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14 Articles in Volume 21, Issue #5
Analgesics of the Future: Interleukin-17 Inhibitors for Treating Psoriatic Arthritis
Ask the PharmD: What evidence exists for metformin in treating rheumatoid arthritis pain?
Case Chat: Spasms vs. Spasticity and Muscle Relaxant Options
CDC Opioid Prescribing Guideline Updates Are in the Works: Will the Changes be Enough?
Chronic Pain Management in Marginalized Populations: How to Rebalance the Provider-Patient Relationship
Dantrolene: The Forgotten Molecule for Outpatient Spasticity
Forgotten Analgesics: The Drugs Pain Practitioners Need to Reconsider
Machine Learning Predicts Patient Response to Rheumatoid Arthritis Therapy
Perspective: Where Have All the Rheumatologists Gone?
Rheumatoid Arthritis and Bridge Therapy: Primary Care Considerations
Root Cause of Plantar Fasciitis: Three-Step Exercise Protocol
Shoulder Pain and Rotator Cuff Injuries: Emerging Treatments
Special Report: The Evolution of Rheumatoid Arthritis Treatment, from Gold to Gene Therapy
Transfer of Care: Barriers and Solutions in Chronic Pain Management

Special Report: The Evolution of Rheumatoid Arthritis Treatment, from Gold to Gene Therapy

To slow disease progression and manage RA symptoms, researchers are looking past disease-modifying drugs to specific gene targets, including inflammatory cytokines and matrix-degrading enzymes. Plus, a look at TNF, IL, and JAK inhibitors.

About Treating Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease of unknown etiology that affects approximately 1% of the population. Although the etiology of RA is unclear, it is believed that the disease results from an interaction between environmental factors and an individual’s genetic profile. Rheumatoid arthritis is marked by an inflammatory reaction in the joints. The disease affects people of any age but occurs in women three times more frequently than in men. If untreated, RA can lead to joint destruction, disability, and significant quality of life (QoL) impairment.

Although RA most commonly causes joint stiffness and pain, it may also cause systemic symptoms including fatigue, generalized illness, malaise, and fever. In addition, RA may cause inflammation in organs, such as the lung, heart, eyes, and skin. About 10% to 20% of people with RA develop such extra-articular symptoms. Some individuals develop extra-articular disease prior to experiencing joint symptoms.

While RA can be successfully treated, it is a chronic disease that is often problematic to control, and relapses are common. Thus, RA frequently requires clinical monitoring and treatment adjustment over several decades.

In general, the goal in treating RA is to reduce systemic inflammatory process, which ideally translates into alleviating joint pain and systemic symptoms. The most recent American College of Rheumatology (ACR) Guideline for the Treatment of Rheumatoid Arthritis states that the therapeutic goal is to achieve low disease activity or remission.Although more effective RA treatments are still desired, the therapeutic options have greatly expanded in the past 40 years, with an accelerated pace since the year 2000. Herein, this evolution of RA pharmacotherapy is reviewed – from disease-modifying anti-rheumatic drugs (DMARDs) to gene therapies – and potential new directions for RA management are suggested.

 

Disease-Modifying Anti-Rheumatic Drugs (DMARDs) for Rheumatoid Arthritis: History and Current Treatment Options

Gold Therapy

Disease-modifying anti-rheumatic drugs (DMARDs) are pharmaceutical treatment options for rheumatoid arthritis that aim to slow disease progression. The first DMARD was gold salt that had been used as early as 1928 by Jacques Forestier, a French rheumatologist.Gold therapy was based on the observation of Dr. Robert Koch that gold salt inhibited the growth of the tubercle bacillus. In the early 20th century, tuberculosis was believed to be the cause of RA and many other chronic diseases.In 1961, the Empire Rheumatism Council reported good clinical outcomes from the use of gold salt for the treatment of RA, and recommended this therapy. Based on the Council’s report and practitioner experience, gold salt therapy for RA was often used in clinical practice.2Although gold salt is not used often in clinical practice today, gold preparations were recommended for the treatment of RA by the American Academy of Family Physicians until 2011.With the introduction of several more effective agents, the use of gold has essentially become obsolete.

