Early Rheumatoid Arthritis Treatment and Medications: Current and Future Trends

The accepted definition of “early rheumatoid arthritis” (also called “early RA”) has changed significantly over the years, and especially since around 2015. In the early 1980s, if you had RA for less than two years, that was defined as “early RA.” By 2010, newer criteria were developed which allowed for a diagnosis of early RA within six months after the initial complaint, depending on the pattern of disease. Why only six months? Rheumatologists have learned that the earlier we intervene, the better the outcome for patients.

How do doctors make a diagnosis of rheumatoid arthritis?

We look at X-rays and several laboratory tests, and we consider the duration of the patient's symptoms as well as the pattern and number of joints that are swollen and/or tender. We also look to make sure that the lab results and the clinical findings are not related to a separate underlying inflammatory disease (other than RA) or to some other cause, such as an infection, crystals in the joint, or cartilage damage caused by prior injury.

Rheumatoid arthritis develops in genetically susceptible people who then come into contact with environmental trigger(s). We don’t know what these triggers are, but we are starting to understand more about the genetic components. The presence of certain genes can increase the risk for early RA. Still, not everyone with early RA has these genes. In addition, some people have the genes but then do not develop RA.

Current treatment guidelines, decisions and concerns

The American College of Rheumatology has come up with guidelines on how to treat RA in general as well as early RA. There are four domains to evaluate:

  1. joint distribution (which joints are affected by the disease)
  2. blood test results
  3. duration of symptoms
  4. whether or not joint inflammation is present

Each category is assigned a point score; if the total score is six or more points, a diagnosis for RA is confirmed.

In a comprehensive scheme for treatment, the ACR guidelines address six major topics, which include the use of:

  1. non-biologic medications, such as methotrexate
  2. steroids
  3. biologics such as etanercept (Enbrel) or adalimumab (Humira)
  4. vaccines
  5. screening for tuberculosis (TB)
  6. lab monitoring for disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate, hydroxychloroquine (Plaquenil), and sulfasalazine (Azulfidine)

How does the American College of Rheumatology (ACR) develop guidelines for management of RA?

A panel made up of patients, clinicians and policymakers weighs in on each recommendation based on the available evidence. When the panel is confident that the benefits of treatment outweigh potential harm, that treatment becomes a strong recommendation. However, if there is uncertainty about benefit versus harm, then it becomes a conditional recommendation.

What is the most common way that early RA is treated according to ACR guidelines?

If a person has had an early RA diagnosis for less than six months and has met the criteria for a diagnosis of RA, they will be treated with a conventional synthetic disease-modifying anti-rheumatic drug (DMARD ). Almost always, the initial DMARD chosen is methotrexate, unless there is a specific reason not to use it. The continued treatment plan, even after six months, is still the same and always balances drug safety with the person’s level of improvement.

It is important for a clinician to assess the patient’s disease activity and that there be a standard method to do so. Therefore, there are objective tools doctors use to measure disease activity. These tools are the:

  • Disease activity score (DAS)
  • Health assessment questionnaire
  • Routine Assessment of Patient Index Data 3 (RAPID3)

The DAS, also referred to as DAS 28, considers and scores the tenderness and swelling in 28 joints. A DAS of 3.3 indicates mild disease, while a score of 5.6 points or more indicates severe disease. This scale can be used to determine whether specific therapies are working. If, after treatment, the patient still has moderate-to-high disease activity, then the doctor can choose to add an additional therapy, such as a biologic medication.

A biologic medication is a substance made from a living organism or its products. These medications are used in the prevention, diagnosis or treatment of disease. In the case of rheumatoid arthritis, the biologic agents applied are often antibodies. For example, there are five biologics in the class of medications that block the inflammatory chemical called TNF, and there are also several classes of non-TNF biologics that work in different ways. These can be used alone or combined with methotrexate treatment to bring disease activity to low or ideally remission level.

The US Food and Drug Administration (FDA) is concerned with a drug’s safety as much as how effective it is, if not even more so. For a drug to be approved by the FDA, the FDA needs to carefully balance overall risk and benefit. A specific and sensitive risk-benefit analysis is conducted on all patients studied during the drug’s clinical trials, and at all stages of the patients’ disease. The FDA will then look at the incidences of different adverse events in patients who take a drug. This includes cancers, viral infections, heart disease or heart failure, and infections. In the case of RA, the last of these is the biggest concern.

It is true that people with RA, even without treatment, can have a higher risk of infection. However, extensive studies have demonstrated that numerous medications (such as the biologic agents) have been shown to decrease the immune system's overactivity that causes RA without unacceptably increasing the patient's risk of infection.

How do doctors measure activity of disease in early RA?

