Integrative Approaches to the Testing and Treatment of Rheumatoid Arthritis: A Comprehensive Review

Arthritis-related pain and immobility are a leading cause of disability among adults in the U.S., with around 1.5 million Americans impacted by rheumatoid arthritis. Rheumatoid arthritis is an autoimmune disease where the immune system attacks the lining of joints, causing painful swelling that can lead to pain, bone erosion, and joint deformity. This chronic inflammatory condition can also cause damage beyond the joints, impacting the lungs, heart, and blood vessels. 

An integrative approach to rheumatoid arthritis aims to rebalance the immune system and facilitate healing. This involves uncovering factors contributing to inflammation and autoimmunity through laboratory testing, incorporating an anti-inflammatory whole foods-focused diet that nourishes the gut and microbiome, as well as targeted supplementation. 

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What is Rheumatoid Arthritis?

Rheumatoid arthritis is an autoimmune disease where the immune system mistakenly attacks its own tissues. In rheumatoid arthritis, the main target of this attack is the synovium that lines the inside of joints. 

Your bones are protected from wear and tear at your joints by an articular capsule which includes an inner layer of connective tissue called the synovial membrane. This membrane secretes synovial fluid to cushion, lubricate, nourish, and protect the joint. The autoimmune process that occurs in rheumatoid arthritis leads to the release of many pro-inflammatory cytokines and other inflammatory mediators, which circulate within the bloodstream and impact the synovial joint spaces. This leads to chronic inflammation in the synovial space that causes the lining membrane to become swollen and painful. The inflammation and painful swelling can eventually lead to erosion of the bone, tendons, and cartilage which results in deformity of the joints.

The resulting chronic inflammation that occurs in rheumatoid arthritis can also cause damage beyond the joints, impacting the lungs, heart, and blood vessels. 

Around 1.5 million Americans are affected by RA, with the highest incidence in women and people over 40 years of age. 

Rheumatoid Arthritis Signs & Symptoms

Rheumatoid arthritis involves chronic inflammation and autoimmunity that impacts the joints and can also spread to other areas of the body. The symptoms are chronic but may fluctuate in severity over time and come and go with intermittent flares. 

Some common signs and symptoms of rheumatoid arthritis resulting from inflammation of the joints include:

• Tender, warm, swollen joints
• Stiffness in the joints that is worse in the morning and after not moving for periods of time that last for at least 30 minutes
• Pain in the joints
• Deformity of joints
• Rheumatoid nodules or firm lumps under the skin, usually over joints exposed to trauma

Early on in the disease, the smaller joints are usually impacted first, especially the fingers and toes. With the progression of the disease, larger joints throughout the body can become involved, including the wrists, knees, ankles, elbows, hips, and shoulders. The same joints on both sides of the body are usually affected. With time, rheumatoid arthritis can cause damage to the bones and cause deformity to the joints that can shift out of place.

Around 40% of people with rheumatoid arthritis also experience signs and symptoms that impact the body beyond the joints. These can include:

• Fatigue
• Fever 
• Loss of appetite
• Inflammation in the heart, lungs, blood vessels, nerves, eyes, salivary glands, kidneys, and skin

For example, people with rheumatoid arthritis can develop an inflammation of blood vessels or vasculitis that leads to skin ulcers and tissue destruction (gangrene). If the lining of the heart or lungs becomes inflamed, pericardial or pleural effusions or fluid can collect around these organs. There is also a higher risk of thickening of the artery walls (atherosclerosis) and heart attacks. In the eyes, people with rheumatoid arthritis may experience inflammation in the form of episcleritis that impacts the superficial layer of the outer layer of the eyeball (sclera) or more painful inflammation of the sclera itself (scleritis) in addition to keratoconjunctivitis sicca when the eyes cannot make enough tear fluid to keep them moist. Similar dryness can occur in the mouth and salivary glands. 

Rheumatoid Arthritis Possible Causes 

Rheumatoid arthritis occurs in people with genetic predisposition and exposure to environmental risk factors that trigger an immune response. This leads to the formation of autoantibodies, like rheumatoid factor and anti-cyclic citrullinated peptides, that are targeted against proteins found in the joints. 