Glucocorticoids

Cortisone – one of the glucocorticoids – was first clinically used in 1948 to treat a debilitating case of RA. Within two years of treatment, Drs. Philip Hench, Edward Kendall, and Tadeus Reichstein received the 1950 Nobel Prize in Physiology or Medicine for elucidating the anti-inflammatory properties of glucocorticoids.Although long-term glucocorticoid use is not recommended for the treatment of chronic RA due to severe side effects, it is often used for the management of acute flares of the disease.

Aminopterin and Conventional DMARDs

In the early 1950s, Dr. Richard Gubner found that aminopterin was effective for the treatment of RA. Aminopterin (C19H20N8O5) is similar in chemical structure to methotrexate (C20H22N8O5) with the only difference being that methotrexate contains a N-terminal methyl (-CH3) rather than a hydrogen (-H) for aminopterin at one location (Figure 1).Current ACR guidelines on RA recommend conventional DMARDs (cDMARDs) such as methotrexate, hydroxychloroquine, sulfasalazine, and leflunomide. Methotrexate, originally a cancer treatment, is the cDMARD of choice for the treatment of RA and is usually the initial or first-line approach. More outcome data are available concerning the use of methotrexate for RA than for any other agent.

 

Emerging DMARDs: TNF and JAK Inhibitors

Advances in immunology in the 1980s led to impactful advances in the treatment of RA. Tumor necrosis factor (TNF) (meaning that this molecule causes tumor-cell necrosis) was identified by Dr. Lloyd Old at Memorial Sloan Kettering Cancer Center in New York City.Dr. Bruce Beutler and colleagues discovered cachectin (meaning that this entity causes wasting) independently during the same time period.It was subsequently determined that TNF and cachectin were identical; this is an example of pleiotropy, where a cytokine has different actions depending on its location.

An antibody to TNF was developed, named cA2 (Centoxin), which is a chimeric antibody composed of a variable region of mouse antibodies joined to human IgG sequences. Researchers thought that Centoxin could be used to treat sepsis; however Centoxin sepsis trials failed to show a significant benefit and the drug, and failed to earn FDA approval.Centoxin was then used in a clinical trial for RA, and the drug was found to significantly improve symptoms as well as reduce inflammatory markers. Further successful trials of Centoxin in RA led to the drug becoming the first TNF inhibitor approved by the FDA in 1998 under the name of infliximab (Remicade).

FDA approval of infliximab opened a new era of biologic DMARDs (bDMARDs or biologics) for the treatment of rheumatoid arthritis.Biologics may be considered in patients who fail to adequately respond to a cDMARD or have a contraindication to cDMARD use. Over the past two decades, five anti-TNF biologic agents have been approved for RA. Many other categories of bDMARDs, such as Interleukin (IL)-6 inhibitors and T-cell and B-cell modulators, have been developed and approved to treat individuals with RA and other inflammatory conditions as well.

Janus Kinase inhibitors (JAKi), targeted synthetic small molecule DMARDs (tsDMARDs), represent the most recent class of drugs approved for the treatment of rheumatoid arthritis. These inhibitors are oral preparations and therefore less cumbersome to use than most of the biologic drugs that require an injection or intravenous administration. JAK inhibitors block Janus Kinase, an enzyme that is involved in the Janus kinase signal transducer and activator of transcription (JAK-STAT) pathway. This enzyme regulates gene expression and transcription of many cytokines, thereby inhibiting Janus Kinase enables control of inflammatory symptoms.

 

Gene Therapy: A Quick Overview

The American Society of Gene and Cell Therapy (ASGCT) defines gene therapy as the introduction or removal of genetic material or modification of gene expression to alter the biological function of an individual’s genetic code with the objective of achieving a therapeutic benefit. Gene therapy uses genetic material (DNA or RNA) as a “drug,” and the target location is usually the nucleus of the target cells. The first meaningful gene therapy research was reported in 1990 for the treatment of topical melanoma by gene transfer into human cells by retroviral gene transduction.10

Gene therapy involves the manipulation of the genes in patients, and may involve:11

  • gene replacement therapy: replacing a disease-causing gene with a fully functioning healthy gene
  • gene addition: introducing a new gene into the body to fight against disease such as cancer or infection
  • gene inhibition: inactivating a disease-causing or mutated gene so that it does not produce RNA or subsequently problematic proteins
  • gene editing: causing a specific gene sequence change

The use of gene therapy is currently limited to specific disease areas, mostly in oncology (see Table I). There are only handful of FDA-approved gene therapies, and currently, there are no FDA-approved gene therapies for RA or other rheumatologic conditions.

