Therapy progress with JAKi and earlier diagnosis

The treatment of ankylosing spondylitis (AS) is primarily aimed at using anti-inflammatory medication to relieve pain and prevent the development of ankylosis [1]. In this interview, Prof. Dr. Denis Poddubnyy from the Charité in Berlin gives an insight into the challenges and advances in AS therapy management.

AS is a chronic inflammatory disease that primarily manifests itself in the sacroiliac joints (SIJ) and the spine [2]. Those affected suffer from inflammatory back pain and can experience mobility restrictions as the disease progresses [2]. With TNF inhibitors (TNFi), interleukin-17 inhibitors (IL-17i) and Janus kinase inhibitors (JAKi), there are already effective drugs that can counteract inflammation and the progression of structural changes [3, 4]. Prof. Poddubnyy explains how the establishment of Janus kinase inhibitors (JAKi) and earlier diagnosis of AS can further improve the treatment outcome of patients.

Prof. Dr. Denis Poddubnyy, Head of Rheumatology, Charité Universitätsmedizin Berlin, Germany

DIAGNOSIS

What are the biggest challenges in diagnosing AS today?

Despite steady improvement, there is still a long delay in diagnosis. About 20 years ago, the average diagnosis delay in Europe was still around 10 years, whereas today it is around 5-6 years. However, this is still very long. In most cases, the late diagnosis is due to people with AS being referred to rheumatologists too late. The primary point of contact for patients with back pain is often their family doctor or orthopaedist. They must remember that inflammation may also be behind the pain. Especially when chronic back pain occurs in young people under the age of 40 and has inflammatory characteristics, it should be clarified by a rheumatologist. Inflammatory characteristics include, for example, back pain that worsens at rest, occurs at night, and is accompanied by morning stiffness in the back.

Furthermore, there are no absolutely reliable diagnostic parameters. Inflammatory back pain can also occur in patients with degenerative diseases. In addition, certain changes in the X-ray image or MRI may be non-specific. This applies in particular to bone marrow edema in SIJ, a core symptom of active sacroiliitis. Bone marrow edema can also occur as a reaction to mechanical overload, such as in women after childbirth. To distinguish mechanically induced edema from typical inflammatory bone marrow edema, the localization in the joint is relevant. A central localization in the joint is rather unspecific, while structural changes such as erosions are typical of AS. There is an unmet need in the training of rheumatologists and orthopaedists to differentiate between mechanical and inflammatory problems in imaging – this would significantly improve diagnostics.

Why is it important to make an early and accurate diagnosis of AS?

A short duration of symptoms at the start of therapy is associated with a good response to therapy. Firstly, it prevents the centralization of pain. As a result, patients can achieve very good therapy results by inhibiting inflammation, and possibly become completely free of symptoms and inflammation. Secondly, structural progression is avoided. The earlier the control of inflammatory activity is started, the greater the likelihood that pronounced ankylosis and thus irreversible structural damage and functional limitations can be avoided. Therefore, the earlier we treat, the better, because early diagnosis also goes hand in hand with early treatment.

In daily clinical practice, do you differentiate between radiographic, i.e. AS, and non-radiographic axial spondyloarthritis (axSpA) patients?

This distinction is not relevant for everyday clinical practice. I make the diagnosis “axSpA” and also note “ankylosing spondylitis” and “AS” so that everyone can understand. The concept of non-radiographic axSpA is important when patients do not have pronounced structural changes. In this case, one must be very careful, since in the absence of structural changes, the specificity of active inflammatory changes from bone marrow edema decreases. Bone marrow edema in the absence of structural changes is almost always less specific than bone marrow edema on the background of structural changes. The structural changes that axSpA causes tend to appear early in the course of the disease. Cross-sectional imaging such as MRI or CT can detect these very well, which is why imaging plays such an important role in the diagnosis and interpretation of active inflammatory changes.

MANAGEMENT & MONITORING

How do you involve your patients in treatment decisions and the definition of treatment goals?

It is very important that patients understand what illness they have and what we want to achieve. It must be explained to them that AS is a chronic inflammatory disease and that our measures are aimed at keeping the inflammation under control and maintaining physical function. To achieve this, both doctors and patients need to be active. Doctors give medication and advice, while patients should contribute by, for example, doing regular physiotherapy exercises, staying active and not smoking. These are important factors that can contribute to the success of therapy and the long-term maintenance of performance and functionality.

