Systems Therapeutics and Disease Modifiers

Reposted from Medium 2023

“Design’s purpose is always the same — inspire insight, evoke response, transform thought.”

Clement Mok in Designing Business

Summary

Systems therapeutics has previously been described in detail, illustrating how pharmacologic processes and pathophysiologic processes interact to produce clinical therapeutic response. Disease modifiers are factors that can potentially influence clinical disease development and progression, but are generally not thought to be involved in the disease initiation processes. The objective of this paper is to provide examples of disease modifiers and explore where to place these within the systems therapeutics diagram.

Systems Therapeutics

Systems therapeutics defines where pharmacologic processes and pathophysiologic processes interact to produce a clinical therapeutic response. Systems therapeutics has previously been described in detail, including a systems therapeutics diagram (1). The organizing principle underlying the systems therapeutics diagram involves two rows of four parallel systems components for pharmacologic processes and pathophysiologic processes, representing the four fundamental biologic levels of interactions between these two processes, i.e., at the molecular level, the cellular level, the tissue/organ level, and the clinical level, in addition to the initiating drivers of these processes and the ultimate clinical therapeutic response. The four different biologic levels of interactions between these processes then determine the four systems therapeutic categories, i.e., Category I (at the molecular level), Category II (at the cellular level), Category III (at the tissue/organ level) and Category IV (at the clinical level).

While systems therapeutics has been described in detail, what has not been discussed includes how disease modifiers might fit into this scheme. Disease modifiers are factors which can potentially influence clinical disease development and progression. These include factors such as sex and age, and risk factors and aggravating factors. Another report discussed how different disease categories could be placed within the systems therapeutics scheme (2).

The objective of this paper is to review disease modifiers and explore where to place these within the pathophysiologic process part of the systems therapeutics diagram. Note that the biologic modifiers age and sex can also affect the pharmacologic processes, principally drug exposure, but this topic is beyond the scope of the present paper.

Disease Modifiers

There are different kinds of clinical disease modifiers, which are factors with the potential to influence different aspects of clinical disease development and progression. By themselves these are generally thought to be separate from disease initiation processes, but can be important determinants of the clinical disease expression. These modifiers are the biologic modifiers age and sex, aggravating factors and risk factors; these are briefly outlined below.

Biologic modifiers — age: This modifier, while not causative per se, influences at what age range a specific disease is most likely to manifest clinically. Specific ranges for age of disease onset are not provided in the examples below, instead only very general age ranges.

Examples of age of onset:

Acute lymphocytic leukemia (ALL): early childhood;

Schizophrenia: early adulthood;

Osteoarthritis: late adulthood;

Alzheimer’s disease: late adulthood.

Biologic modifiers — sex: Aside from specific male diseases and female diseases, this modifier, presumably acting via sex hormones, directly or indirectly, while not causative per se, influences the likelihood of getting a disease, and thus determines the relative sex prevalence. Specific values for sex preference ratios are not provided in the examples below, instead only very general sex preferences.

Examples of sex preference:

Rheumatoid arthritis: more common in females;

Systemic lupus erythematosus (SLE): more common in females;

Autoimmune diseases: more common in females;

Asthma: more common in females.

Aggravating factors: These are factors which can act as triggers of disease symptoms; the list for individual diseases is for illustration purposes, and not intended to be comprehensive.

Examples of aggravating factors for specific diseases:

Asthma: allergens, tobacco smoke, pets, air irritants;

Gastroeosopheal reflux syndrome (GERD): alcohol, fatty or fried foods, coffee, spicy food;

Migraine: stress, smells, lights and sounds, bright light;

Endometriosis: stress, caffeine, fatty meat, alcohol.

Risk factors: These are clinical factors which can increase the likelihood of getting a specific disease; the list for individual diseases is for illustration purposes, and not intended to be comprehensive.

Examples of risk factors for specific diseases:

Diabetes: weight, inactivity, family history, ethnicity;

Coronary heart disease: high LDL cholesterol, high blood pressure, family history, diabetes;

Osteoporosis: aging, inactivity, smoking, ethnicity;

Lung cancer: smoking, radon, family history, occupational chemicals;

Age-related macular degeneration: hypertension, smoking, diabetes, family history.

Disease Modifiers in Systems Therapeutics

As has already been mentioned while disease modifiers are factors that can potentially influence disease development and progression, they are generally not thought to be involved in disease initiation.

While not thought to play a direct etiologic causative role for individual diseases, risk factors and aggravating factors can be considered to influence the processes of disease development and progression. Risk factors can influence pathogenic pathways, while aggravating factors can influence symptomatic pathophysiologic processes. Examples of risk factors include the well known relationships between coronary heart disease, hypertension and hypercholesterolemia, presumably involving interconnected network pathways. Examples of aggravating factors include those that bring on clinical symptoms, such as in GERD and migraine.

Chart 1. Disease origination followed by disease development and progression; also shown are where the disease modifiers risk factors and aggravating factors, and the biologic modifiers sex and age, interact with disease development and progression.

The biologic modifiers age and sex can also be considered to be involved in the general processes of disease development and progression, but would not be considered to be generally involved in the disease initiation processes. The biologic modifier sex would be assumed to act, directly or indirectly, through the respective sex hormones, and thus acting during the early phases of disease development. The biologic modifier age, on the other hand, is of special interest as regards its role in determining the age range at which diseases start or manifest themselves. While different diseases start clinically at different age ranges, it is often assumed the underlying etiologic causative mechanisms have typically been in place for some time, perhaps years or decades. A commonly proposed explanation to account for the differently delayed onset of diseases involves the theory that varying durations of time are required for the pathophysiologic processes to progress before a disease becomes clinically manifest, from a few months to several decades.

Conclusions

The present paper has provided outlines of different clinical disease modifiers and explored where to place these within the systems therapeutics paradigm, as illustrated in Chart 1. It is generally thought that these modifying factors are not directly involved in disease initiation processes, although major research efforts are needed to elucidate how these interact with individual disease processes and networks, in both early and late disease development and progression.

In the systems therapeutics diagram the systems components presented in disease initiation have been referred to as intrinsic operator and etiologic causative factor. The hypothetical intrinsic operator was introduced, in part to simplify and depict similarly the initial events of both pharmacologic processes and pathophysiologic processes, and in part to stimulate discussions about disease origination. The etiologic causative factor has been envisioned as a singular abnormal biomolecular entity or an abnormal network, representing the molecular abnormality or malfunction characterizing the disease under consideration. Thus, the intrinsic operator represents the initiator or driver of the pathophysiological process, and the etiologic causative factor/network contains the seeds of the disease and determining the specific disease expression. We hope these pathophysiologic systems components will some time be as well understood as the interaction between a pharmacologic agent (drug) and a pharmacologic response element (receptor).

References

  1. Bjornsson TD. Systems therapeutics: Framework, Diagram, Categories, Definitions, Examples. tri-institute.org. January 2023
  2. Bjornsson TD. Systems Therapeutics and Disease Categories. Medium, July 22, 2023.