All CADTH review teams include at least one clinical specialist with expertise regarding the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process including providing guidance on the development of the review protocol; assisting in the critical appraisal of clinical evidence; interpreting the clinical relevance of the results; and providing guidance on the potential place in therapy. The following input was provided by one clinical specialist with expertise in the diagnosis and management of AS.
Description of the current treatment paradigm for the disease
The treatment of AS aims to alleviate symptoms of back pain and stiffness. Some patients manage with no pharmacological treatment, preferring exercise and activity to minimize pain and stiffness. Physiotherapy can be a useful adjunct, especially when directed at preservation of posture and spinal range of motion. In a specific patient, the rate of progression of AS is unpredictable and symptom intensity itself is not necessarily a harbinger of a poor outcome of total spinal ankylosis.
NSAIDs are the first-line pharmacologic treatment. There are numerous RCTs of NSAIDs in AS, demonstrating not only symptom relief but also inhibition of radiographic progression. However, some of the most effective NSAIDs such as selective cyclooxygenase-2 inhibitors including rofecoxib (Vioxx) and etoricoxib (Arcoxia) are no longer available in Canada due to increased cardiovascular events. Another NSAID, phenylbutazone was also withdrawn due to hematologic AEs. The remaining available NSAIDs are associated with other significant morbidities such as neurologic, renal, gastrointestinal, cardiac, and hepatic toxicity. AS is a spinal disease and studies, including RCTs, of conventional DMARDs (MTX, sulfasalazine, leflunomide) have not shown efficacy in managing AS.
Failure of NSAIDs lead to the use of TNF inhibition, which is effective in controlling symptoms and inhibiting radiographic progression. Access to TNFis (and their biosimilar equivalents) require—depending on province or country—failure of two or three NSAIDs administered for two to four weeks, and a level of disease activity usually defined as a BASDAI score greater than four. All Canadian insurers, including provincial formularies, provide access to TNFis. Most recently, IL-17 inhibition by SEC (Cosentyx) has been shown to be effective in AS. IXE is the second IL-17 inhibitor seeking approval from Health Canada for the treatment of AS.
The Janus kinase (JAK) inhibitor tofacitinib (Xeljanz) has a single phase II study showing efficacy in AS and is currently under evaluation in a Phase III RCT. It is expected that manufacturers of JAKs such as baricitinib and upadacitinib will evaluate their products in AS.
Other biologic drugs such as IL-6 inhibitors (abatacept and rituximab) and IL-23 inhibitors (apremilast) are not currently used for AS and are NOT likely to be tried off label, in some instances because of data showing lack of effectiveness, and in other instances because the sponsor has decided not to pursue development of their drug for the AS market.
Treatment Goals
Treatment reduces the severity of symptoms and prevents ankylosis (fusion) of the spine and nearby joints. Effective treatment could allow less exposure to NSAIDs, and their associated AEs, and steroids, which for many years were the only drug therapy available when symptoms could not be managed by NSAIDs alone. The relief of symptoms improves function and quality of life and should manifest in fewer days lost from work and the enjoyment of life. Prevention of ankylosis has additional implications, among them allowing the cervical spine to turn to check blind spots while driving, and maintaining pulmonary function. Because hips and shoulders can be involved in AS, it is expected that control of AS should reduce the future need for hip and shoulder replacements. Complications of untreated AS such as aortic insufficiency, pulmonary fibrosis, and renal amyloidosis causing kidney failure are expected to disappear.
Unmet Needs
There remains an ongoing need for drug development in AS for many reasons including; non-responsiveness of some patients to all available treatments; the development of treatment-refractory response in some patients; treatment intolerance and associated poor compliance; and lack of convenience of available treatments.
Place In Therapy
Current treatment regimens permit ongoing treatment with NSAIDs, but there is no reason to think that IL-17 inhibitors will be combined with TNFis or JAK inhibitors in the future. AS can occur in patients with psoriatic disease and inflammatory bowel disease, and in patients with psoriatic disease IL-17 inhibitors carry the advantage of controlling skin disease in addition to the spine and peripheral joints. In patients with psoriatic disease and peripheral joint arthritis, IXE can be combined with conventional DMARDs such as methotrexate. In patients with known inflammatory bowel disease, IL-17 inhibitors are not an optimal choice because of the risk of increased flares of bowel disease when IL-17 is inhibited. In the two IXE trials that comprise this report, patients with inactive inflammatory bowel disease were not excluded and four cases of inflammatory bowel disease were seen with IXE compared to one case with placebo.
