Astonishing Breakthroughs in Rheumatic diseases Treatment: Navigating the Next Frontier of Challenges

2023/08/03

The Division of Rheumatology inside the Department of Internal Medicine at the Keio University School of Medicine treats immune-mediated intractable diseases of unknown causes, such as rheumatoid arthritis, systemic lupus erythematosus, polymyositis, and dermatomyositis. The treatment of rheumatoid arthritis, in particular, has witnessed a paradigm shift over the past two decades. Here, Professor Yuko Kaneko, the head of the department, sits down to discuss those changes and the challenges that lie ahead. She also touches on why the collective effort of team medicine works and why there is no need to aim for perfection, messages she hopes to impart to the next generation of researchers.

Rheumatoid arthritis is a condition marked by symptoms that include joint pain and swelling, morning joint stiffness, fever, and fatigue. But what exactly is it?

“We call the system that identifies, combats, and eliminates foreign invaders such as bacteria and viruses in our body ‘immunity.’ This is supposed to be our protective shield, but when this function goes awry and starts attacking our healthy cells and tissues, we find ourselves dealing with what we call an ‘autoimmune disease.’ Rheumatoid arthritis is one of these autoimmune diseases, where the immune system assaults the soft tissues of the joints, called the synovium, causing inflammation. This can lead to the eventual destruction of the bones and cartilage that make up the joints.”

As rheumatoid arthritis progresses, it slowly erodes the bones and cartilage of the joints, which can lead to the deformation of the joints. Furthermore, symptoms may emerge in various organs, including the lungs, blood vessels, eyes, and skin, alongside other systemic symptoms, such as fever, fatigue, and loss of appetite. It’s estimated that up to 800,000 people in Japan are affected by rheumatoid arthritis, 80% of them being women, with the disease striking most individuals between the ages of 30 and 60.

“When I was a medical student, there were few effective treatments for rheumatoid arthritis and connective tissue diseases. Using painkillers and steroids to provide symptomatic relief was the main approach to treatment. When I chose to specialize in this field, I was driven by a desire to shed light on the many mysteries that surround this condition. Little did I know that before long, there would be a major shift in the treatment of rheumatoid arthritis.”

There is one astonishing figure, in particular, that demonstrates the paradigm shift that took place in the treatment of rheumatoid arthritis. That figure is the rate of remission, which is the percentage of rheumatoid arthritis patients who end up free of symptoms or signs that interfere with their daily life after treatment. In 2001, the remission rate was just 7.8%. Fast forward 20 years to 2021, and that rate had surged dramatically to 60.8%.

Prof. Kaneko attributes this remarkable progress to two key factors.

“One is the emergence of groundbreaking therapeutic drugs. Methotrexate, the current go-to anti-rheumatic drug, was finally approved in Japan in 1999. It inhibits the action of vital folate in immune cells, helping to reduce inflammation, improve symptoms, and suppress the progression of joint destruction. Then, in 2003, approval was given to TNF inhibitors that block the inflammatory cytokine TNFα, which is secreted by immune cells. These biological drugs worked so well, they surprised even us rheumatologists, and we saw an increase in cases where we could effectively control the disease.”

Prof. Kaneko says that the second key factor driving this change has been the establishment of what are called “treatment strategies.”

“Between the 1990s and 2000s, various assessment indices were developed to quantify rheumatoid activity, including the number of painful or swollen joints, serological responses, and patient self-assessments. In 2010, the medical strategy ‘Treat to Target’ (T2T) was proposed globally, which established a common understanding of regularly checking disease activity and adjusting treatment toward the goal of achieving remission. Treatment approaches for rheumatoid arthritis previously varied from doctor to doctor, but this presented a clear strategy focused on remission.”

The remarkable advancements in therapeutic drugs and treatment strategies have collectively raised the standard of rheumatoid arthritis care.

