Navigating Precision Medicine Challenges in IMIDs

The diagnosis of patients with an immune-mediated inflammatory disease (IMID) is often delayed for up to 3 months since the onset of symptoms, causing subsequent delays to the initiation of treatment resulting in disease progression and poorer prognoses.

Multiple related factors can lead to an increase in the time from symptom onset to diagnosis:

1. Disease related: variability of clinical and imaging manifestations,
2. Physician-related: insufficient primary care physician knowledge,
3. Testing-related: lack of specific testing; and
4. System-related: unavailability of diagnostics facilities and specialized centres and physicians.

To overcome these barriers, we should prioritize enhancing physician and testing components. This involves implementing physician education programs for primary care providers, enabling them to promptly recognize patients at the onset of disease and symptoms. Additionally, we should streamline the process of requesting specific tests during the patient journey. These efforts will result in earlier diagnoses, improved access to targeted therapies, and better patient outcomes.

After diagnosis, many patients do not get started on the appropriate treatment. Untreated or inadequately treated IMIDs naturally progress, causing severe tissue damage and disability, resulting in a reduced quality of life and increased mortality. In addition, IMIDs are associated with emergency room visits, hospitalizations, and surgeries, all of which substantially elevate both short-term and long-term healthcare costs. There are a few reasons why IMID patients may not receive the right treatment at the right time, with one of the most significant factors being the process of trial and error as physicians experiment with different targeted therapies (i.e. synthetic or biological disease-modifying drugs (DMDs)). The conventional approach of following a pre-determined path for treatment experimentation does not align with the precision medicine approach, which is needed for these patients when considering the highly diverse disease phenotypes associated with IMIDs.

Biologic agents, or biologic DMDs, have revolutionized the treatment of IMIDs. However, 30% to 40% of patients still do not respond to therapy. The reasons behind this are complex and include:

1. alternative inflammatory pathways to the one targeted by the specific biologic therapy,
2. development of neutralizing antidrug antibodies, and
3. pharmacodynamic or pharmacokinetic reasons.

The burden of this issue significantly affects patients, clinicians, and healthcare systems alike. To address it, Diaceutics proposes implementing a precision medicine approach throughout the patient journey. This involves enhancing physician awareness, optimizing existing diagnostic tools, and creating new tests that consider the intricate molecular landscape of these patients. Additionally, treatment developers should consistently enhance their offerings, while ensuring that the ongoing exploration of new disease pathways is taken into account.

A key problem is that IMID patients, who are often diagnosed very late after the onset of their symptoms, can present mixed phenotypes. This can be due to the high degree of variability associated with the disease, but can also be caused by the patient accumulating more than one condition within the spectrum of IMIDs. The complexity of the situation, associated with the diagnosis being mainly based on a clinical evaluation of symptoms and not on specific biomarker testing, can further delay diagnosis and therefore hinder patient access to the right treatment which positively affects their disease outcome.

Our concern here is both the total lack of, as well as delayed patient access to the proper targeted treatment. Instead of going down a precision medicine route, the current therapeutic avenue for IMIDs is based on a conventional trial and error approach, often starting with broad spectrum options like nonsteroidal anti-inflammatories (NSAIDs), corticosteroids, such as prednisone and cortisone, or conventional synthetic disease-modifying antirheumatic drugs (DMARDs), such as methotrexate and sulfasalazine, followed by biological DMARDs. When entering the biological DMARDs, most patients will be prescribed tumor necrosis factor (TNF) inhibitors, without any prior molecular study, with many patients failing to achieve optimal response - approximately 30-40% will end up being non-responders and discontinuing treatment, perpetuating the trial and error and fail-first treatment approach which results in uncontrolled diseases, aggravating tissue damage and increasing the chance of a poor prognosis.

Diaceutics recommendations:

1: Primary care physicians

1. Stay aware of IMIDs and their early symptoms and manifestations in your patients.
2. Direct patients under suspicion of an IMID diagnosis as early as possible to specialized care.
3. Recognize the importance of comprehensive testing.

2: Treating specialists

1. Incorporate a precision medicine mindset into treatment practices.
2. Keep up to date with research, innovative diagnostics techniques, and targeted therapies.
3. Incorporate technologies such as PrismRA into clinical practice to decrease time spent in the trial-and-error process.

3: Diagnostics

1. Continue developing support tools and testing to guide appropriate treatment strategies.
2. Develop stratification methods to identify which patients will benefit most from each treatment.

4: Pharma

1. Include testing within new clinical trials to increase the efficacy of targeted treatments.
2. Incorporate a precision medicine, patient-centered approach, as current targeted treatments are targeted to a molecular target, not specific to one patient or group of patients.