axial spondyloarthritis is more complex. People who have clinical signs and symptoms of axial spondyloarthritis together with MRI changes showing inflammation are the easiest to diagnose, although sometimes repeat MRI scanning may be needed to detect changes. A smaller number do not have MRI changes but have other objective markers of inflammation (that is, elevated levels of Creactive protein). In general, clinicians are much less confident of the diagnosis based on symptoms alone, in the absence of MRI or Creactive protein changes. Clinical and patient experts explained the importance of early diagnosis and treatment in order to prevent or delay progressive and irreversible damage, which could ultimately cause people to need a wheelchair or be unable to get out of bed because of the severity of their physical disability. They noted that delayed diagnosis is common, and that the mean time from the development of symptoms to diagnosis in the UK is about 8.4 years. The Committee heard that reasons for delayed diagnosis include a low awareness of the conditions in the general population; a presenting symptom that is nonspecific (for example, back pain); lack of a clear clinical pathway; and lack of followup for people who do not present with Xray changes. The Committee also heard that although MRI scanning shows inflammation before it becomes visible on Xray, accurate diagnosis with MRI needs particular scanning techniques and appropriate specialist interpretation.
The Committee explored the differences, and relationship between ankylosing spondylitis and nonradiographic axial spondyloarthritis. It heard from the patient and clinical experts that these are 2 distinguishable conditions within a single spectrum of disease. Clinical experts suggested that some people with nonradiographic axial spondyloarthritis will develop ankylosing spondylitis (about 10% over 2 years and 50% over 10 years). The Committee heard that it is difficult to predict which people with nonradiographic axial spondyloarthritis will progress, and at what rate it would happen.
The Committee discussed the impact on quality of life of both conditions. The Committee understood from both the clinical and patient experts that these are chronic, progressive conditions associated with pain, stiffness and increasing spinal and other joint damage. It noted that there may be extraarticular manifestations of disease such as uveitis, colitis, psoriasis, and cardiovascular problems, as well as symptoms such as depression, fatigue and lack of sleep. The Committee was aware that these conditions have a significant impact on a person's mobility, social life, employment, mental health and overall quality of life. The Committee understood that the families of people with these conditions may also be substantially impacted.
The Committee discussed the current management of ankylosing spondylitis. The Committee heard that symptoms will not be controlled by NSAIDs in 40% of people with ankylosing spondylitis, and others will be not be able to tolerate NSAIDs. The Committee noted that adalimumab, etanercept and golimumab were recommended by NICE as treatment options for people with severe, active ankylosing spondylitis whose condition has responded inadequately to conventional therapy (NICE technology appraisal guidance on adalimumab, etanercept and infliximab and golimumab for treating ankylosing spondylitis). The Committee understood that access to other TNFalpha inhibitors, such as certolizumab pegol and infliximab, would allow patients and clinicians a greater choice of treatment options. The Committee heard from patient experts that TNFalpha inhibitors had completely changed some people's lives by restoring mobility and reducing pain, and could allow people to continue working and fulfilling parental and carer duties. A patient expert stated that his TNFalphainhibitor treatment had also stopped flareups of uveitis. The Committee heard from the clinical experts that individual TNFalpha inhibitors have different effects on extraarticular manifestations and so the choice of TNFalpha inhibitor in clinical practice is based on individual patient characteristics. The Committee also heard that the TNFalpha inhibitors have different modes of administration; adalimumab, certolizumab pegol, etanercept and golimumab are given by subcutaneous injection and infliximab is given by infusion in hospital. The Committee heard from the patient experts that infliximab may be a preferable treatment option for patients who may have difficulty with or who are unable to selfinject. It also heard that infliximab may also be more suitable for people who need more time between treatments to allow them to travel, although the Committee noted that golimumab is given only every 4 weeks. The Committee understood the importance of TNFalpha inhibitors for treating ankylosing spondylitis.
The Committee considered the use of TNFalpha inhibitors in people with nonradiographic axial spondyloarthritis. The patient and clinical experts emphasised that there is a misconception that this condition is less severe than ankylosing spondylitis. They explained that both conditions result in the same level of pain, reduced function and poor quality of life. People severely affected by the condition found it hard to understand why they had to wait for changes to be visible on Xrays before being eligible for treatment with TNFalpha inhibitors.The Committee noted that adalimumab, certolizumab pegol and etanercept have UK marketing authorisations for use in people with nonradiographic axial spondyloarthritis. It understood that golimumab had recently been given regulatory approval for this indication, but was not included in this appraisal because the positive Committee for Medicinal Products for Human Use opinion was received at a late stage in the appraisal process. Although there are 4 TNFalpha inhibitors available for this indication, the Committee heard that there was extreme variability in access to TNFalpha inhibitors across the country, and that access was based on individual funding requests. The Committee understood that there was clinical support for the use of TNFalpha inhibitors in people with nonradiographic axial spondyloarthritis, whose disease is not controlled by, or who cannot tolerate, NSAIDs. The clinical experts stated that early treatment with TNFalpha inhibitors could prevent spinal damage in these people. The clinical experts clarified the diagnosis of nonradiographic axial spondyloarthritis, and further divided people with symptoms of the condition into 3 groups: people with MRI changes; those with no MRI changes but elevated Creactive protein levels; and those without MRI changes and without elevated Creactive protein. The experts suggested that people with symptoms of nonradiographic axial spondyloarthritis, but without objective signs of inflammation are less likely to benefit from TNFalphainhibitor treatment. The Committee understood that TNFalpha inhibitors are not indicated for people with symptoms of nonradiographic axial spondyloarthritis, but without objective signs of inflammation and concluded that it could not make recommendations for treatment with TNFalpha inhibitors in this group of patients.
