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"Medical Journeys" is a set of clinical resources reviewed by physicians, meant for the medical team as well as the patients they serve. Each episode of this 12-part journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease of the joints, characterized by pain, swelling, and ultimately, if inadequately treated, joint destruction. The peak years of RA onset are in the 5th decade of life, but it can develop at any age, including in children -- when it is referred to as juvenile idiopathic arthritis -- and among the elderly.

Women are affected three times as often as men. In , the age-adjusted prevalence of RA in the U.S. in 2014 ranged from 0.29% to 0.31% for men and 0.73% to 0.78% for women.

Despite recent advances in laboratory testing and imaging, the diagnosis of RA remains a clinical one, according to experts.

RA Disease Classification

In 2010, a collaborative initiative between the American College of Rheumatology and the European League Against Rheumatism (EULAR) established classification criteria for RA. In , the members of the joint working group determined that for a patient with undifferentiated inflammatory synovitis, a diagnosis of definite RA required confirmation of synovitis in at least one joint, the absence of another diagnosis that could better account for the synovitis, plus a total score of 6 out of 10 in four disease domains: the number and site of affected joints (score range 0-5), serologic abnormalities (scores 0-3), acute phase reactants (scores 0-1), and duration of symptoms (scores 0-1).

It has become clear in recent years that the development of RA is a gradual process that begins with genetic and environmental risk factors, followed by loss of self-tolerance and the appearance of systemic autoimmunity, then the development of symptoms without clinically apparent arthritis, and finally to unclassified arthritis and eventual RA.

The preclinical phase of RA may provide a window of opportunity in which intervention might be able to delay or possibly even prevent the onset of RA and the subsequent joint damage. In 2016, a EULAR task force defined a group of characteristics for individuals with arthralgia but without clinical arthritis as a disease phenotype that was more likely to progress to RA, referred to as .

These characteristics were detected during history taking:

• Recent onset (<1 year) of joint symptoms

• Symptoms present in the metacarpophalangeal joints

• Morning stiffness persisting for more than 1 hour

• Severest symptoms apparent in early morning

• First-degree relative with RA

In addition, factors apparent on the physical examination included:

• Difficulty with making a fist

• Positive squeeze test for the metacarpophalangeal joint

If three or more of the factors were present, the sensitivity and specificity for subsequent development of clinical inflammatory arthritis were 90% and 74%, respectively.

Clinical Findings

"Ultimately it's pretty simple for the rheumatologist to make the diagnosis," said Stephen Paget, MD, of the Hospital for Special Surgery in New York City.

"It's all about patterns," he said. "The classic presentation is the patient who comes in with inflammation, redness, swelling, stiffness, in the wrists, knuckles, ankles and feet, maybe the knees and elbows, and they have fatigue and functional limitations."

The initial presentation might be just an inflamed knee, but within a few months the patient is going to evolve into the definitive pattern for RA, which is symmetrical joint inflammation of the small joints of the hands and feet, he noted. "But there are many other types of arthritis that could present with one or multiple joint symptoms and that makes it more complicated."

One type of arthritis that should be ruled out is osteoarthritis, which is more of a wear-and-tear condition that can sometimes cause swelling and pain, usually in one knee, or the back, or the hip, or the basal joint of the thumb. The presentation is not symmetrical, systemic symptoms such as fatigue are not typically present, and the small joints of the hands and feet are never involved, except for the tips of the finger joints. In RA, the tips of the fingers are not typically affected; rather, metacarpophalangeal and proximal interphalangeal joints and wrists are involved.

The articular manifestations of psoriatic arthritis also differ from RA, in that it can affect the joints at the tips of the fingers and the large joints in the lower extremities. Enthesitis also can be present.

Gout and pseudogout also can be differentiated from RA by the location of the symptoms. Gout, characterized by the deposition of uric acid crystals, usually involves the first joint of the big toe, while pseudogout, with deposition of calcium pyrophosphate crystals, usually presents in the knee, where calcifications can be seen on x-rays.

"Systemic lupus, particularly in young women, can present with a rheumatoid-type pattern of arthritis, affecting the small joints of the hands and feet, but they have other disease manifestations such as skin rashes, hair loss, fever, and kidney problems that are not characteristic of RA," Paget explained.

But the crucial factor today is early diagnosis, with prompt referral to a rheumatologist. "I think people have been beating that drum long enough about early diagnosis and aggressive treatment that we are probably seeing more early patients," said Jack Cush, MD, director of clinical rheumatology at the Baylor Research Institute in Dallas.

"The problem is that no one but the Europeans have built a pathway for early RA patients to get into the clinic. There are many early arthritis clinics built into the system in the U.K. and Europe, but we don't have the equivalent here. It doesn't fit into our financial model," he said. "Rheumatologists need to promote what they do to get the early RA patients in to see them, rather than as train wrecks that have been mismanaged."

Lab Tests: What They Can -- and Can't -- Tell You

Certain laboratory tests can help confirm the diagnosis of RA. For example, elevations in acute phase reactants such as erythrocyte sedimentation rate and C-reactive protein suggest the presence of inflammation, but are not specific for RA as these biomarkers can be elevated in many other clinical circumstances such as infection and malignancy.