Females are two to three times more likely to develop rheumatoid arthritis due to the impact of sex hormones on immune system regulation.  

Many genes have been identified as risk factors for rheumatoid arthritis, including the human leukocyte antigen (HLA) DRB1 gene. These genetic factors interact with epigenetic influences from the environment to increase the chance of developing rheumatoid arthritis. For example, environmental and lifestyle exposures like smoking, obesity, consuming sugar-sweetened beverages, never giving birth, and having a mother who smoked seem to increase the risk of developing rheumatoid arthritis, while women who have breastfed have a decreased risk.

Many of these environmental and lifestyle factors likely have an impact on the development of autoimmunity, at least in part due to their impact on the microbiome and gut health. Autoimmune diseases like rheumatoid arthritis develop from the interaction of genetic factors, environmental triggers, and imbalances in the gut, including increased intestinal permeability. Around 70-80% of the body's immune cells are in the gut, and the microbes that inhabit the gut influence the immune system at a systemic level. Imbalances in gut microbes (dysbiosis) contribute to inflammation within the mucosal surface of the gastrointestinal tract that damages tight junctions between gut cells and disrupts the epithelial barrier dysfunction, increasing intestinal permeability.

Increased intestinal permeability, or "leaky gut," allows larger molecules to pass through the normal gut barrier and enter the bloodstream, where they are seen as a threat and trigger an immune response that causes increased inflammation and potential autoimmunity via molecular mimicry. 

Many factors contribute to increased permeability of the gut barrier, including prolonged alcohol consumption, imbalances in the gut microbiome, vitamin D deficiency, issues with the protein that normally helps seal the gut zonulin, food sensitivities, mycotoxins, chemicals in food, medications (i.e., NSAIDs, oral contraceptives, antibiotics), and chronic stress. 

Ruling Out Differential Diagnoses

Several other conditions can cause inflammatory arthritis that may appear similar to rheumatoid arthritis. Findings on history and physical examination, along with laboratory testing, can help narrow down the proper diagnosis of joint pain. 

The differential diagnosis of rheumatoid arthritis includes osteoarthritis, psoriatic arthritis, sarcoidosis, infectious arthritis such as from rubella, parvovirus B-19, or Lyme disease, reactive arthritis associated with infections of the genitourinary or gastrointestinal tract, and other types of arthritis that impacts many joints (polyarthritis) caused by various connective tissue diseases including systemic lupus erythematosus and Sjogren's syndrome. 

Often the pattern of affected joints and/or other signs and symptoms that go along with joint pain can help determine the cause of arthritis. For example, osteoarthritis typically affects the distal interphalangeal joints of the fingers, while rheumatoid arthritis affects the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints. 

On the other hand, psoriatic arthritis can appear very similar to rheumatoid arthritis since they both present with asymmetric polyarthritis, but patients with psoriatic arthritis often also have psoriasis and do not have rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPAs) antibodies.

Other rheumatic arthritis diseases can usually be distinguished from rheumatoid arthritis by the presence of other systemic signs, such as rashes, dry mouth and dry eyes, myositis (muscle inflammation), nephritis (kidney inflammation), and various autoantibodies.

Polyarthritis due to viral infections like parvovirus B-19 or rubella usually lasts much shorter than rheumatoid arthritis, for only a few days to several weeks. In these cases, RF may be positive, but ACPAs are usually negative.

Functional Medicine Labs to Test for Root Cause of Rheumatoid Arthritis

Functional medicine testing can help elucidate factors that may underlie the autoimmune process and inflammation occurring in rheumatoid arthritis. This allows for a more targeted approach to treatment. 

Antibody Testing

Both rheumatoid factor (RF) and antibodies to cyclic citrullinated peptides (anti-CCP) may be elevated in people with rheumatoid arthritis.

While approximately 60-80% of rheumatoid arthritis patients have elevated levels of these antibodies, sometimes they are not elevated (seronegative). These antibodies have been associated with a higher risk of bone erosion. 

Gut Health Assessment

A Comprehensive Stool Test measures amounts of healthy and unbalanced gut microbes (dysbiosis), inflammatory markers, and measures of leaky gut. 