The Committee discussed the response criteria used to determine whether TNFalphainhibitor treatment is continued in clinical practice. It heard from clinical experts that in UK clinical practice, response to TNFalphainhibitor treatment is usually assessed after 3 months. They defined an adequate response to treatment as an improvement in BASDAI score of at least 50%, or of at least 2 units. The experts explained that, in some people, the disease will not show a response to treatment until 6 months, but that most responses or partial responses occur within 3 months. The Committee heard from the patient expert that his disease responded to treatment after only 8 weeks. The Committee also heard that the probability of response to TNFalpha inhibitors is higher in clinical practice than in clinical trials (about an 85% response rate in practice compared with 5060% in clinical trials). The clinical experts suggested that this could, in part, be because of the more restrictive definition of response used in clinical trials compared with clinical practice. The Committee concluded that an improvement of 2 units in the BASDAI score represented a meaningful and clinically significant benefit, independent of the baseline BASDAI score.
The Committee heard from the clinical experts that, in people who cannot tolerate a first TNFalpha inhibitor or have adverse reactions, the disease is no less likely to respond to an alternative agent. People whose condition either does not respond to a first TNFalpha inhibitor, or relapses after an initial response, are also likely to benefit from an alternative TNFalpha inhibitor. The experts stated that the number of patients with ankylosing spondylitis or nonradiographic axial spondyloarthritis needing a subsequent TNFalpha inhibitor is likely to be relatively small (around 6000), and may be related to differences in the drugs' mechanisms of action of or the development of antibodies. The Committee noted that switching between TNFalpha inhibitors was not recommended in NICE's previous technology appraisal guidance on adalimumab, etanercept and infliximab and golimumab for treating ankylosing spondylitis, except when intolerance to the first agent occurs in the first 3 months of treatment, before the assessment of response. For treatment switching after failure of a first TNFalpha inhibitor, the patient expert commented that stopping TNFalphainhibitor treatment after loss of response would mean returning to reliance on NSAID therapy, which has already been shown to provide inadequate symptom control, and is associated with longterm adverse effects. The Committee also noted that some patients are unable to take NSAIDs. The clinical and patient experts stated that the inability to switch agents results in many patients remaining on their suboptimal TNFalpha inhibitor indefinitely because of the lack of access to an alternative more effective option. They suggested that it was preferable to switch to another agent at the same cost rather than continue with a less effective one. The patient experts emphasised that patients currently feel under extreme pressure to make the right first choice, knowing that they will not have the opportunity to try an alternative TNFalpha inhibitor if their disease fails to respond to the first, or if it responds but subsequently gets worse again. The Committee acknowledged that predicting a disease response in advance was not possible, and that this could have a major impact on a lifelong condition. The Committee concluded that there was a clinical need for subsequent TNFalpha inhibitor treatments.

## Clinical effectiveness
The Committee considered the clinicaleffectiveness evidence for each condition separately. The Committee agreed that the trials in ankylosing spondylitis were generalisable to clinical practice in the UK but noted substantial heterogeneity in the baseline characteristics in the trials of nonradiographic axial spondyloarthritis (such as variation in levels of Creactive protein and the proportion of patients with MRI changes). The Committee heard from the clinical experts that the trial patient populations generally reflected the patients seen in UK clinical practice, although expressing some reservations about the inclusion of people without objective signs of inflammation, for whom TNFalpha inhibitors are not indicated according to their UK marketing authorisations. The Committee concluded that the trials were generalisable to the NHS.
The Committee discussed the results of the Assessment Group's metaanalysis for each condition. The Committee noted that all the TNFalpha inhibitors showed a benefit compared with placebo at 1016 weeks in both conditions. The Committee noted that infliximab appeared to be more effective at 12 weeks than other TNFalpha inhibitors in ankylosing spondylitis, but questioned whether this benefit was sustained longterm. The Committee considered the results of the Giardina et al. trial (see section 4.8) and agreed that, on balance, there was not enough evidence to indicate that infliximab was more effective in the longer term than the other TNFalpha inhibitors. The Committee concluded that TNFalpha inhibitors were clinically effective compared with placebo and, given the lack of difference in effect between them, they should be considered as a class with broadly similar, even if not completely identical, effects.
