That's debatable! Doctors dissect 5 hot topics in rheumatology

There's a well-worn adage in rheumatology circles that if two experts evaluate the same patient, they'll almost certainly come up with three conflicting opinions. Controversies and lively debates are pervasive throughout the field.

Rheumatology is a rapidly advancing, but relatively young subspecialty. Accordingly, an understanding of the pathophysiology, treatment, and classification of rheumatic disease is still emerging.

Plus, the lack of protocol-defined guidelines for treatments gives rise to differing practices—and, yes, opinions—all paving the way for a better understanding of rheumatic diseases and more informed patient care.

Controversy #1: Treating pre-RA

Early treatment, advanced therapies, and treat-to-target strategies have been clinically meaningful in RA patients.[1] These approaches, however, occur only after inflammatory arthritis manifests, and patients can no longer return to their pre-RA symptoms. Therefore, researchers have trained their sights on prevention.

Additionally, delays in diagnosis, the rising prices of drugs, and hampered access to rheumatologists further underscore the immediate need for preventive approaches.

Various studies have pointed to a period of development in RA called “pre-RA” that is marked by antibody abnormalities or the presence of biomarkers sans clinical symptoms. 

“This was a major debate at the American College of Rheumatology's 2022 meeting," said Dr. Anita Chandrasekaran. "There is no clear definition for pre-RA, but it could be defined as those who have positive markers for RA (ie, positive rheumatoid factor and/or anti-CCP) or those who have joint pain with abnormal ultrasound findings, but may not have positive markers."

Even though a clear definition of the term pre-RA may be lacking, specialists do treat it.

“Treating preclinical rheumatoid arthritis involves intervening at an early stage of the disease before symptoms like joint pain and swelling appear. This approach is based on the understanding that joint damage can occur even in the absence of noticeable symptoms,” said Dr. David Ozeri.

“Studies have shown that early treatment of RA, including during the preclinical phase, can lead to better long-term outcomes. It can help reduce joint inflammation, control disease activity, and prevent or minimize irreversible joint damage. Early treatment also increases the likelihood of achieving remission or low disease activity, which improves quality of life for patients,” he added.

"These medications work to suppress inflammation and modify the underlying disease process, aiming to prevent or delay the onset of symptomatic RA and its associated complications,” he said.

Dr. Chandrasekaran also focuses on lifestyle interventions in these patients. "In those who have joint pain or intermittent swelling, I do consider early treatment, which may not prevent disease, but may delay onset of full-blown clinical RA,” she added.

Controversy #2: Using dual biologics to treat PsA

Novel treatments of inflammatory arthropathies have improved clinical outcomes in many patients, yet there remains a contingent of patients who are refractory.

Dual-biologic therapy targeting different inflammatory pathways could be effective in treating inflammatory diseases like psoriatic arthritis (PsA) and RA that have complex and heterogeneous pathology, according to the authors of a review published in Rambam Maimonides Medical Journal.[2] 

To date, several randomized controlled trials have assessed the safety and efficacy of dual-biologic treatment of RA, but the results have been mixed, which has raised safety concerns. 

Analysis of one case series of successful use of dual-biologic therapy in PsA found that IL-12/23i (ustekinumab)+TNFi, IL-23i (guselkumab)+TNFi, and IL-17i (secukinumab)+TNFi could be effective.

“To date, many questions remain unanswered regarding this novel field of therapy,” wrote the review article authors, “including the choice of the most efficacious anti-cytokine biologics, along with the most appropriate timing, sequence, frequency, and duration of treatment."

A potential strategy to decrease adverse events,” they suggested, “would be to use a lower dose of each therapy and consider asynchronous use of biologics with a loading dose of one drug followed by a sequential administration of another drug.” 

In addition, they added, “Along the rapidly evolving field of [immune-mediated disease] treatment, dual therapy may constitute an efficacious and safe add-on treatment to biologic therapy, but properly conducted clinical investigations are needed. In the meantime, dual biologic therapy used by physicians’ discretion requires close monitoring of patients with an emphasis on the safety profile."

Dr. Chandrasekaran warned that dual-biologic therapy may not be for every patient.

However, she also said that it's not uncommon for patients with psoriasis or psoriatic arthritis to experience treatment failure with two or more biologics in the clinical setting, "and in patients who have tried multiple biologics, either on their own or in combination with a standard DMARD, this is a reasonable option."

Dr. Ozeri also stressed a personalized approach to deploying dual therapy.

"However, this treatment approach is still being researched, and the use of multiple biologic medications simultaneously carries potential risks, including increased immunosuppression and the potential for adverse effects or drug interactions,” he said.

“The decision to pursue dual-biologic therapy in psoriatic arthritis should be made in consultation with a rheumatologist or healthcare provider experienced in the management of psoriatic arthritis. They will consider individual patient factors, treatment goals, potential risks, and benefits to determine the most appropriate treatment approach for each patient,” he advised.

Controversy #3: Risks vs benefits of AI in rheumatology

Large-language models such as AI chatbots/GPT can increase access to information, help with patient education, and support decision-making, said Dr. Ozeri. Limitations include lack of personalization, clinical experience, and emotional connection. The use of large-language models in healthcare is also fraught with ethical and legal concerns. 

