Overcoming Drug Resistance in Difficult-to-Treat Rheumatoid Arthritis

Key Summary:

• Drug resistance affects up to half of methotrexate users and one-third of biologic-treated individuals.
• Acquired resistance stems from multidrug efflux pumps, anti-drug antibodies, and alternative cytokine loops.
• Emerging approaches like cellular therapy and targeted nanocarriers offer paths to overcome refractory disease

RHEUMATOID arthritis management encounters major hurdles when complex drug resistance mechanisms undermine frontline and targeted pharmacotherapies. Despite substantial advances in synthetic and biologic therapies, approximately 6% to 21% of individuals develop difficult-to-treat  rheumatoid arthritis, experiencing persistent inflammation and functional decline despite trying multiple targeted agents. Methotrexate resistance occurs in roughly 30% to 50% of clinical cases, while resistance to biologic agents reaches 30% to 40%. Unraveling these pharmacologic and molecular roadblocks is crucial for clinicians striving to restore therapeutic control.

Transporter and Epigenetic Drivers of Drug Resistance

Frontline treatment failure with methotrexate frequently involves cellular transport disruptions. Impaired influx via organic anion transporter 3 and reduced folate carriers limits intracellular drug accumulation. Simultaneously, ATP-binding cassette efflux pumps, notably P-glycoprotein and breast cancer resistance protein, actively remove the antimetabolite from synovial cells and lymphocytes. Metabolic shifts, including accelerated glycolysis driven by the hypoxia-inducible factor pathway, provide excess energy to sustain this active drug efflux. Epigenetic modifications, such as aberrant DNA methylation and altered non-coding RNA profiles, lock fibroblast-like synoviocytes into an aggressive, inflammatory state that evades apoptosis.

Immunogenicity and Cytokine Bypass Pathways

For biologic disease-modifying antirheumatic drugs, the formation of anti-drug antibodies represents a primary cause of secondary therapeutic failure. These antibodies neutralize active binding sites or trigger rapid clearance by macrophages. Chimeric constructs pose higher immunogenic risks, whereas fully human antibodies and fusion proteins demonstrate variable susceptibility influenced by patient human leukocyte antigen haplotypes. Concomitant immunosuppressants, such as methotrexate, help mitigate antibody generation by expanding regulatory B cell populations and boosting adenosine release. Beyond immunogenicity, persistent joint destruction occurs when inflammatory signaling shifts toward alternate cytokine pathways, including interleukin-6, interleukin-17, and granulocyte-macrophage colony-stimulating factor cascades that circumvent targeted receptor blockade.

Innovative Approaches to Refractory Joint Disease

Addressing refractory disease requires comprehensive evaluation of true pharmacologic failure, treatment adherence, and misdiagnoses. Emerging strategies focus on precision interventions, including chimeric antigen receptor T-cell therapies that eradicate autoreactive B cells and engineered nanocarriers designed to suppress synovial efflux pumps. Dual cytokine inhibition, low-dose interleukin-2 therapy to expand regulatory T cells, and implantable vagus nerve neurostimulation devices also demonstrate clinical potential. Leveraging multi-omics profiling will ultimately enable personalized treatment selection, helping rheumatologists overcome multi-agent resistance and achieve lasting clinical remission.

 

 

 

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New Canadian study investigates how cancer adapts its metabolism to overcome therapies

Knowing what cancer will do next could lessen the likelihood of it becoming resistant to treatment. A new Canadian study investigates how cancer adapts its metabolism to potentially overcome therapies still in development.

"Several clinical trials have failed because metabolism is such an adaptive process by which cancer cells gain drug resistance," says Michael Aregger, a co-lead author and Research Associate working with Jason Moffat, Professor of molecular genetics in the Donnelly Centre for Cellular and Biomolecular Research at the University of Toronto, who co-led the work. "If you know how cells are able to adapt to perturbations, maybe we can target them more specifically to avoid resistance from developing."

The research was also led by Brenda Andrews and Charles Boone, University Professor and Professor of molecular genetics at the Donnelly Centre, respectively, and Chad Myers, a Professor of computer science at the University of Minnesota-Twin Cities.

The study, published in the journal Nature Metabolism, is the first to investigate global changes in cancerous cells as they adapt to a shortfall of critical nutrients such as fat molecules, or lipids, which make up the cell's outer envelope.

When cancer cells are unable to make their own lipids, they gobble them up from their environment to ensure a steady supply of these essential building blocks, the study found. Lipids also serve as fuel and chemical signals for communication between cells, among other roles.

The switch in metabolism could be bad news for drugmakers seeking to target cancer by reducing its lipid reserves. In particular, drugs that inhibit an enzyme called FASN, for fatty acid synthase, involved in an early step of lipid synthesis, are being explored in patient trials. Fatty acids are precursors of larger lipid molecules and their production is increased in many cancers thanks to elevated FASN levels, which are also associated with poor patient prognosis.

The U of T study suggests that the effectiveness of FASN inhibitors could be short-lived owing to cancer's ability to find another way to procure lipids.

Because FASN is upregulated in many cancers, fatty acid synthesis is one of the most promising metabolic pathways to target. Given that we know there is a lot of plasticity in metabolic processes, we wanted to identify and predict ways in which cancer cells can potentially overcome the inhibition of lipid synthesis."

