The WCC Note

Development of sensitive biomarkers for disease surveillance is crucial in clinical trial studies.  MRI affords just such a window into the disease activity of rheumatoid arthritis (RA).  It allows the disease to be monitored when RA is below the threshold for patient symptomatic complaint, but still at a level that can cause joint destruction.  MRI therefore provides a barometer of drug response, one that holds utility in establishing a pharmaceutical trial’s ability to make quiescent the destructive inflammatory cascade of RA.  This issue of The WCC Note continues our examination of MRI’s place in the diagnosis and management of RA.

APPEARANCE & SYMPTOMS

What is the MRI appearance of rheumatoid arthritis?

1. Early RA often first affects the wrist, MCP, and MTP joints.  Abnormalities include:
   a.  Synovitis.  Thickening of the synovial membrane, appearing as quick enhancement after gadolinium on T1-weighted, fat-suppressed images.
   b.  Tenosynovitis.  Any tendon may be involved, but flexor digitorum, extensor digitorum, and extensor carpi ulnaris are frequent.
   c.  Bone erosions.  Sharply marginated trabecular bone loss with cortical defects and often with snynovitis.  More frequently in the capitate, triquetrum, lunate, raial aspect of the second and third MCPs, and lateral fifth metatarsal.
   d.  Bone-marrow edema, usually at the synovial membrane insertion where a small gap between it and the cartilage leaves a “bare area.”
   e.  Bursitis.  Between or beneath metatarsal heads.
2. Additional joints of involvement may include these:
   a.  Knees:  Synovitis, effusion, subsequent erosions.
   b.  Shoulders:  RA incidence and prevalence increase to about age 85.  RA onset in the elderly has been described as having striking large-joint involvement, particularly of the shoulders, hips, and wrists (with sparing of the hands mimicking polymyalgia rheumatica).
   c.  Hips:  When RA is advanced, it may result in acetabular protusion from axial migration.
   d.  Elbows:
   1.  More than half of RA patients
   2.  RA is the most common rheumatological cause of elbow instability
   3.  Isolated elbow involvement is present in only 5% of cases
   4.  Synovitis, joint capsule distention causes patients to hold the elbow flexed, leading to risk of flexion deformity
   5.  Laxity of annular ligament with radial head instability
   6.  Laxity of anterior medial ligament, leading to valgus instability
   7.  Trochlear erosion can lead to proximal ulnar subluxation
   e.  Hand:  Radial and ulnar aspects of the bases of the hand, proximal phalanxes, and PIP joints, typically sparing the DIPs.
   f.  Additional wrist:  Marginal erosion of the styloid tip.
   g.  Cervical spine:
   1.  Laxity of transverse ligament with subluxation of atlantoaxial joint, most commonly anterior type
   2.  Vertical subluxation with odontoid superiorly migrating
   3.  Erosions of odontoid process and apophyseal joints
   4.  Subluxation of lower cervical spine, most commonly at C3-4
   5.  Thoracic and lumbar involvement proves rare
   h.  Clavicle:  Distal clavicular, pencil-like erosions.
3. Technique:  Yao, et al., report contrast-enhanced, T1-weighted images depict more periarticular bone findings in RA than fat-suppressed, T2-weighted images.

ASYMPTOMATIC CHANGES

Do the MRI or immunologic changes of RA occur before a patient has symptoms?
Yes.  RA immunological changes with anti-CRP and RF occur years before clinically apparent disease, which may then be triggered by the proper genetic milieu in combination with environmental factors – such as heavy smoking.  Ultrasound and MRI may show synovitis when the clinical findings are still nonexistent.

POSITIVE MRI FINDINGS

What do positive RA MRI findings mean, even when a person has no symptoms?

1. A direct relationship exists between subclinical synovitis in asymptomatic patients and joint structural damage, with MRI and ultrasound imaging evidence predicting subsequent progression in such patients.  As written in a 2009 article in Nature Clinical Practice Rheumatology, studies have shown synovial inflammation can persist even in clinical remission.  The report profiled a recent study of 102 patients with RA who were receiving DMARDs and were thought to be in remission clinically, but 19% of whom demonstrated significant radiologic disease progression at one year.  Imaging-detected baseline synovitis presaged the likelihood of progression.  The authors state that conventional criteria for remission prove insensitive to low-level disease; therefore, the assessment should be made by imaging.
2. MRI findings prove common in early RA, and bone-marrow edema independently predicts radiographic damage.

INTERVENTION

What is the optimal time to intervene in RA?
Noting that bone damage occurs early, the argument for early disease-modifying agent (DMA) therapy has received attention.