In your opinion, what are the most important recommendations and specific challenges in monitoring AS patients?

Monitoring essentially depends on how active the disease is. The well-being of patients is relevant in everyday clinical practice. In order to standardize this, certain scores are used that play a role both in clinical studies and in everyday clinical practice. The BASDAI* was used for a long time, but nowadays the ASDAS* is recommended. In addition to the BASDAI, the ASDAS also includes a global assessment of disease activity by the patient. I also do the BASFI* with my patients about twice a year to check the functional restrictions and to see if the movement restrictions are getting worse. However, the control of structural progression is not firmly prescribed. This is because there are no practical consequences. If I see that a patient has developed two new syndesmophytes in the last few years, my treatment approach would not change. To avoid future syndesmophytes and ankyloses, disease activity must be kept under control. This corresponds to a BASDAI of <4 or ASDAS <2.1, in the best case <1.3.

What is your treatment goal? And are there specific endpoints that are particularly clinically relevant to achieving your goal?

With AS, our goal is clearly to achieve remission. Remission is defined as freedom from symptoms and inflammation (ASDAS value <1.3), which is nowadays a perfectly achievable goal. If remission cannot be achieved for various reasons, the aim is to keep disease activity as low as possible. An ASDAS <2.1 would still be acceptable. If the value is above this, you should always check why you are not achieving the therapy goal. Is it really because the inflammatory activity is not under control? Or are there other reasons for pain and failure to achieve acceptable symptom control?

TREATMENT

In your experience, what is the greatest unmet need in the treatment of AS?

In particular, we should look at patients who are being treated with a probably effective anti-inflammatory therapy but are still not achieving our therapy goals. There may be several reasons for the poor response. Firstly, there are patients who do not respond biologically or immunologically to the therapy. In AS patients, however, this is only about 5-10% of all non-responders. Secondly, there are patients who do not respond due to central sensitization. This poses a much greater problem in everyday clinical practice, as central sensitization can lead to the development of a chronic pain syndrome. It is not yet clear how to tackle this problem. Due to the diversity of non-responders, patients must be inspected closely to determine whether a change in therapy or an escalation of therapy is more appropriate. If there is an indication of central sensitization, such as pain over large areas of the body, it is necessary to resort to measures that are currently available in pain medicine. This requires complex treatment, not just medication, and represents one of the largest and most relevant Unmet Needs in this area.

How important is a fast onset of action for AS treatment?

Patients often only come to us after they have been suffering from pain for months or years. We remember that the average time to diagnosis is 5-6 years. One month more or less plays less of a role in the course of the disease. It is much more important to diagnose the disease as early as possible.

They were involved in the upadacitinib program from the very beginning. What is your experience with JAKi in general and upadacitinib in the treatment of AS?

Just 7-8 years ago, we were still wondering whether JAKi had any effect at all on inflammation in AS. At that time, there were already several drugs, such as IL-6 inhibitors, which were promising but then failed in clinical trials. Then came the first phase 2 trials with tofacitinib and filgotinib and later with upadacitinib, all of which showed clear superiority over placebo. Studies on gene expression analyses then showed that JAKi can achieve a very broad inhibition of inflammatory signaling pathways. The blockade of multiple signaling pathways most likely determines the efficacy of JAKi in AS. We now have a new class of substances that is just as effective in the musculoskeletal domain as established biologics. It is now known that TNFi, IL-17i or JAKi can be used for axial inflammation, with all showing comparable efficacy. However, there are differences in extra-musculoskeletal manifestations. Robust data are available for TNFi in uveitis, and IL-17i are very strong in the skin. So what niche do the JAKi occupy? To me, it looks like JAKi follow the pattern of TNFi, with efficacy in musculoskeletal and extra-musculoskeletal manifestations. For example, several JAKi have already been approved for chronic inflammatory bowel diseases. New data is now also available on psoriatic arthritis and uveitis. For example, it has been shown that patients treated with upadacitinib are significantly less likely to develop uveitis compared to placebo. I think we will get more clarity in the next few years and JAKi will also find its way into the treatment recommendations.

UPADACITINIB

Based on the clinical SELECT-AXIS program [2, 5-7] and your experience the strengths of upadacitinib in the treatment of AS? How important is it to demonstrate consistent efficacy in different patient populations?

