Oral Janus kinase inhibitors (JAKi) have been expanding the treatment landscape for inflammatory rheumatoid diseases for several years. In the following interview, Prof. Dr. med. Gerd Burmester explains what this means for the management of these diseases and what points there are to consider with regard to the effectiveness and safety of JAKi. 

   Prof. Dr. med. Gerd Burmester, Berlin

1. what advances in the management of inflammatory rheumatoid diseases have you seen during your medical career? What were the three biggest innovations for you?

This question is relatively easy to answer when looking at innovations in therapy.

In my opinion, there are three milestones here: First, the development of methotrexate (MTX) or the use of MTX in rheumatology. The next milestone was the development of biologics, with particular emphasis on tumor necrosis factor inhibitors (TNFi) and, for the treatment of rheumatoid arthritis (RA), IL-6 receptor inhibitors, but also co-stimulation inhibitors or B-cell-directed therapy. As a third milestone, I see the development of Janus kinase inhibitors (JAKi), which can also work when, for example, biologics have failed. JAKi show a very good spectrum of efficacy and have in some cases performed better than known biologics in controlled clinical trials.

2. the JAKi class represents the latest addition to the therapy landscape in RA. How do you evaluate the safety profile of these drugs? 

The data on the long-term use of JAKi is very extensive. Thus, there are already findings from controlled long-term extension studies, there are large registry studies from the USA and also first registry studies from Europe, which show a very good safety profile for JAKi, which roughly corresponds to the safety profiles known from biologics.

All JAKi are accompanied by a clear signal for herpes zoster. However, I am optimistic that we can significantly reduce the risk of herpes zoster with appropriate vaccination. In addition, JAKi show a signal for elevated creatine kinases (CK) levels. However, these are generally not clinically relevant.

The data just described are supplemented by the relatively recent results of the randomized, prospective, controlled ORAL Surveillance Study. In this, no non-inferiority of JAKi tofacitinib versus TNFi was shown in RA patients with at least one additional cardiovascular risk factor. In addition, incidences of malignancy and cardiovascular events were numerically higher with tofacitinib than with TNFi, which was not observed in other JAKi trials. When interpreting the results of the ORAL surveillance study, it must be taken into account that a highly selected, critically ill patient population was included. The overall study evidence does not suggest an increased risk of cardiovascular or malignant events with JAKi compared with TNFi. Overall, one must always evaluate the individual risk profile of a patient when deciding on a therapy.

3. how would you address potential patient safety concerns when considering treatment with JAKi?

Shared decision making is a very important point. Nowadays, patients primarily ask not about the effectiveness of the drugs, but about the range of side effects. This is perfectly understandable, since the drugs are sometimes taken for more than 10 years. Of course, there are classic problems, such as infections or tuberculosis in TNFi. However, the risk of this could be reduced by 80% with careful screening and preemptive therapy. In JAKi, we have to pay attention to cardiovascular pre-existing conditions and malignancies and include this in the decision-making process – always knowing that our patients very often prefer oral therapy, want to take only one tablet per day and would like to stop co-medication, e.g. with MTX. This is understandable, as many patients take multiple preparations for multiple conditions. From the patient’s point of view, medication should therefore be as straightforward and simple as possible and, for example, allow travel without the need for time-consuming carrying of syringes.

4) How do you evaluate the integrated safety study of upadacitinib (UPA), in which all three indications – RA, ankylosing spondylitis (AS) and psoriatic arthritis (PsA) – have been analyzed in detail, with regard to your confidence in the long-term safety of UPA [1]?

Some side effects, e.g. malignancies, can only be observed after a certain time and not already after 6 to 12 months. In this respect, long-term safety data are extremely important. For UPA, we also have such available in comparison with MTX and adalimumab (ADA). Current data suggest a good safety profile for UPA. With the exception of an increased incidence of herpes zoster and elevated CK levels with UPA, there was no evidence of safety differences compared with biologics.

5 The stated therapeutic goal in RA, AS and PsA is to achieve durable remission. [5]. To what extent have we come closer to this goal through the introduction of JAKi?

In many studies, JAKi are superior to the respective comparator in terms of remission rates and improvements in other disease aspects. In particular, the TNFi ADA has been studied as a comparator, or, in RA, the T-cell inhibitor abatacept in biologics failures. Here, the remission rate is higher with JAKi, although only by 10 to 20%. I am happy about every additional patient who achieves remission and consider this very valuable. It’s an important finding that we can still do a little bit more with JAKi than we can with biologics, which are already good drugs, especially if the biologics have already failed in a patient. Here, we used to have our backs to the wall in the face of a lack of therapy options. Today, we can get much more out of JAKi for these patients.