The Committee questioned whether the efficacy of TNFalpha inhibitors was the same in both conditions. The Committee noted that the class effect results for TNFalpha inhibitors were less favourable in nonradiographic axial spondyloarthritis compared with ankylosing spondylitis (except for outcomes measured on the healthrelated quality of life instrument: SF36). The Committee heard from the clinical experts that they would not expect a differential response to treatment in the two conditions. Clinical experts stated that their limited clinical experience of TNFalpha inhibitors in nonradiographic axial spondyloarthritis suggested that the magnitude of response was the same in both conditions. The Committee noted comments from the Assessment Group that heterogeneity across the trials of nonradiographic axial spondyloarthritis may have confounded the outcomes for TNFalpha inhibitors. The Committee heard from the clinical experts that these trials included some people who were less likely to benefit from TNFalpha inhibitors (people without objective signs of inflammation such as MRI changes and elevated Creactive protein, for whom TNFalpha inhibitors are not indicated according to their UK marketing authorisations; see sections 4.48, 4.52 and 4.55). The Committee noted that clear guidelines for the diagnosis of nonradiographic axial spondyloarthritis would be helpful to identify patients who are more or less likely to benefit from TNFalphainhibitor treatment. The Committee agreed that the clinical trials may have underestimated the benefit of TNFalpha inhibitors in nonradiographic axial spondyloarthritis. The Committee concluded that people with nonradiographic axial spondyloarthritis are likely to achieve a similar benefit from TNFalpha inhibitors as people with ankylosing spondylitis.
The Committee discussed whether there were any differences between the TNFalpha inhibitors and heard from clinical experts that TNFalpha inhibitors are well tolerated in both conditions, and that people rarely stop treatment because of adverse events (see section 4.54). The Committee noted comments from experts that there are differences between the TNFalpha inhibitors in their effects on extraarticular manifestations (see section 4.51). The Committee heard from the clinical experts that in clinical practice the choice of TNFalpha inhibitor is based on individual patient characteristics. The Committee concluded that TNFalpha inhibitors are relatively well tolerated and that the clinical characteristics of the patient, particularly any extraarticular manifestations of the disease, would need to be considered when choosing a TNFalpha inhibitor.
The Committee considered the clinical evidence for treatment with a second or third TNFalpha inhibitor for a person whose disease does not respond or stops responding to treatment (sequential treatment). The Committee noted the absence of randomised controlled trial data, but noted data from the DANBIO registry for ankylosing spondylitis and comments received on the appraisal consultation document identifying other registries and studies, including ATTRA, NORDMARD, RAPIDaxSpA and RHAPSODY. It agreed that, despite a decrease in response rates for each subsequent treatment, sequential treatment with TNFalpha inhibitors can be beneficial in ankylosing spondylitis. The Committee also noted consultation comments from a patient and carer group stating that a survey of 864 people with ankylosing spondylitis or nonradiographic axialspondyloarthritis showed that 26% of those surveyed had received at least 1 other TNFalpha inhibitor (about half of these because of adverse reactions and half because of a loss or lack of response); 79% of these people considered that switching had provided a moderate (11%) to large benefit (68%). The Committee also noted consultation comments stating that other appraisals, such as NICE's technology appraisal guidance on etanercept, infliximab and adalimumab for psoriatic arthritis, had not placed a restriction on subsequent TNFalphainhibitor use. However, the Committee was concerned that that there was very little evidence on sequential use, and was uncertain about the true magnitude of the benefit in ankylosing spondylitis. What evidence there was did not show a convincing differential effect, related to the reason for switching. However, the Committee noted that the RAPIDaxSpA study included some people with nonradiographic axial spondyloarthritis who had switched to a second or third TNFalpha inhibitor. The Committee heard from the company that the study showed that, after 2 years, the clinical response was the same for those receiving a secondline TNFalpha inhibitor as those receiving a firstline TNFalpha inhibitor. The Committee also heard that the study showed the disease was more likely to respond to a second treatment in people whose first treatment had failed because of adverse events, intolerance or lost efficacy than in people whose disease did not respond to initial treatment. The Committee concluded that predicting response to a second agent was difficult because it may or may not be affected by the reason for switching. The clinical experts agreed that the relative efficacy of a second TNFalpha inhibitor would be comparable in nonradiographic spondyloarthritis and ankylosing spondylitis. The Committee concluded that sequential treatment with TNFalpha inhibitors is likely to be beneficial, but that clinical data are limited.

## Cost effectiveness
The Committee considered the evidence for the cost effectiveness of TNFalpha inhibitors in ankylosing spondylitis and nonradiographic axial spondyloarthritis. It noted that although the models from the companies and the Assessment Group all used changes in BASDAI and BASFI scores to model costs and utilities, the underlying assumptions in each model were very different. The Committee noted that the Assessment Group divided the models into 3 key stages: the probability of initial response, the size of initial response for patients whose disease had responded or not, and the longterm trajectory of BASDAI and BASFI scores (conditional on response status). The Committee noted the Assessment Group's criticism that some of the company models combined the latter 2 stages. The Committee decided to focus on the Assessment Group's model for decisionmaking purposes.
The Committee explored the uncertainties relating to key assumptions in the Assessment Group's costeffectiveness analysis. The Committee discussed the first key stage of the model: the probability of initial response (defined as a 50% improvement in BASDAI score). The Committee heard that in the Assessment Group's model, 'responders' had lower baseline BASDAI and BASFI scores compared with 'nonresponders' (a difference that was reduced in scenario 2). The Committee noted that this assumption implied that people with more severe disease did not benefit as much from TNFalpha inhibitors as people with less severe disease, because someone with more severe disease (higher baseline scores) must have larger absolute improvements than someone with less severe disease to achieve a BASDAI 50 response. It concluded, based on discussion with clinical and patient experts, that there was no evidence to suggest that people with severe disease were less likely to have a clinically meaningful benefit than those with less severe disease.