Keith Lawson, a co-lead author and Ph.D. student in Moffat's lab enrolled in the Surgeon-Scientist Program at the Faculty of Medicine

To block fatty acid synthesis, the researchers employed a human cell line from which the FASN coding gene was removed. Using the genome editing tool CRISPR, they deleted from these cells all ~18,000 or so human genes, one by one, to find those that can compensate for the halt in lipid production. Such functional relationships are also referred to as 'genetic interactions'.

Data analysis, performed by Maximilian Billmann, a co-lead author and a postdoctoral fellow in Myers' lab at Minnesota-Twin Cities, revealed hundreds of genes that become essential when cells are starved of fat. Their protein products clustered into well-known metabolic pathways through which cells hoover up dietary cholesterol and other lipids from their surroundings.

Cells' intake of cholesterol has become textbook knowledge since it was discovered half a century ago, winning a Nobel Prize and inspiring the blockbuster drug statin and many others. But the new study found that one component of this process remained overlooked all this time.

The gene encoding it was only known as C12orf49, named after its location on chromosome 12. The researchers re-named the gene LUR1, for lipid uptake regulator 1, and showed that it helps switch on a set of genes directly involved in lipid import.

"This was a big surprise to us that we were able to identify a new component of the process we thought we knew everything about," says Aregger. "It really highlights the power of our global genetic interaction approach that allowed us to identify a new player in lipid uptake in a completely unbiased way."

By a remarkable coincidence, two groups working independently in New York and Amsterdam also linked C12orf49 to lipid metabolism, lending further support for the gene's role in this process. The New York team published their findings in the same journal issue as Moffat and colleagues.

Inhibiting LUR1, or other components of lipid import, along with FASN could lead to more effective cancer treatments. Such combination therapies are thought to be less susceptible to emerging drug resistance because the cells would have to simultaneously overcome two obstacles--blocked lipid production and import--which has a lower probability of occurring.

"Therapeutic context that comes out of our work is that you should be targeting lipid uptake in addition to targeting lipid synthesis and our work highlights some specific genes that could be candidates," says Lawson.

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New technology to monitor anti-drug antibodies in MS patients may have potential for COVID-19 testing

A new study led by Queen Mary University of London has demonstrated the effectiveness of using a novel light technology to monitor the presence of anti-drug antibodies in the treatment of multiple sclerosis (MS), which can lead to drug resistance and treatment failure.

The researchers say that they have also applied the technology to COVID-19 for potential use in antibody testing to determine whether someone has previously been infected with the virus.
Antibodies are proteins that are made by the immune system to fight infection. They can also be used as drugs to fight disease. Alemtuzumab is an antibody designed to kill T and B cells - the major cellular components of the adaptive immune response - and was first used in white blood cell cancers and more recently in MS. However, this can sometimes result in the production of anti-drug antibodies, which prevent Alemtuzumab from working as effectively and lead to patients not responding to treatment.

The GloBody™ platform is a new tool which uses a light-producing enzyme, called nanoluciferase, to detect if anti-drug antibodies are present in a patient sample, which can cause allergies and stop the treatment from working. This is used to show which people are likely to respond to treatment and can predict which people are likely to fail treatment before it occurs, so that they can be switched to a different drug. This can prevent people from accumulating disability due to treatment failure.

This study, published in the journal Neurology: Neuroimmunology & Neuroinflammation and carried out in collaboration with Cardiff University, demonstrated the high reliability of using the GloBody™ platform to detect the anti-drug antibodies and predict which patients were subsequently likely to fail treatment.

The results from the study can be used to improve the safety of drug treatments for MS, and testing has already been moved into the researchers' and others' clinical practices. The researchers hope that their work will help more people to recognize the importance of anti-drug antibodies and use a simple method to monitor these in patients and avoid the issues that they cause.

Although we only looked at anti-drug antibody responses in multiple sclerosis, this approach can be applied to any therapeutic antibody in any clinical condition. The technology can also be used in pre-clinical animal models, saving time and effort before moving to clinical trials in humans.

 If you can predict that a drug will not work in a patient, then you prevent them from receiving futile and often expensive treatments. Some of these treatments cost the NHS close to half a million pounds per person a year, so being able to tell if a treatment is not working is important so you can quickly switch to something else."

 Dr. Angray Kang, Lead Researcher, Queen Mary University of London

The researchers say that the technology has also been developed to detect immune responses against infections and monitor disease outbreaks, including COVID-19.

Dr Kang added: "With COVID-19, we know there has been a lot of attention on the potential of antibody testing to see if someone has previously been infected.The GloBody™ tests have potential to be applied to COVID-19 in this way. Some antibody tests will only give you a 'yes' or 'no' answer, however GloBody™ technology could tell you how much antibody is present and if the antibodies can block re-infection. This will be needed when assessing the effectiveness of a vaccine.

"Within a few days, we have already been able to produce sufficient amounts of the COVID-19 GloBody™ reagent to potentially test 1.6 million people for COVID-19. That's enough to test all of the NHS staff in the UK. And if the virus mutates, a new test could be made just as quickly."

The researchers caution that any GloBody™ COVID-19 antibody test would first need to be validated as an accurate test before being put into widespread use. The validation process has started within Barts Health NHS Trust and Queen Mary University of London.

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