Table I data based on: FDA. Approved cellular and gene therapy products. June 15, 2021. Available at: www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products. Accessed: July 2021.

 

 

Gene Therapy Targets for Rheumatoid Arthritis

As mentioned, RA is considered to be associated with an interaction between a genetic predisposition and environmental exposures. Specific genes and environmental factors involved in the development of RA have not yet been identified. Therefore, it is currently premature to propose clinical gene therapy trials for RA. However, research concerning risk factors and genomic associations in RA is ongoing and suggests that gene therapy may be a plausible effective treatment of this disease.

Although the specific genes that contribute to the development of RA remain unknown, clinical observations and research have identified several possible targets for effective RA gene therapy. These include genes involved with inflammatory cytokines, matrix degradation enzymes, and hormones that regulate RA related proteins and cytokines.

Inflammatory Cytokines

Inflammatory cytokines may be pro-inflammatory or anti-inflammatory. Disease progression of rheumatoid arthritis is associated with up-regulation of pro-inflammatory cytokines that evoke the production of several more pro-inflammatory mediators in downstream cascade. Tumor necrosis factor is the prototypical pro-inflammatory mediator in RA. Other pro-inflammatory cytokines involved with RA pathophysiology include IL-1 and IL-6.  Immune suppression via T-cell or B-cell modulation is also used to treat RA.  Since the first TNF inhibitor infliximab was introduced in the late 1990s, an RA treatment strategy of inhibiting pro-inflammatory cytokines has been the leading approach.

FDA-approved drugs for rheumatoid arthritis that work by this mechanism include numerous monoclonal antibodies (mAbs):

  • TNF alpha inhibitors: adalimumab (Humira), etanercept (Enbrel), golimumab (Simponi, Simponi-Aria), certolizumab (Cimzia), infliximab (Remicade)
  • IL-1 inhibitors: anakinra (Kineret), canakinumab (Ilaris), rilonacept (Arcalyst)
  • IL-6 inhibitors: tocilizumab (Actemra), sarilumab (Kevzara)
  • T-cell or B-cell modulators: abatacept (Orencia), rituximab (Rituxan)

The aforementioned biologics drugs are not considered a form of gene therapy as no genes are being manipulated. However, the fact that drug therapy that blocks proinflammatory mediators is effective in RA suggests that alteration of the genes that regulate these mediators may be of great benefit for managing RA symptoms.

(See also our primers on monoclonal antibodies for psoriatic arthritis and TNF inhibitors.)

Another potential treatment approach for RA is to activate anti-inflammatory cytokines, such as IL-4 and IL-10. Steen-Louws and colleagues reported using these anti-inflammatory cytokines successfully in a proteoglycan-induced arthritis (PGIA) mouse model.12 Their results suggest that gene therapy directed at inducing anti-inflammatory cytokines may be a useful RA treatment approach.

Matrix-degrading Enzymes

Matrix-degrading enzymes play major role in connective tissue breakdown in joint cartilage structure that is composed of proteoglycan aggrecan and type II collagen. Two key enzymes in this category are:

  • matrix metalloproteinases (MMPs)
  • a disintegrin-metalloproteinases (ADAMs) or A disintegrin-metalloproteinases with thrombospondin motifs (ADAMTSs)

These two enzymes are produced by macrophages or fibroblast-like synoviocytes stimulated by inflammatory cytokines or growth factor.13 Although MMPs have been demonstrated to be involved with inflammation and joint damage in RA, antibody therapy versus these molecules has demonstrated minimal benefit.14,15 Despite the lack of efficacy of mAbs versus matrix-degrading enzymes, researchers remain optimistic about gene therapy in this area.16

Miscellaneous Targets: Hormones, Latitude, and Seasonal Effects

Additional factors such as hormones, latitude of residence, and seasonal effects are potential targets for gene therapy as well. Although the effect of sex hormones on RA disease onset and progression are not completely understood, female sex is a well-established risk factor for the disease. Mohammad and associates reported that estrogen receptor alpha (ERa) in T lymphocytes is associated with immune disorders. A preclinical mouse model involving ERa deletion in T lymphocytes resulted in reduced activation and proliferation rates of these cells.17