The Committee discussed the longterm effect of TNFalpha inhibitors on disease progression (assessed using BASFI) in people whose disease responds to treatment. The Committee heard that most company submissions assumed that TNFalpha inhibitors completely prevent long term disease progression (measured by BASFI). In addition, some company submissions presented more optimistic scenarios in which physical function continued to improve beyond the initial response period, implying further improvement beyond 12 weeks, which subsequently plateaued. The Committee noted that the assumption of no deterioration (measured by BASFI) during treatment was based on small, singlearm followup trials that were subject to selection bias and were therefore unreliable. It heard from clinical experts that their impression was that physical function (measured by BASFI) continues to deteriorate during treatment with a TNFalpha inhibitor, but that treatment slows the rate of deterioration. The clinical experts disagreed with the Assessment Group's assumption that a TNFalpha inhibitor's effect on progression is delayed until year 4, and the Committee agreed that it was not clinically plausible for disease progression to slow at a specific time point during treatment. The Committee concluded that the precise effect of TNFalpha inhibitors on the long term BASFI trajectory was uncertain. It agreed that it was biologically plausible for physical function (measured by BASFI) to continue deteriorating during TNFalphainhibitor treatment, but at a slower rate compared with the natural history of the disease.
The Committee considered what happens when a patient stops TNFalphainhibitor treatment. For the impact of stopping treatment on BASFI scores, the Committee noted that two rebound scenarios had been presented by the companies and the Assessment Group. In the rebound to baseline scenario, the BASFI score returns to the patient's baseline score. The alternative scenario (rebound to natural history) assumes a greater deterioration in physical function (measured by BASFI) after treatment stops, to the level that it would have been if the disease had not initially responded to therapy. The Committee heard from the clinical experts that in clinical practice patients would be most likely to rebound back to their baseline scores, rather than deteriorate to a poorer state of health than they were at baseline. The Committee concluded that the rebound to baseline scenario was the more plausible assumption of the two.
The Committee noted that the ICERs produced by the Assessment Group's basecase model for ankylosing spondylitis appeared to be consistent with the results of the company models, despite differences in the assumptions used. The Committee also noted that the ICERs for certolizumab pegol and golimumab included the discount agreed in the patient access schemes. The Committee noted that the ICERs for adalimumab, certolizumab pegol, etanercept and golimumab compared with conventional care ranged from about 19,200 per QALY gained for certolizumab pegol (with the patient access scheme) to 21,600 per QALY gained for etanercept in the Assessment Group's base case (assuming rebound to baseline). The Committee considered that these ICERs were all within the range considered to be a costeffective use of NHS resources and concluded that adalimumab, certolizumab pegol, etanercept and golimumab could be recommended as options for treating adults with ankylosing spondylitis whose disease has responded inadequately to, or who cannot tolerate, NSAIDs.
The Committee noted that the Assessment Group's base case ICERs for infliximab for ankylosing spondylitis (rebound to baseline scenario) were about 40,600 and 36,800 per QALY gained compared with conventional care, using the original and biosimilar list prices respectively. The Committee considered that these ICERs are above the range normally considered costeffective in the NHS. However, the Committee noted comments received in response to the appraisal consultation document about the infusion cost of infliximab and the lower prices of the biosimilar versions of infliximab as a result of the tendering process. The Committee first discussed the infusion cost, stating that the infusion cost of infliximab was too high in the Assessment Group's model and that a recent NICE consultation document for rheumatoid arthritis had used the price of 154 for infliximab infusion. The Committee noted that the cost of infusion for infliximab used in the Assessment Group's model was 291 and was based on the Healthcare Resource Group codes for delivery of subsequent elements of chemotherapy, derived from the NHS reference costs 201213. The Committee also noted that a range of sources had been used in other appraisals including inpatient and outpatient day costs. The clinical experts stated that infusion costs in their respective hospital trusts ranged between 140 and 168. The Committee was aware that the national tariff to deliver simple parenteral chemotherapy was 159, and the clinical experts agreed that this cost was reasonable. The Committee concluded that the cost of infliximab infusion was likely to be lower than that used in the Assessment Group's model and that the national tariff cost for delivering simple parenteral chemotherapy provided a better estimate.
The Committee considered the costs of infliximab treatment. The Committee was aware that the amount of infliximab given is based on a patient's weight and, because infliximab is provided in 100 mg vials, there is an issue of waste. The Committee heard from the clinical experts that, in practice, infliximab vial sharing is done to avoid waste. However, the Committee agreed that it could not factor vial sharing into the analyses because there would be variation in this practice in the NHS. The Committee also heard from 1 biosimilar company that its product can be supplied in a preprepared bag, so that hospitals pay per milligram of drug rather than per vial. However, the Committee was unsure about what additional costs this would involve. The clinical experts stated that, although not within its marketing authorisation, the dose of infliximab is often reduced to 3 mg/kg and the time between treatments is extended. The Committee concluded that it should base its decision on analyses using the assumption that whole vials are used.