Specific testing to further evaluate intestinal permeability can also be carried out, including the lactulose: mannitol (LM) test, which measures the ability of two non-metabolized sugar molecules—lactulose and mannitol—to permeate the intestinal mucosa and fecal calprotectin which measures a protein that indicates the migration of immune cells (neutrophils) to the intestinal lining.

This type of thorough assessment of gut health can help uncover factors contributing to the inflammation and autoimmunity that occurs in rheumatoid arthritis since dysbiosis and leaky gut are key factors in the development of autoimmunity. This can be followed over time with treatment to adjust targeted interventions to improve the balance of the microbiome and reduce inflammation. 

Food sensitivities can also contribute to increased intestinal permeability, inflammation, and the development of autoimmunity, so ELISA testing can help identify which foods an individual is sensitive to.

Inflammatory Markers

Markers of systemic inflammation, such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), are often elevated in rheumatoid arthritis and can be followed to help assess levels of inflammation over time.

Any Other Lab Test to Check 

 X-rays, MRI, or ultrasound imaging may be used to assess the joints and track the progression of rheumatoid arthritis over time. 

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Conventional Treatment for Rheumatoid Arthritis 

The conventional approach to treating rheumatoid arthritis involves a combination of medications that are used to try to reduce inflammation, modulate the immune system, and reduce pain. These include non-steroidal anti-inflammatory drugs (NSAIDs) to reduce pain and inflammation, systemic corticosteroids such as prednisone to reduce inflammation and pain and slow joint damage, and disease-modifying antirheumatic drugs (DMARDs), including more modern biologic agents. 

Conventional DMARDs such as methotrexate (Trexall, Otrexup, others), leflunomide (Arava), hydroxychloroquine (Plaquenil), and sulfasalazine (Azulfidine) are sometimes used in combination with a newer class of DMARDs known as biologic response modifiers like abatacept (Orencia), adalimumab (Humira), anakinra (Kineret), certolizumab (Cimzia), etanercept (Enbrel), golimumab (Simponi), infliximab (Remicade), rituximab (Rituxan), sarilumab (Kevzara), and tocilizumab (Actemra). DMARDs carry the risk of liver damage and severe lung infections. 

When conventional DMARDs and biologics are not effective, targeted synthetic DMARDs like Baricitinib (Olumiant), tofacitinib (Xeljanz), and upadacitinib (Rinvoq) may be used.

When joints are severely damaged, surgery is sometimes used to reduce pain and increase function. For example, a synovectomy removes the inflamed lining of the joint (synovium), while surgically fusing a joint can help to stabilize or realign the area for pain relief. In other cases, a total joint replacement removes the damaged parts of the joint and replaces them with a prosthesis.

An integrative medicine approach commonly uses conventional treatment methods alongside nutrition, supplements, and lifestyle approaches to address the disease process and improve quality of life and function. For example, tai chi is a mind-body movement approach that combines gentle exercises and stretches with deep breathing. Research suggests that tai chi may improve mood and quality of life in people with rheumatoid arthritis when used alongside other treatment modalities. 

Functional Medicine Treatment Protocol for Rheumatoid Arthritis

An integrative functional medicine treatment approach to rheumatoid arthritis aims to uncover factors contributing to inflammation and autoimmunity that can be targeted with diet, lifestyle, and supplementation to help rebalance the immune system and facilitate healing. Incorporating an anti-inflammatory whole foods-focused diet and targeted supplementation can help to nourish and heal the gut and microbiome, balance inflammation, and restore more comfortable function. 

Therapeutic Diet and Nutrition Considerations for Rheumatoid Arthritis

An anti-inflammatory diet can help balance inflammation, prevent autoimmunity, and reduce pain. This involves an individualized diet that removes any foods a person is sensitive or allergic to, processed foods and sugars, conventionally-raised red meats, and inflammatory vegetable oils from corn, safflower, sunflower, and cottonseed that contain mostly n-6 linoleic acid and emphasizes colorful fruits and vegetables, whole grains, lean protein, healthful fats like olive oil, and foods rich in omega-3 fatty acids. Omega-3 fatty acids in walnuts, salmon, and flaxseeds are converted into mediators that help to resolve excess inflammation and reduce pain. The quality and balance of these fats overall can influence inflammation levels in the joints and body.