“Liability is an important consideration when using large-language models or AI chatbots in rheumatology or any other medical field," he said.

“Liability issues can arise if there are errors, inaccuracies, or adverse outcomes resulting from the use of AI chatbots. Determining liability may involve assessing factors such as the design and development of the AI system, the training and deployment of the model, the communication of limitations and disclaimers to users, and the involvement of human healthcare professionals in the decision-making process,” he said.

“To mitigate liability risks, it is crucial to ensure that AI chatbots in rheumatology comply with applicable regulations and guidelines. Transparency in the capabilities and limitations of the system, clear communication of the boundaries of its advice, and the presence of human oversight are essential. Collaborating with legal experts and following best practices in the development and deployment of AI technologies can help minimize liability concerns,” he noted.

“Ultimately, liability for the use of AI chatbots in rheumatology or any medical context is a complex legal and ethical issue that requires careful consideration, adherence to regulations, and ongoing evaluation of the technology's performance and impact,” Dr. Ozeri reflected.

Dr. Chandrasekaran wonders about the veracity of findings but sees promise in large-language models.

"On the other hand, I think it may be a future way for patients to receive more education about their diagnoses and management options outside of visits with their physicians, which will improve health literacy,” she added.

Controversy #4: Winding down DMARD therapy in RA patients with sustained remission

Enhanced treatment strategies and higher rates of remission in RA have caused researchers to shift their interests to the potential to achieve sustained remission. In the Rheumatoid Arthritis in Ongoing Remission (RETRO) study, German researchers examined the effects of tapering or stopping DMARDs in patients in sustained remission.[3]

In the phase 3 trial (n=316), investigators randomized 303 patients with DAS28-ESR remission (ie, >6 months) who were taking stable conventional synthetic or biologic DMARD treatment into three groups: (1) continuation on 100% DMARD dose (CONT); (2) tapering to 50% of the DMARD dose (TAP); (3) 50% tapering followed by DMARD withdrawal (STOP). The number of patients who continued in remission at 1 year was 81.2% in the CONT arm, 58.6% in the TAP arm, and 43.3% in the STOP arm. Predictors for flare-ups were female sex, longer disease duration, RF/ACPA positivity, and higher DAS-28 scores at baseline.

Dr. Chandrasekaran reflected on the study results.

“Remission is typically defined as no tender or swollen joints, and normal inflammatory markers (ESR and CRP)," she said.

“I typically wait until my patients are symptom free for at least 1-2 years before tapering off medications slowly, and usually do so in a stepwise fashion; ie, initially steroids and/or NSAIDs, then biologics, then finally standard DMARDs (hydroxychloroquine, methotrexate),” she added.

Dr. Ozeri also takes a measured approach to reducing or withdrawing DMARDs in RA patients.

“The decision to adjust immunosuppressive medications depends on several factors, including the individual's disease activity, treatment response, and overall health status, and the specific medications being used,” he said.

“In general,” he added, “the goal of RA treatment is to achieve disease control and minimize symptoms while minimizing medication side effects."

He noted, “The process of reducing or withdrawing immunosuppression is typically gradual and carefully monitored. It may involve stepwise tapering of medications, regular monitoring of disease activity and inflammatory markers, and assessing the patient's overall health status. The healthcare provider will assess the risk-benefit ratio, considering factors such as the likelihood of disease flare-ups, the impact on joint damage, and the potential for medication-related adverse effects.”

Controversy #5: The interplay between long COVID and autoimmune disease 

The focus of long COVID has been on the respiratory and cardiovascular symptoms, but the effects on autoimmune disease management and treatment is a rising concern.

“Many of the symptoms of long COVID, or ‘long-hauler's syndrome,’ are symptoms commonly found in autoimmune diseases, such as post-exertional fatigue, myalgias/polyarthralgia, and neurocognitive dysfunction (brain fog),” said Dr. Chandrasekaran. 

"It is also unknown whether autoimmune patients are more likely to develop long COVID than those without autoimmune disease at baseline. Certainly, some patients with autoimmune disease can have a flare of their disease after developing COVID-19. At this time, there is no role for immunosuppression in the treatment of long COVID, but if this changes in the future, rheumatologists will have a crucial role to play in managing these patients,” she remarked.

Dr. Ozeri explained that long COVID can trigger or exacerbate autoimmune disease flares in individuals who already have pre-existing autoimmune conditions.

There is also a concern that immunosuppressants used to treat rheumatic disease can increase the risk of long COVID.

“Many autoimmune disease treatments involve immunosuppressive medications, which can potentially increase the risk of severe COVID-19 infection. Individuals with autoimmune diseases and long COVID need careful evaluation to balance the management of autoimmune disease activity while considering the risks associated with immunosuppression and potential susceptibility to viral infections,” cautioned  Dr. Ozeri.

The takeaway

Despite rapid advances in the field of rheumatology, there is still much to learn. After all, rheumatology is still a relatively young subspecialty, and the lack of protocol-defined guidelines for treatments results in differences in practice among rheumatologists.

Moreover, rheumatology patients often experience chronic symptoms that are challenging to treat and clinical response to treatment can vary widely. All of these factors predispose the field to controversy, debate, and discussion.