“For patients who have been diagnosed in the last 20 years, severe joint destruction is now almost nonexistent. There has also been a significant decrease in the number of cases that require surgical treatment. Japan’s rheumatology care, which used to lag behind other advanced countries by about 5 to 10 years in terms of approval for therapeutic drugs, has completely caught up over the past 20 years, to the point where now some medications are approved in Japan before anywhere else.”

While there have been groundbreaking advances in the treatment of rheumatoid arthritis, the mechanisms behind its onset remain unclear, and many medical needs are still left unmet.

“One challenge we face is the presence of rheumatoid arthritis that is difficult to treat. Despite the availability of several effective new drugs, about 10 to 20% of patients see no improvement no matter what we do, making treatment optimization a significant challenge. In recent years, we have also seen an increase in cases of late-onset rheumatoid arthritis in individuals in their 60s and 70s. For older individuals, the presence of other diseases and side effects from interaction with other medications often make standard treatments unfeasible, prompting ongoing research into their symptoms and treatment methods. Clinical trials aimed at preventing the onset of rheumatoid arthritis itself are also being conducted worldwide.”

Under the leadership of Prof. Kaneko, the Division of Rheumatology is actively engaged in studies that range from basic research aimed at understanding the mechanisms of the disease at the molecular level to clinical research for the development of novel treatments. This April, a research group led by Prof. Kaneko was the first in the world to demonstrate the potential for reducing the dosage of the anti-rheumatic drug methotrexate. (Reference:Press release)

“The standard global treatment for rheumatoid arthritis typically begins with methotrexate, and if that proves insufficiently effective, only then are biological agents introduced. When treating a patient with biological agents, it was common to continue with the same dosage of methotrexate, as it was thought to enhance the therapeutic effect. However, a higher dose of methotrexate can increase side effects like digestive symptoms, hair loss, liver disorders, and a decrease in blood cells, not to mention the added financial burden. This led us to conduct a clinical trial to see if we could at least reduce the dosage.”

The results of the clinical trial on 300 early-stage rheumatoid arthritis patients at facilities both in Japan and overseas showed that the remission rate in patients using TNF inhibitors was 38% for the group that continued with the same dosage of methotrexate (13.2mg/week) compared to 44% for the group that had a reduced dose (7.6mg/week). Even in the reduced-dose group, the effectiveness of the TNF inhibitor did not decrease, and no difference was observed regarding the degree of joint destruction or functional impairment. Meanwhile, the incidence of adverse events following the addition of TNF inhibitors stood at 35% for the group that continued with the same dosage of methotrexate and 20% for the group with a reduced dose.

“This study has shown that the methotrexate dosage can be halved when starting to use a biological agent. Going forward, we aim to evaluate the long-term effectiveness and safety of this treatment, with the hope of providing a safer alternative.”

Prof. Kaneko says that when studying immunology at the School of Medicine, she was captivated by the subject's intricacies and intrigue. But what are the particular aptitudes that determine whether someone is suited to specialize in the field?

“One aspect could be finding a sense of fulfillment and fascination in the hazy ambiguities that come with the field. Say you use a gastroscope to find and remove some cancer tissue. That’s quite straightforward. Rheumatology is different. For instance, when there's joint pain, you need to be careful in determining whether it's caused by rheumatism or some other disease. Determining whether a joint is swollen or not requires the expertise of a seasoned physician. Even if blood tests show positive rheumatoid factors, it doesn't necessarily mean that it's rheumatism, and there are other cases where inflammation indicators are high, but no other symptoms are found. This is all to say that rheumatism and collagen diseases require an integrated diagnosis using all the knowledge you’ve gained from patient interviews, examinations, imaging, and tissue samples. People who are intrigued by this kind of ambiguity, or should I say 'versatility,' are probably well-suited to work in this field.”

Another crucial aspect, she says, is having the resolve to treat patients holistically over the long term.

“Rheumatism is a chronic illness, meaning you will be treating patients over long periods of time. Nothing is more gratifying for a clinician than seeing their patients happy because the treatment is working. However, it's crucial to stay by your patient's side, working together on a treatment plan, and always striving for better outcomes, even when progress isn't as you'd hoped.”