The Committee also discussed the new ICERs, presented in response to the appraisal consultation document, by the companies that market biosimilar versions of infliximab. These used lower prices to reflect the tendering process that was taking place during the consultation period. The companies' representatives present at the meeting were able to confirm that the tendering process was complete and that Commercial Medicines Unit contract prices are now available in the NHS. The Committee noted the updated basecase analyses provided by the Assessment group (that included the highest price the NHS would need to pay for infliximab based on the contract prices, and infusion costs based on the national tariff to deliver simple parenteral chemotherapy) and it agreed that these analyses showed that the costeffectiveness of infliximab was within the range considered to be a costeffective use of NHS resources. The Committee noted section 5.5.2 of the NICE guide to the methods of technology appraisal (2013) which states: 'When there are nationally available price reductions, for example for medicines procured for use in secondary care through contracts negotiated by the NHS Commercial Medicines Unit, then the reduced price should be used in the referencecase analysis to best reflect the price relevant to the NHS.' The Committee therefore concluded that infliximab could be recommended as an option for treating adults with ankylosing spondylitis whose disease has responded inadequately to, or who cannot tolerate, NSAIDs provided that the infliximab product with the lowest acquisition cost is used. People already receiving infliximab should be able to continue on their existing product.
The Committee considered the costeffectiveness results for the TNFalpha inhibitors in nonradiographic axial spondyloarthritis. It noted that the ICERs produced by the Assessment Group's model, and one of the company models, were higher than the corresponding ICERs for ankylosing spondylitis. The Committee noted that the Assessment Group's base case for the rebound to baseline scenario included ICERs ranging from about 28,200 for certolizumab pegol (including the patient access scheme) to 29,800 for etanercept per QALY gained, compared with conventional care. The Committee referred to the clinical discussions, where it had concluded that the benefit of TNFalpha inhibitors was potentially underestimated in the clinical trials because of heterogeneous patient characteristics. It also noted that the Assessment Group's assumption of a slower disease progression rate (measured by BASFI) in this condition compared with ankylosing spondylitis was not confirmed by the clinical experts, and that this would in part have driven the higher ICERs compared with ankylosing spondylitis. Taking this into account, the Committee considered that the most plausible ICERs were likely to be below those presented by the Assessment Group and agreed that the ICERs for adalimumab, certolizumab pegol and etanercept were within the range that would be considered a costeffective use of NHS resources. The Committee concluded that adalimumab, certolizumab pegol and etanercept could be recommended as options for treating adults with nonradiographic axial spondyloarthritis whose disease has responded inadequately to, or who cannot tolerate, NSAIDs.
The Committee noted that the Assessment Group was unable to use the 2point BASDAI change in the definition of response in their model (because of lack of data) and therefore used only BASDAI 50 to define response. The Committee noted the earlier discussions about what is used to define response in clinical practice. The Committee heard that clinical experts considered it unreasonable to restrict the definition of adequate response in clinical practice to a 50% improvement in BASDAI, because this means that someone with more severe disease (a higher baseline BASDAI score) must have a greater absolute improvement in BASDAI than someone with less severe disease to qualify for continued treatment. The Committee noted that the clinical experts had stated that a 2 unit improvement in BASDAI represents a significant and clinically meaningful change. Therefore, the Committee concluded that the decision to continue treatment in clinical practice should be based on the broader definition of response to treatment outlined in British Society of Rheumatology (BSR) guidelines and the previous technology appraisal: a reduction of the BASDAI to 50% of the baseline value, or a reduction of 2 units or more, together with a reduction in the spinal pain visual analogue scale (VAS) by 2 cm or more. If an adequate response is not achieved 12 weeks after treatment initiation, treatment should be stopped.
The Committee discussed whether it was appropriate to consider treatment with a second or third TNFalpha inhibitor for a person whose disease does not respond to treatment or stops responding, or who has an adverse reaction or becomes intolerant to treatment. The Committee noted that results from registries in ankylosing spondylitis showed around a 30% reduction in response rate with each subsequent TNFalpha inhibitor (10% absolute reduction). It heard from the Assessment Group that this implies that the ICER would be correspondingly higher, but that the Assessment Group had not modelled sequential use. The Committee noted that one company had explored a population containing both people receiving their first TNFalpha inhibitor and a few switching to a subsequent TNFalpha inhibitor. Taking into account the small number of patients switching (about 6% in their model) and the reduced efficacy of subsequent TNFalpha inhibitors in previous treatment failures, there was only an estimated 1000 increase in the ICER per QALY gained in the population containing both patient groups compared with the group containing only patients receiving their first TNFalpha inhibitor. The Committee noted that the Assessment Group did not consider this analysis valid. However, the Committee considered that it was reasonable to quote an ICER for the whole population if only a small number of people switched treatments. The Committee noted earlier comments (see section 4.54) that some patients would remain on a suboptimal treatment if they were unable to switch, at a comparable cost but with decreased QALYs. It also noted the consultation comments that other trials, including the ATTRA registry, NORDMARD registry, RAPIDaxSpA study and RHAPSODY study, provided further data, although limited, on the efficacy of subsequent TNFalpha inhibitor treatment. The Committee agreed that all patients receiving TNFalpha inhibitors for ankylosing spondylitis should be recruited into the ongoing British Society for Rheumatology Ankylosing Spondylitis Register. The Committee concluded that, although there was limited costeffectiveness evidence for subsequent TNFalphainhibitor use, and an exact ICER could not be determined, it considered the ICER would be within the range considered to be costeffective use of NHS resources and subsequent TNFalphainhibitor treatment could be recommended.