The autoimmune protocol (AIP) diet is a specific type of anti-inflammatory diet that is helpful for improving autoimmune disease symptoms, immune markers, and inflammation. This approach eliminates potential inflammatory triggers from the diet, including grains, dairy, eggs, legumes, nightshades, coffee, alcohol, nuts, seeds, refined and processed sugars, refined oils, and food additives, and instead focuses on freshly prepared, nutrient-dense foods, fermented foods, and bone broth to help heal the gut. After a period of time, some individuals may reintroduce foods gradually to identify individual dietary triggers.

Supplements Protocol for Rheumatoid Arthritis

Supplements can be used to help target immune health, gut health, and inflammation. Boswellia, curcumin, borage oil, and green tea have all been shown to reduce inflammation and pain in people with rheumatoid arthritis. 

Boswellia

Boswellia serrata or Frankincense inhibits the synthesis of pro-inflammatory cytokines that promote free-radical damage and inflammation. It has traditionally been used in Ayurvedic medicine for its antirheumatic and anti-arthritis activity. 

Boswellia Prescription

Studies suggest that boswellia helps to reduce joint swelling and has anti-inflammatory and immune-balancing properties that help reduce autoimmunity in patients with rheumatoid arthritis.

Dose: 400-1200 mg two or three times per day 

Duration: 1-6 months

Curcumin 

Curcumin is used extensively as a culinary spice as turmeric and has traditionally been used in Ayurvedic medicine. Curcumin has powerful antioxidant properties and has been shown to improve Inflammation levels and clinical symptoms in patients with rheumatoid arthritis. Curcumin seems to act in several ways that are beneficial for reducing the disease process. For example, curcumin improves dysfunctional immune cells and inhibits pathways that increase inflammatory cytokines. 

Curcumin Prescription

Dose: 250-1500 mg/day 

Duration: 8-12 weeks

Borage oil

Borage oil contains significant amounts of the essential fatty acid of gamma linoleic acid (GLA), which has anti-inflammatory and immunomodulating properties. Research shows that GLA reduces inflammation and the need for NSAIDs in rheumatoid arthritis patients. 

Borage Oil Prescription

Dose: 4.5-7.2 g/day Borage seed oil

Duration: 24 weeks

Green Tea

Green tea (Camellia sinensis) contains active polyphenols and constituents such as epigallocatechin-3-gallate (EGCG), which inhibit inflammatory mediators that contribute to bone degradation. Due to these antioxidant and anti-inflammatory properties, studies show that green tea alone or in combination with infliximab or an exercise program resulted in significant improvement in disease activity, inflammatory markers including C-reactive protein, and erythrocyte sedimentation rate, swollen and tender joints counts, and levels of bone resorption markers in the blood. 

Dose: 4–6 cups of green tea (60-120 mg of active compounds catechins) per day
Duration: 6 months

When to Retest Labs

To monitor treatment and the progress of treatment, clinical symptoms and/or repeat laboratory testing should be reviewed after 6-8 weeks. This can help guide the direction of continued management or any needed modification.

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Summary

Rheumatoid arthritis is the most common autoimmune type of arthritis and occurs when the immune system attacks the synovial lining joints. This results in significant inflammation in joints and various other organs that causes joint pain, stiffness, swelling, and decreased flexibility that persists over time.

In addition to a complete physical examination, laboratory testing can look for rheumatoid factor and anti-CCP antibodies, markers of systemic inflammation, and signs of dysbiosis and leaky gut that occur in patients with rheumatoid arthritis. 

An integrative medicine approach to rheumatoid arthritis uncovers the factors contributing to inflammation and autoimmunity and addresses these using diet, lifestyle, and supplementation to help rebalance the immune system and facilitate healing. An anti-inflammatory diet and targeted supplementation with herbs and nutrients like boswellia, curcumin, borage oil, and green tea can help to nourish and heal the gut and microbiome, balance inflammation, and restore more comfortable joint function.