Residence at higher latitude was demonstrated to be associated with a higher prevalence and disease severity of rheumatoid arthritis by the Nurse’s Health Study.18 The association between RA and latitude of residence may reflect not only ethnic and racial factors but also the effects of the circadian rhythm and seasonal variation on the function of the immune system. Seasonality has been shown to have significant effects on RA symptoms with significant worsening of RA symptoms and more flares of the disease in the spring season followed by winter.19 Recent work by Dopico and colleagues demonstrated increased pro-inflammatory gene expression during the winter season.20More research is needed to understand the immunologic mechanisms responsible for RA risk factors that may lead to promising targets for effective RA gene therapy.

Personalized Medicine and Adverse Events in RA Treatment

It is worth noting that gene therapy research aimed at modulating inflammation is active, albeit pre-clinical and experimental. Table II summarizes target genes that appear related to the development of RA and are recognized as a promising target for future RA gene therapy. Table III displays human genes that have been found to be related to the effectiveness of DMARD treatment. These genes represent another group that could be effective targets for RA gene therapy. Such effective gene therapy would be considered a form of personalized medicine, as treatment would be based on the individual patient’s genetic disposition to enhance the patient’s response to the DMARDs.

All medication comes with the potential for adverse drug reactions and gene therapies may not be an exception. Caution is required when manipulating genes as there are risks of over- or under-expression of certain gene, which could lead to over- or under-production of corresponding proteins and cytokines that could lead to unexpected results.

Delivery of Gene Therapy: Viruses as Vectors

An important hurdle to overcome in order for gene therapy to be effective in disease management is the efficient delivery of therapeutic genes to the target cell’s nucleus without harming the individual. Viruses used as vehicles for gene delivery into target cells are called vectors. Adenovirus, retrovirus, lentivirus, and adeno-associated viruses (AAVs) have been studied for this purpose.21

Vectors should be non-pathogenic, non-immunogenetic, harmless, and should be capable of carrying the mass of genetic material that is required to be transported into the cell. Immunogenicity is particularly not a suitable feature for RA gene therapy, as the disease is an autoimmune condition. Adenovirus was initially a popular vector for gene therapy, as an attenuated or genetically inert form of this virus was thought to have a minimal risk of causing an actual adenovirus infection. However, it was subsequently found that adenovirus can trigger strong immune responses.22 AAVs are currently recognized as most promising virus vector for gene therapy.23

Genetic modification can occur in either in vivo or ex vivo.24 In vivo transmission of genes can be achieved by direct injection of a vector containing a therapeutic gene into the joint with genetic changes occurring in the location of the injection site. An ex vivo approach involves extracting specific host cells, then performing genetic manipulation on these cells in vitro, and finally readministering these genetically manipulated cells back to the body locally or systematically via injection or infusion.

Each of these approaches has advantages and disadvantages. The in vivo approach is relatively simple and is less costly. A disadvantage of the in vivo approach, however, is that RA usually affects many joints and, thus, many injections would be required. In addition, in vivo administration has been associated with higher risks of oncogene activation, excessive immunosuppression, and infection. Ex vivo studies showed fewer risks than that of in vivo, and are suitable for RA with systemic manifestations. However, ex vivo gene therapy is more costly.24

 

Rheumatoid Arthritis Therapy's Future 

Innovations in RA therapy have accelerated exponentially over the past 50 years. Prior to 1998, RA could be treated with only a handful of DMARDs, and no biologic drugs were available. Advancement in immunologic research led to the development of numerous effective mAbs drugs for RA and other rheumatologic conditions. These drugs greatly reduced patient suffering and improved the quality of life of RA patients. Although currently only at a preclinical stage, gene therapy holds promise to further improve RA care. We suspect that further advances in understanding the relevant genes involved in RA, as well as the efficient and safe transport and delivery of genes into cells will lead to effective gene therapy for rheumatoid arthritis.

 

Disclosure: The author discloses that she is a consultant for Wolters Kluwer (Lexicomp) as a content expert for rheumatology. 

Last updated on: September 9, 2021
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