The Committee was aware that, in principle, potential differences between the TNFalpha inhibitors in their effects on extraarticular manifestations may have cost implications, but noted that there was insufficient evidence to incorporate extraarticular manifestations into the costeffectiveness analysis. However, the Committee concluded that because the TNFalpha inhibitors had been considered as a class, the choice of treatment for both conditions should be based on clinical appropriateness, which may include consideration of associated conditions. If different TNFalpha inhibitors are equally suitable, the product with the lowest acquisition and administration costs should be used.
The Committee was aware of NICE's position statement on the Pharmaceutical Price Regulation Scheme (PPRS) 2014, and in particular the PPRS payment mechanism and accepted the conclusion 'that the 2014 PPRS payment mechanism should not, as a matter of course, be regarded as a relevant consideration in its assessment of the cost effectiveness of branded medicines'. The Committee heard nothing to suggest that there is any basis for taking a different view with regard to the relevance of the PPRS to this appraisal. It therefore concluded that the PPRS payment mechanism was not relevant for its consideration of the cost effectiveness of any of the technologies in this appraisal.
The Committee considered whether its recommendations were associated with any potential issues related to equality. It concluded that when using BASDAI and spinal pain VAS scores to confirm the presence of sustained active spinal disease, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect the responses to the questionnaires and make any adjustments they consider appropriate.

# Summary of Appraisal Committee's key conclusions
TA383
Appraisal title: TNFalpha inhibitors for ankylosing spondylitis and nonradiographic axial spondyloarthritis (including a review of TA143 and TA233)
Section
Key conclusions
Adalimumab, certolizumab pegol, etanercept and golimumab and infliximab are recommended, within their marketing authorisations, as options for treating active ankylosing spondylitis in adults whose disease has responded inadequately to, or who cannot tolerate, nonsteroidal antiinflammatory drugs.
Infliximab is recommended only treatment is started with the least expensive product. People currently receiving infliximab should be able to continue treatment with the same product until they and their NHS clinician consider it appropriate to stop.
Adalimumab, certolizumab pegol and etanercept are recommended, within their marketing authorisations, as options for treating nonradiographic axial spondyloarthritis in adults whose disease has responded inadequately to, or who cannot tolerate, nonsteroidal antiinflammatory drugs.
The choice of treatment should be made after discussion between the clinician and the patient about the advantages and disadvantages of the treatments available. This may include considering associated conditions such as extraarticular manifestations. If more than 1 treatment is suitable, the least expensive (taking into account administration costs and patient access schemes) should be chosen.
The response to adalimumab, certolizumab pegol, etanercept, golimumab or infliximab treatment should be assessed 12 weeks after the start of treatment. Treatment should only be continued if there is clear evidence of response, as defined in section 1.4.
Treatment with another tumour necrosis factor (TNF)alpha inhibitor is recommended for people who cannot tolerate, or whose disease has not responded to, treatment with the first TNFalpha inhibitor, or whose disease has stopped responding after an initial response.
Current practice
Clinical need of patients, including the availability of alternative treatments
Ankylosing spondylitis and nonradiographic axial spondyloarthritis result in the same level of pain, reduced function and poor quality of life. Early treatment is important in order to prevent or delay progressive and irreversible damage, which could ultimately cause someone to need a wheelchair or be unable to get out of bed.
Adalimumab, etanercept and certolizumab pegol have UK marketing authorisations for use 'in people with nonradiographic axial spondyloarthritis whose condition has responded inadequately, or who are intolerant, to conventional therapy with nonsteroidal antiinflammatory drugs (NSAIDs)'. However there is extreme variability in access to TNFalpha inhibitors across the country for people with this condition.
In about 40% of people with ankylosing spondylitis, symptoms will not be controlled by NSAIDs and others will not be able to tolerate them. Adalimumab, etanercept and golimumab are recommended by NICE as treatment options for people with severe, active ankylosing spondylitis whose condition has responded inadequately to conventional therapy. The Committee heard that access to other TNFalpha inhibitors, such as certolizumab pegol and infliximab, would allow patients and clinicians a greater choice of treatment options.
The technology
Proposed benefits of the technology
How innovative is the technology in its potential to make a significant and substantial impact on healthrelated benefits?
Patient experts reported that use of TNFalpha inhibitors to treat both ankylosing spondylitis and nonradiographic axial spondyloarthritis had completely changed some people's lives by restoring mobility and reducing pain, and could allow people to continue working and fulfil parental and carer duties.
The Committee was aware that potential differences between the TNFalpha inhibitors in their effects on extraarticular manifestations may have cost implications, but noted that there was insufficient evidence to incorporate extraarticular manifestations into the costeffectiveness analysis.
What is the position of the treatment in the pathway of care for the condition?
The Committee heard that symptoms will not be controlled by NSAIDs in 40% of people with ankylosing spondylitis, and others will be not be able to tolerate NSAIDs. The Committee noted that adalimumab, etanercept and golimumab were recommended by NICE as treatment options for people with severe, active ankylosing spondylitis whose condition has responded inadequately to conventional therapy.
The Committee understood that there was clinical support for the use of TNFalpha inhibitors in people with nonradiographic axial spondyloarthritis, whose disease is not controlled by, or who cannot tolerate, NSAIDs.