The most common RA-specific serologic tests are for rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPAs; also referred to as antibodies against cyclic citrullinated peptides, or CCP). ACPAs are more specific for RA than RF, which can be detected in up to 5% of the general population and in many other conditions. Positivity for ACPA, and the presence of very high titers of these antibodies are suggestive of a more aggressive disease course and radiographic damage.

Newer autoantibodies that have also been detected in early RA include anticarbamylated P antibodies, antivimentin antibodies, and the 14-3-3η protein, which have all been linked with a worse outcome and erosive disease. The use of additional serologic tests is evolving, and ultimately may provide earlier diagnosis, but at present, these tests don't really change the story and spending more money is not necessarily going to provide greater specificity, said Cush.

Seropositivity is most reliable in established disease, with RF being detectable in an estimated 80% of patients with longstanding disease, but is found in only about half of patients in the first 6 months following symptom onset. It's important to remember that RA is a clinical, not a serologic, diagnosis, Cush said. An estimated 20-25% of RA patients are seronegative.

"Seronegative patients are in many ways different from seropositives," he continued. "They have to have more evidence of arthritis that's convincingly rheumatoid-like, so they may have more severe disease," he continued. "Seronegatives also always have the potential to evolve into something else. They may later be diagnosed with Crohn's disease with arthritis, or lupus, or calcium , or seropositive RA."

In addition to being serologically different, the genotypes seen in seronegative RA are clearly different from those seen in seropositive disease. "So I think we can surmise that they must be etiologically different as well," Cush said. The implication is that serologically negative RA may be another disease that has yet to evolve and be diagnosed, or that "RA is not in fact not one disease but many diseases with many etiologies that have a final common pathway that is expressed in a rheumatoid-like way," he said.

Role of Imaging in RA Diagnosis: Research vs Clinical Use

The role of imaging in RA diagnosis continues to evolve, with some experts advocating wider use of ultrasound and even MRI for earlier diagnosis. However, the most common use of advanced imaging has been in research settings such as clinical trials.

For example, in a review of MRI and ultrasound in RA, researchers from the University of Leeds in England -- home to a renowned early arthritis clinic -- noted that MRI has been used extensively for the assessment of the efficacy of biologic agents in preventing bone erosions and joint damage. In using a treat-to-target approach with methotrexate plus intra-articular steroids with or without adalimumab found that osteitis and tenosynovitis were decreased at 1 year in the biologic-treated patients.

assessing clinical remission in an early RA cohort during 2 years found that MRI inflammatory scores were lower during apparent clinical remission, but no patients had an MRI score of zero, suggesting that subclinical inflammation persisted.

In addition, comparing MRI outcomes among patients with RA being treated with tofacitinib (Xeljanz) alone or in combination with methotrexate confirmed that patients receiving the JAK inhibitor showed greater improvements at 3 and 6 months on various MRI endpoints such as synovitis, bone marrow edema, and erosive damage.

But those were not real-world settings, where there are concerns about cost effectiveness. "I can never recommend MRI as a tool for early diagnosis other than to exclude other etiologies, or if I'm looking for pathology in bone or periarticular tissues," Cush explained. "A good rheumatologist with good training should be able to make the diagnosis with the tools already available that are less expensive."

However, he said, "my congratulations to the new generation of rheumatologists trained in doing ultrasound. With power Doppler you can identify synovitis and tenosynovitis much earlier than you can on exam and do it in a very cost-efficient manner."

Paget agreed that there can be circumstances when ultrasound can be helpful: "If you want to get a sense of whether there are erosions or tendon inflammation, or if patients present in somewhat atypical ways, you may get a better sense of what's going on," he said.

In of 100 consecutive ACPA-positive individuals who had only nonspecific musculoskeletal symptoms, 50 developed inflammatory arthritis or RA at a median of 7.9 months. The researchers, also from the Leeds clinic, developed a scoring model for predicting progression to inflammatory arthritis based on four factors: tenderness in the joints of the hands and feet; early morning stiffness of more than 30 minutes, high levels of autoantibodies, and a positive ultrasound power Doppler signal. No patients with scores of 0 progressed to inflammatory arthritis compared with 62% of patients with scores of 3 or higher.

What Next?

Once the diagnosis of RA has been made, patients and clinicians together decide upon the initial therapy, whether it be nonsteroidal anti-inflammatory drugs, a short course of steroids, or a disease-modifying agent such as methotrexate. These options will be discussed in the next segment of this series.

"I tell patients that on a scale of 0 to 10, if 10 is the worst you could feel and 0 means no problems with pain, redness, warmth, or swelling, I want you to email me every day or two and tell me how you are doing, with the goal being a score of 0," Paget said. "But if your symptoms and functional status don't improve, we'll switch the medications around. Often this can be done without the patient coming to the clinic, which can be more complicated during the time of COVID, such as through videoconferencing."

Read Part 1 of this series: RA Beginnings: Before the Painful Joints