IXE is the second IL-17 inhibitor to be approved in AS and joins five TNFis and their biosimilars in this therapeutic area. Most likely to arrive soon will be the JAKs, with three currently on the market and more to arrive. IXE will be available as treatment after failure of NSAIDs and as treatment after failure of a TNFi. There is no data regarding whether failure on the other IL-17 inhibitor, SEC, will predict success or equal failure on IXE. IXE is not expected to shift current treatment algorithms until there is data to show superior efficacy or safety compared to other available therapies.
The 2019 ACR guidelines on the treatment of AS8 state: TNFis are recommended over SEC or IXE as the biologics of first choice. SEC or IXE is recommended over a second TNFi in patients with a primary non-response to the first TNFi. Co-administration of methotrexate with a TNFi is not recommended, nor is it recommended to use a treat-to-target strategy, to discontinue, or taper biologics in patients with stable disease.
These recommendations represent the state of therapy likely to be followed by Canadian rheumatologists. However, tapering strategies have not been well studied and in clinical practice, many patients take less medication. Full discontinuation of a biologic is discouraged, but appropriate studies are required before rheumatologists have the data to support such a strategy.
Patient Population
According to current reimbursement criteria of plans which participate in the CADTH Common Drug Review (CDR), at this time the singular basis for initiation of treatment is the BASDAI score. The BASDAI is a six-question instrument ranging from 0 to 10 and a BASDAI score of greater than four, despite treatment with NSAIDs, allows application for a biologic. There are no well-studied predictors of response to treatment. In the RCTs, patients with total ankylosis of the spine are excluded, but in the opinion of the clinical specialist consulted by CADTH, this is a “clinical trial strategy” predicated on excluding patients that are not likely to demonstrate changes in numerous outcome measures. In reality, such patients may well demonstrate considerable decreases in pain, stiffness, and fatigue and meaningful improvements in quality of life. Because most payers base reimbursement criteria on the inclusion or exclusion criteria used in RCTs, such patients who may well benefit from treatment may be declared ineligible.
The RCTs were conducted on patients with unequivocal AS on X-ray, defined as Grade II or higher bilateral sacroiliitis or Grade III or IV unilateral sacroiliitis. Thus, the diagnosis of AS must be quite definitive and is usually easily established by a qualified radiologist or rheumatologist. Defined in this way, patients with AS are easily identified using simple and relatively inexpensive methods. Over-diagnosis of AS is unlikely but under-diagnosis can occur. The presence of sacroiliitis in the Canadian context almost always means AS. However, infections such as tuberculosis and brucellosis, and tumours, particularly sarcomas, can also cause “sacroiliitis” and on occasion need to be considered by the treating rheumatologist.
Under-diagnosis of AS occurs. At this time payers will likely exclude patients with non-radiographic AS, an accepted clinical entity diagnosed usually by MRI and eligible for treatment with TNFis. An RCT in such patients may be required to obtain reimbursement for MRI positive, non-radiographic AS with IXE. Other patients with symptoms of inflammatory low back pain but negative X-ray and MRI have been identified in research studies by biopsy of the SIJ. These patients do not meet current eligibility criteria for TNFis or IL-17 inhibition.
Currently, a pre-symptomatic state of AS is not recognized. There are no studies to consider prevention of disease in patients at high risk, for example an HLA-B27 positive individual with a parent or sibling with definite AS.
Patients with AS and active inflammatory bowel disease and/or uveitis are less suited for IL-17 inhibitors as there is a possibility of exacerbation of their bowel or eye disease. Patients with inactive bowel or eye disease can be treated with proper vigilance. In contrast, IL-17 inhibition would be considered first-line therapy in patients with a personal or family history of MS because TNFis are associated with exacerbations of MS.
At this time, it is not possible to identify those patients who are most likely to exhibit a response to treatment with the drug under review.
Assessing Response To Treatment
The BASDAI is currently used to determine eligibility for treatment. A reduction of BASDAI by 50% and/or an absolute decrease in two units of the 10-point scale is necessary for drug renewal. Other outcomes exist but are not required to determine eligibility or renewal.
The reduction in BASDAI of 50% and/or two units on the 10-point scale is considered a clinically meaningful response to treatment. Other outcomes are important to the patient but not considered when it comes to approving ongoing treatment.
The initial treatment response should be evident by three months and an application for a change in therapy will be made between three and six months. Renewals are yearly or less often, depending on the province or insurer.
Discontinuing Treatment
Lack or loss of clinical response or drug toxicity determine discontinuation of treatment by the physician. Patient-related causes include loss of insurance, depression, and fear or distrust of the medication.
Prescribing Conditions
IXE is self-administered as a subcutaneous injection at home. A rheumatologist usually makes the diagnosis and initiates treatment. As there are “hard” criteria for diagnosis of AS, and for eligibility for initiation and renewal of treatment (i.e., self-administered BASDAI questionnaire), ongoing management of AS managed by a family doctor or nurse practitioner.