Adverse reactions
The Committee heard from clinical experts that TNFalpha inhibitors are well tolerated in both conditions, and that people rarely stop treatment because of adverse events. It concluded that the clinical characteristics of the patient would need to be considered when choosing a TNFalpha inhibitor.
Evidence for clinical effectiveness
Availability, nature and quality of evidence
The Assessment Group identified 24 relevant randomised controlled trials (RCTs): 19 recruited people with ankylosing spondylitis, 4 recruited people with axial spondyloarthritis without radiographic evidence of ankylosing spondylitis (nonradiographic axial spondyloarthritis), and 1 recruited people with either condition. All except 2 of the trials were placebocontrolled. Of the 24 RCTs, 17 had openlabel extension studies, with 11 studies having a total duration of at least 1 year.
Relevance to general clinical practice in the NHS
The trial populations generally reflected patients seen in UK clinical practice, although with some reservations about the inclusion of people without objective signs of inflammation (for whom TNFalpha inhibitors are not indicated according to their UK marketing authorisations). The Committee concluded that the trials were generalisable to the NHS.
Uncertainties generated by the evidence
Infliximab appeared to be more effective at 12 weeks than other TNFalpha inhibitors in ankylosing spondylitis, but the Committee agreed that there was not enough evidence to show that the superior benefit of infliximab was sustained longterm. Given the lack of difference in effect between the TNFalpha inhibitors, they were considered as a class with broadly similar, even if not completely identical, effects.
In the network metaanalysis, the class effect results for TNFalpha inhibitors were less favourable in nonradiographic axial spondyloarthritis compared with ankylosing spondylitis. However, the Committee heard that the clinical experts would not expect a differential response to treatment in the 2 conditions. The Committee noted that heterogeneity across the trials of nonradiographic axial spondyloarthritis may have confounded the outcomes for TNFalpha inhibitors and that the trials included people who were less likely to benefit from TNFalpha inhibitors (people without objective signs of inflammation, for whom TNFalpha inhibitors are not indicated according to their UK marketing authorisations). The Committee agreed that clinical trials may have underestimated the benefit of TNFalpha inhibitors in nonradiographic axial spondyloarthritis and concluded that people with this condition may achieve a similar benefit from TNFalpha inhibitors as people with ankylosing spondylitis.
Are there any clinically relevant subgroups for which there is evidence of differential effectiveness?
There are no clinically relevant subgroups for which there is evidence of differential effectiveness.
Estimate of the size of the clinical effectiveness including strength of supporting evidence
The network metaanalysis of randomised controlled trial data showed that TNFalpha inhibitors are clinically effective compared with placebo at 1016 weeks in both conditions (within their marketing authorisations).
No randomised controlled trial data were available to assess the effect of sequential treatment with TNFalpha inhibitors. Registry data showed that, despite a decrease in response rates for each subsequent treatment, sequential treatment with TNFalpha inhibitors can be beneficial in ankylosing spondylitis. There were no registry data for people with nonradiographic axial spondyloarthritis who had switched to a second or third TNFalpha inhibitor, but clinical experts stated that the efficacy of a second TNFalpha inhibitor in this condition would be considered similar to the efficacy of a second TNFalpha inhibitor in ankylosing spondylitis. The Committee concluded that sequential treatment with TNFalpha inhibitors is likely to be beneficial, but that clinical data are limited.
How has the new clinical evidence that has emerged since the original appraisal (TA143 and TA233) influenced the current recommendations?
Since the publication of NICE's technology appraisal guidance on adalimumab, etanercept and infliximab for ankylosing spondylitis, certolizumab pegol has received a marketing authorisation in the UK for ankylosing spondylitis and for nonradiographic axial spondyloarthritis. Adalimumab and etanercept also now have marketing authorisations for nonradiographic axial spondyloarthritis. All are recommended within their marketing authorisations as treatment options for ankylosing spondylitis or nonradiographic axial spondyloarthritis.
Evidence for cost effectiveness
Availability and nature of evidence
Although the models from the companies and the Assessment Group all used changes in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Bath Ankylosing Spondylitis Functional Index (BASFI) scores to model costs and utilities, the underlying assumptions in each model were very different. The Assessment Group divided the models into 3 key stages: the probability of initial response, the size of initial response for 'responders' and 'nonresponders', and the longterm trajectory of BASDAI and BASFI scores (conditional on response status). The Committee noted the Assessment Group's criticism that some of the company models combined the latter 2 stages. The Committee decided to use the Assessment Group's model for its decisionmaking.
Uncertainties around and plausibility of assumptions and inputs in the economic model
In the Assessment Group's model, 'responders' had lower baseline BASDAI and BASFI scores compared with 'nonresponders' (a difference that was reduced in scenario 2), implying that people with more severe disease did not benefit as much from TNFalpha inhibitors as people with less severe disease. The Committee concluded that there was no evidence to suggest that people with severe disease were less likely to have a clinically meaningful benefit than those with less severe disease.
The Committee agreed with the Assessment Group's assumption that physical function (measured by BASFI) continues deteriorating during TNFalpha inhibitor treatment, but at a slower rate compared with the natural history of the disease. However, it disagreed with the Assessment Group's assumption that a TNFalpha inhibitor's effect on progression is delayed until year 4.