6. UPA shows high efficacy in remission not only in RA but also in AS and PsA in the clinical trials. [6-9]. What is your experience in this regard? 

Our experience with UPA has been good and in line with the results of clinical trials. However, this would not necessarily have been predicted. Many felt that JAK-1-specific inhibitors acted more through the IL-6 pathway, and we know that IL-6 inhibition does not play a major role in either PsA or AS. In this respect, it was surprising that the JAKi worked so well in these diseases. Indirect mechanisms may be involved here, so that less IL-17 and TNF are secreted via general inhibition of inflammation and thus these clear successes are achieved.

7. the rapid onset of action, especially the rapid pain reduction, are special characteristics of UPA [6]. How important is this point in the treatment of your patients? 

This point is critically important! This is because patients nowadays expect fast pain relief. I can still remember earlier times when patients woke up at night with extreme pain in their fingers. That must have been quite a terrible life if every little movement of the fingers caused enormous pain. Based on our experiences, e.g. with toothache or headache, we know what it means to suddenly be free of pain. This makes it easy to understand, even as a person with normal joints, that the aim is to achieve a rapid onset of action. As pain is relieved, functional ability also improves. For example, patients can walk or climb stairs better again and perform daily activities. For many patients, it is already a major hurdle to fasten a button or tie a shoelace. The invention of Velcro was an immense improvement for patients at the time. This can no longer be imagined today, since we can now treat so well.

8. MTX intolerance is a major challenge for the rheumatologist. What can it mean for patients to start with JAKi as monotherapy on the one hand and to be able to stop MTX under a JAKi on the other hand?

Monotherapy is extremely important for our patients because, on the one hand, they sometimes do not tolerate MTX well and, on the other hand, they often take numerous other drugs, e.g., for osteoporosis prophylaxis or to lower blood pressure. Even for experienced patients, it is not always easy to keep track of everything. Here it is optimal to have to take only one tablet per day. In a good disease situation, MTX can be discontinued carefully – often the initiative comes from the patient. From my point of view, this works very well in most cases.

9. which aspects of the treatment with JAKi would you emphasize compared to conventional therapies with biologics?

TNFi, especially ADA, are usually used in combination with MTX in RA. While there are some patients who do well without MTX, anti-drug antibodies often develop and ADA efficacy wanes. This problem does not exist with JAKi. Another advantage of JAKi from the patient’s perspective is the simple once-daily oral administration. In addition, JAKi have a very short half-life. If there is a desire to have children, JAKi can be discontinued at shorter notice compared to biologics. Clinical studies have also shown that JAKi are more effective than classical TNFi in many areas and can achieve good therapeutic success even when all other biologics have failed.

10. unlike biologics, JAKi inhibit the signaling cascade of many cytokines. What advantages does this offer you in the sustainable treatment of your patients?

We have often considered whether multiple biologics can be combined to inhibit multiple cytokines simultaneously. But of course, this would require very elaborate study programs. JAKi naturally interfere with various signaling cascades and are thus helpful in a variety of diseases – not only RA, but also AS, PsA, and atopic dermatitis. We hypothesize that with the low doses used, a balance was found in which JAKi scavenge excess cytokines produced in a chronic inflammatory situation without affecting the physiological action of JAK enzymes.

About Prof. Dr. med. Gerd Burmester

Prof. Dr. med. Gerd Burmester is University Professor of Internal Medicine, Rheumatology and Clinical Immunology and was Director of the Medical Clinic with focus on Rheumatology and Clinical Immunology at Charité – Universitätsmedizin, Freie Universität and Humboldt-Universität zu Berlin from 1993 to 2022. Previous stations of his medical-scientific career include the Friedrich-Alexander University Erlangen-Nuremberg, the Rockefeller University and the Mount Sinai School of Medicine in New York, USA, as well as the Hannover Medical School.

Prof. Dr. med. Gerd Burmester has played a major role in shaping rheumatology through his activities in various professional societies, including the German Society of Rheumatology (DGRh), the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). Over the course of his scientific career, he contributed significantly to understanding the inflammatory processes underlying RA. His findings shaped several large studies on the therapy of rheumatic diseases with new active substances. For example, he already led the large integrated safety study of TNFi adalimumab (HUMIRA®) and now the integrated safety study of JAKi upadacitinib (RINVOQ®) [1, 10]. The results were presented and discussed at this year’s SGR annual congress. Prof. Dr. med. Gerd Burmester is now committed to his field as a senior professor and continues to contribute to the growth of scientific knowledge, in particular also through editorial activities for scientific journals.

References

The references can be requested by professionals at medinfo.ch@abbvie.com.

Report and interview: Dr. sc. nat. Jennifer Keim

To the brief technical information of RINVOQ®.

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

CH-RNQR-220088_10/2022

Article online since 17.11.2022