The program began with a rather small study that only included patients with radiological axSpA, i.e. AS, who had not previously been treated with biologics. Patients after TNFi or biologics failure were then also included in a follow-up study. In all studies, upadacitinib was clearly superior to placebo with regard to the endpoints. I would particularly like to emphasize the good efficacy even after biologics failure. In patients who do not respond sufficiently to biologics, it is often difficult to achieve a good response after changing therapy. Upadacitinib has delivered convincing results in this patient group, with similar efficacy as in bio-naïve patients. This is very unique in the AS sector. The safety aspects of the study were also important, as there is still a great deal of discussion regarding the safety of JAKi. However, there were no new safety concerns and we hardly recorded any events at the beginning of the studies that would have caused a stir, such as serious cardiovascular events or cancer cases.

The MRI was developed as part of the SELECT-AXIS program [8] and consistently showed improvements in the SPARCC* values for the spine and SIJ. How important are MRI results in addition to meeting clinical endpoints such as ASAS and ASDAS?

In clinical studies, imaging is a very good indicator of the objectifiable anti-inflammatory effect of medication. If there is a strong reduction in inflammatory activity in the SIJ and spine with a particular therapy, such as upadacitinib, then we know that the drug is working. This also reduces all symptoms associated with inflammation. It also shows that the progression of structural changes, particularly in the spine, is also very likely to be inhibited. If the inflammation is kept permanently under control, there is no reason for new syndesmophytes to develop. JAKi thus probably have a similar effect on radiographic progression as TNFi, for example. It has already been shown that the inhibition of radiographic progression occurs – albeit with a delay – if the inflammation is permanently controlled.

What place does upadacitinib have in your treatment algorithm for patients with AS?

According to current recommendations, biologics are generally recommended as first-line therapy after the failure of non-steroidal anti-inflammatory drugs. However, there is nothing to stop doctors from also using JAKi, for example upadacitinib, as first-line therapy for AS. It is also important to consider the form in which the medication is administered. Biologics are always administered in the form of injections and there are certainly people who clearly prefer tablets to injections. In situations where an oral dosage form is clearly preferred or there is no alternative, oral substances such as upadacitinib come in first place.

Conclusion

In summary, early but also correct diagnosis is very important. I therefore appeal to all doctors to check young people with inflammatory back pain for AS. Once the diagnosis has been made, we must try to control the inflammatory activity by all means. This not only leads to symptom control, but also prevents long-term structural progression.

BOX 1: The most important facts in brief from the interview with Prof. Dr. Poddubnyy

On average, AS is only diagnosed in Europe after 5-6 years of illness.
However, early diagnosis is necessary to prevent the centralization of pain and the progression of ankylosis.
Cross-sectional imaging using MRI or CT is relevant for the diagnosis and interpretation of active inflammatory changes.
Certain scores, such as the ASDAS or BASFI, are used to standardize the assessment of the disease burden.
The treatment goal is remission, or at least low disease activity, in order to prevent the formation of ankyloses.
In the treatment of radiographic axSpA (AS), in addition to TNFi and IL-17i, JAKi, e.g. Upadacitinib, is used.
One of the biggest unmet needs in the treatment of AS is the correct approach to non-responders due to central sensitization.
JAKi such as upadacitinib cause a very broad inhibition of the inflammatory signaling pathways, which is why they are highly effective in AS.
The results of the SELECT-AXIS program are convincing with regard to the efficacy of upadacitinib even in AS patients with previous biologics failure and good safety results [2, 5-7].
MRI data indicate an inhibition of structural progression with upadacitinib [8].

*ASAS: Assessment in Spondylo Arthritis international Society; ASDAS: Ankylosing Spondylitis Disease Activity Score; BASDAI: Bath Ankylosing Spondylitis Disease Activity Index; BASFI: Bath Ankylosing Spondylitis Functional Index; JAKi: Janus Kinase Inhibitor; Si joints: sacroiliac joints; SPARCC: Spondyloarthritis Research Consortium of Canada.

Brief information Rinvoq®

This article was produced with the financial support of AbbVie AG, Alte Steinhauserstrasse 14, Cham.

CH-RNQR-230084 09/2023

This article has been released in German.

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