The Assessment Group presented 2 alternative basecase costeffectiveness analyses to reflect their uncertainty about what happens when a patient stops TNFalpha inhibitor treatment (the 'rebound' assumption). The Committee concluded that rebound to baseline was the most plausible assumption and considered the incremental costeffectiveness ratios (ICERs) from this analysis.
Sequential use of TNFalpha inhibitors was not modelled. The Committee noted that some patients would remain on a suboptimal treatment if they were unable to switch, at a comparable cost but with decreased qualityadjusted life years (QALYs).
Incorporation of healthrelated qualityoflife benefits and utility values
Have any potential significant and substantial healthrelated benefits been identified that were not included in the economic model, and how have they been considered?
The Committee was aware that potential differences between the TNFalpha inhibitors in their effects on extraarticular manifestations may have cost implications, but noted that there was insufficient evidence to incorporate extraarticular manifestations into the costeffectiveness analysis. However, the Committee concluded that because the TNFalpha inhibitors had been considered as a class, the choice of treatment for both conditions should be based on clinical appropriateness, which may include consideration of associated conditions.
Are there specific groups of people for whom the technology is particularly cost effective?
There are no specific groups of people for whom the technology is particularly cost effective.
What are the key drivers of cost effectiveness?
The difference in the ICERs between the individual TNFalpha inhibitors was driven entirely by different acquisition and administration costs.
ICERs were sensitive to assumptions about the magnitude of the difference in baseline BASDAI/BASFI scores between 'responders' and 'nonresponders'.
Most likely costeffectiveness estimate (given as an ICER)
For ankylosing spondylitis the ICERs for adalimumab, certolizumab pegol, etanercept and golimumab compared with conventional care ranged from about 19,200 per QALY gained for certolizumab pegol (with the patient access scheme) to 21,600 per QALY gained for etanercept in the Assessment Group's base case (assuming rebound to baseline). The Committee concluded that these ICERs were all within the range considered to be a costeffective use of NHS resources.
The ICERs for infliximab for ankylosing spondylitis were about 40,600 and 36,800 per QALY gained compared with conventional care, using the original and biosimilar prices respectively, in the Assessment Group's base case. However, the Committee noted comments received in response to the appraisal consultation document about the infusion cost of infliximab and the lower prices of the biosimilar versions of infliximab as a result of the tendering process. The Committee also discussed the new ICERs, presented by the companies marketing biosimilar versions of infliximab in response to the appraisal consultation document, that used lower prices to reflect the tendering process that was taking place during the consultation period. The Committee therefore concluded that infliximab could be recommended as an option for treating adults with ankylosing spondylitis.
For nonradiographic axial spondyloarthritis the ICERs for adalimumab, certolizumab pegol and etanercept compared with conventional care ranged from about 28,200 for certolizumab pegol (including the patient access scheme) to 29,800 for etanercept per QALY gained, compared with conventional care. The Committee referred to the conclusion that the benefit of TNFalpha inhibitors was potentially underestimated in the clinical trials. It also noted that the Assessment Group's assumption of a slower disease progression rate in nonradiographic axial spondyloarthritis compared with ankylosing spondylitis was not confirmed by the clinical experts, and that this would in part have driven the increase in ICERs compared with ankylosing spondylitis. Considering both of these issues, the Committee considered that the most plausible ICERs were likely to be below those presented by the Assessment Group and the Committee concluded that adalimumab, certolizumab pegol and etanercept were within the range that would be considered a costeffective use of NHS resources.
The Committee concluded that, although there was limited costeffectiveness evidence for subsequent TNFalphainhibitor use, and an exact ICER could not be determined, it considered the ICER would be within the range considered to be a costeffective use of NHS resources and subsequent TNFalphainhibitor treatment could be recommended.
How has the new costeffectiveness evidence that has emerged since the original appraisal (TA143 and TA233) influenced the current recommendations?
Since the publication of NICE's technology appraisal guidance on adalimumab, etanercept and infliximab for ankylosing spondylitis, certolizumab pegol has gained a marketing authorisation in the UK for ankylosing spondylitis and for nonradiographic axial spondyloarthritis. Adalimumab and etanercept also have marketing authorisations for nonradiographic axial spondyloarthritis. All are recommended within their marketing authorisations as treatment options for ankylosing spondylitis or nonradiographic axial spondyloarthritis.
Additional factors taken into account
Patient access schemes (PPRS)
Merck Sharp & Dohme has agreed a patient access scheme with the Department of Health. This will make the 100mg dose of golimumab available to the NHS at the same cost as the 50mg dose. UCB Pharma has agreed a patient access scheme with the Department of Health. UCB Pharma will provide the first 12 weeks of certolizumab pegol free of charge, which is equivalent to 10 vials.
Equalities considerations and social value judgements
When using BASDAI and spinal pain visual analogue scale (VAS) scores, healthcare professionals should take into account any physical, sensory or learning disabilities, or communication difficulties that could affect the responses to the questionnaires, and make any adjustments they consider appropriate.
, 4.73# Review of guidance
The guidance on this technology will be considered for review 3 years after publication of the guidance. The Guidance Executive will decide whether the technology should be reviewed based on information gathered by NICE, and in consultation with consultees and commentators.Andrew DillonChief ExecutiveFebruary 2016