Biomarkers

Biomarkers (biological markers) are measured indicators of how active a disease is or how likely a disease is to progress. A test that measures levels of inflammation, such as a sedimentation rate or C-reactive protein (CRP) test, can be a non-specific biomarker of more active disease in a patient. A blood test (such as for the antibodies used to diagnose RA, the rheumatoid factor and the anti-CCP antibody,) can sometimes be a biomarker of an increased likelihood that a patient will develop damage to their joints if the disease is not treated.

Biomarkers can be used for predictively, such as a patient's rheumatoid factor predicting whether they will experience more joint damage if their condition is untreated. We still need better tests to predict how an individual patient with early RA will do in the future, but we do get some benefit now from the biomarkers we have.

The microbiome

The microbiome refers to the vast number of microbes in our body that coexist with us. They protect us against germs and break down food to convert it into energy. Each person develops their own microbiome, and this microbiome is different in different parts of the body. For example:

  • Gut microbiomes are influenced by what you eat, the activity of your disease, and which treatments you receive. So, it’s true, in a way, that you are what you eat. A yogurt eater and a non-yogurt eater will have very different gut microbiomes. Gut microbiomes are important because they aid our digestive system and ability to synthesize vitamins.
  • Skin microbiomes help maintain the balance between the environment outside and what is inside your body. This is known as epithelial homeostasis, and it is vital to our survival. We still have much to learn about the microbiome, but we know that changes have an impact on disease susceptibility and disease activity.

Treatments and therapies

Treatments for people with RA vary based on past medical history – such as cancer, hepatitis B or C, congestive heart failure (CHF) – and past serious infections, as well as current conditions the patient may have. For example, a patient with active hepatitis C would be treated for hepatitis C before getting a biologic medication such as a blocker of TNF. Another example would be a patient with a history of many severe infections might get a disease-modifying agent that has not been shown to increase infection, such as hydroxychloroquine (Plaquenil) or sulfasalazine (Azulfidine).

Biosimilars

A biosimilar (short for “biologically similar)” is a clinical equivalent to a brand-name medication. Biosimilars are molecularly and clinically very similar to the product it aims to replace (called the “reference product”). They can be thought of as a “generic biologic generic.” However, while generic medications such as unbranded pregabalin to replace Lyrica or unbranded acetaminophen to replace Tylenol must be chemically identical, biosimilars must only be similar to the reference product.

The FDA evaluates biosimilars to determine whether they are sufficiently identical to the original in safety and efficacy. If so, the agent will be approved for use. For example, the biosimilar of infliximab (Remicade) approved in the US by the FDA is CT-P13 (sold under the names Inflectra, Remsima). There are many biosimilars for a variety of drugs and conditions.

As more and more of these drugs come to market, a number of questions arise:

  • What will drive the decision to use these drugs versus others?
  • Who will get them?
  • If a branded medication is approved for multiple diseases (for example, for RA and also colitis), can we assume that the biosimilar medication will work just as well for both conditions if it is only tested in one of them?
  • Will the switch from the branded product to the biosimilar be optional or mandatory for the patient, depending on insurance coverage?

Much remains to be seen about how biosimilars will be used in the United States.

The variety of RA treatments and future therapies

TNF blockers, such as etanercept (Enbrel), were mentioned above. Xeljanz (tofacitinib) from Pfizer as well as two other medications − baricitinib (Olumiant) from Lilly and upadacitinib (Rinvoq) from AbbVie − work similarly. These are examples of oral medications that use a newer mechanism that can help people with RA. Tofacitinib and its related medications are called JAK-inhibitors, referring to the specific chemical (Janus kinase) that it blocks.

We also have IL-6 blockers, such as tocilizumab (Actemra) and sarilumab (Kevzara), and T-cell activation blockers such as abatacept (Orencia). We have inhibitors of B-cells, such as rituximab (Rituxan).

Fortunately, multiple other mechanisms for stopping RA inflammation are currently being studied. This is great news for people with RA, since the same treatments don’t work for all people, and a treatment that causes side effects in one person may be well tolerated in another. It may turn out that blocking two areas of inflammation in the body at the same time will be especially effective − and this is also being studied. With the progress already made and the new treatments in development, the outlook is brighter than ever for people with RA.

Vaccinations for people with RA

One size does not fit all when it comes to vaccines. In general, however, when it comes to the usual vaccinations (such as the flu shot or pneumonia vaccination) most people with RA are still able to receive them, including those taking medications to treat their RA. Consult with your doctor to find out which annual or seasonal vaccines, including those used for travel, are right for you.

Authors

Image - Photo of Allan Gibofsky, MD, JD, MACR, FACP, FCLM
Allan Gibofsky, MD, JD, MACR, FACP, FCLM
Attending Physician, Hospital for Special Surgery
Professor of Medicine and Public Health, Weill Cornell Medical College
     

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