Rheumatoid arthritis also affects various organs throughout the body, including the lungs, digestive system, blood vessels, and eyes, and is associated with allergies, cancer, and miscarriages.

“While some universities and hospitals delegate care to respective specialists for each organ, our department’s stance is to treat all organs affected by rheumatism and collagen diseases within the department. I believe this field is highly rewarding for those who take pride and joy in treating their patients in a holistic manner.”

Reflecting on a career as a physician and researcher that has spanned more than a quarter century, Prof. Kaneko shares her hopes for the next generation.

“I hope students today don't limit themselves to the confines of Keio. While there is great joy and fulfillment in everyday clinical practice, I urge students not to become complacent. I hope they will constantly keep an eye on the wider world and continue to challenge themselves, to have the audacity to explore the unknown and produce the evidence needed to move the field forward.”

The team at the Division of Rheumatology is thoroughly embracing this ethos, with an impressive output of 123 articles as first or co-author in 2021, as well as regularly presenting their research at international conferences. The department also has five members currently pursuing research at renowned institutions such as Harvard University, the University of Cambridge, and the Karolinska Institute.

“Since my lab is quite small, there is some friendly concern from within the university about whether we can sustain operations on campus when we're sending so many people overseas. [laughs] But, I think it's admirable to dedicate yourself to honing your skills at the forefront of your field and competing on a global scale, and I do whatever I can to support my colleagues. Plus, the very act of conducting research in a completely different culture and environment is guaranteed to lead to personal growth. Almost everyone in our department today has expressed a desire to go abroad.”

The upbeat atmosphere in the Division of Rheumatology also fuels Prof. Kaneko herself.

“There are times when research and clinical practice can feel like a series of setbacks, and I can get quite disheartened when things don't go as planned. It’s in those times that I’m reminded of how truly invaluable my colleagues are. Team medicine and research are a lot like team sports—when one person fails, we all rally around them and give it our best shot in the next round. Everyone is highly ambitious, and I can rely on my team to work hard while we strive to better ourselves and each other. I have great expectations for them.”

Lastly, Prof. Kaneko shared a message for students planning to study at Keio.

“The School of Medicine has traditionally sought an integrated approach to basic science and clinical medicine, aiming to educate research-minded clinicians, what we call ‘physician scientists.’ In fact, it's quite common for insights gained from our patients to inspire our research, and we always strive to leverage our research findings to benefit our patients. The opportunity to engage in both clinical practice and research and to learn in collaboration with places like the Faculty of Pharmacy and the Faculty of Nursing and Medical Care is something that I think is unique to Keio.”

As a physician and researcher, she also had words of encouragement for the next generation of female students.

“It’s true that many women may experience gaps in their careers due to childbirth and childcare. It’s also a reality that they tend to carry a greater share of household chores and childcare responsibilities. But know that you don’t have to do everything perfectly, whether at work or at home. There’s nothing wrong with speaking up and asking those around you for help. It's impossible to constantly run at 120% capacity. That’s true for everyone, not just women raising children. It’s crucial to do your best, but in a way that’s sustainable.”

Prof. Kaneko also stresses that there are various ways to live as a physician.

“Anyone wanting to return to the medical field after taking time off to focus on raising children will be welcomed back with open arms. There are also viable career paths outside the hospital at clinics and pharmaceutical companies. I hope to offer as much support as I can so that everyone can pursue the life they want. Let's work hard—together.”

Yuko Kaneko

Yuko Kaneko graduated from the Keio University School of Medicine in 1997 and joined the school’s Division of Rheumatology in 2004. In 2006, Prof. Kaneko was appointed as an assistant professor at the Center for Clinical Research (now the Clinical and Translational Research Center). After a year studying abroad at the University of Oxford in 2018, she was appointed as an associate professor at the Division of Rheumatology in the Department of Internal Medicine. She has held her current position of full professor since 2021. Her recent publications include the Golden Handbook of Rheumatology, which she co-authored.