Conclusion:  Immunological features occur in rheumatoid arthritis years before clinically apparent disease.  MRI may afford early RA diagnosis even when serology proves negative, which is important because early disease-modification therapy better protects long-term joint function.  MRI can document active RA disease and continued joint destruction – even in asymptomatic patients thought to be in clinical remission.

Development of sensitive biomarkers for disease surveillance is crucial in clinical trial studies.  MRI affords such a window into the disease activity of rheumatoid arthritis (RA).  It allows the disease to be monitored when RA is below the threshold for patient symptomatic complaint, but still at a level that can cause joint destruction.  MRI therefore provides a barometer of drug response, one that holds utility in establishing a pharmaceutical trial’s ability to make quiescent the destructive inflammatory cascade of RA.  This issue of The WCC Note addresses MRI’s place in the diagnosis and management of RA.

As researchers mine innovative science to understand and optimally combat rheumatoid arthritis (RA), perhaps the best way to view the cornerstone role MRI plays in its diagnosis and management is to first step back and see how it fits into the larger foundation of disease knowledge.

In recent years, molecular, microenvironmental, genetic, and epigenetic research on RA joined growing immunological advances to further elucidate the origin and inflammatory erosive events accompanying the disease.  These investigations provided new tools in teh form of biological agents (disease-modifying antirheumatic drugs, or DMARDs) to halt RA progression.

The following questions and answers outline larger scientific inquiries to RA and summarize some of the recent reports regarding MRI’s relationship to them.

DIAGNOSIS WITHOUT MRI

How is rheumatoid arthritis diagnosed without benefit of MRI?
Historically, a combination of factors coalesced to identify a patient’s arthritis as rheumatoid.  Twenty-two years ago, in 1987, these included a set of revised criteria from the American Rheumatism Association.  At that time, a diagnosis warranted consideration if four criteria were met, or the first three were present for at least six weeks’ duration:

1. Morning stiffness lasting at least one hour
2. Soft-tissue swelling or fluid in at least three simultaneous joint areas, at least one in a wrist, MCP, or PIP joint
3. Symmetric arthritis
4. Rheumatoid nodules
5. Abnormal serum rheumatoid factor (RF)
6. Erosions or bone decalcification on hand/wrist radiographs

Rheumatoid factor is an antibody directed against IgG and may or may not be present in rheumatoid arthritis patients.  It is not specific, and may also be found in healthy elderly individuals, as well as in people with other autoimmune and infectious diseases.

A more recently discovered autoantibody called cyclic citrullinated peptide antibody (anti-CCP) has been reported as more specific than RF for diagnosing RA and predicting erosive disease.  Combined RF and anti-CCP may be better than either alone for diagnosing very early RA.

DIAGNOSIS WITH MRI

How does MRI help in RA diagnosis, especially early on in the disease?

1. Currently, MRI factors into the diagnosis because it can help establish an RA diagnosis in people with negative anti-CCP and normal radiographs, according to research at Lille University Hospital in Lille, France.  The authors followed 30 outpatients for one year and found MRI of the hands (T1 fat saturation with contrast) to show MCP erosions in RA patients with 70% specificity, 64% sensitivity.
2. In individuals in whom RA was clinically suspected but who lacked RF and radiographic erosions, a comparison of contrast-enhanced MRI of the hand versus anti-CCP revealed assessment of imaging synovitis with bone erosions or bone marrow edema provided a sensitivity of 100% for RA with one false positive (psoriatic arthritis), and a 78% specificity.  This compared to an anti-CCP sensitivity of 23%, specificity of 100%.  The 2008 study of 40 patients was performed by authors from the Department of Rheumatology in Barcelona, Spain.
3. Unclassified arthritis (despite biochemical and radiograph testing) can be classified as RA with the help of contrast-enhanced MRI of the wrist and MCP joints of the symptomatic hand and whole-body bone scan, according to Department of Rheumatology at Copenhagen University Hospital at Hvidovre (Denmark).  Danish researchers examined patients with unclassified arthritis and, at two-year follow-up, noted a correct classification as RA or non-RA in 39 of the 41 subjects using such imaging.
4. Noting that the 1987 American College of Rheumatology criteria have limited utility in clinical practice due particularly to early diagnostic insensitivity, coupled with the need to institute prompt therapy to prevent detrimental outcome, Keen, et al. reviwed the literature supporting the ability of MRI to detect:
   a.  Bone erosions many months prior to plain films;
   b.  More erosions than radiography;
   c.  Bone edema as a forerunner to erosion development;
   d.  Synovitis and tenosynovitis.

Conclusion:  MRI may afford early rheumatoid arthritis diagnosis, even when serology proves negative, which is important because early disease modification therapy better protects long-term joint function.

JOINT PATHOLOGY

Rheumatoid Arthritis: How MRI Changes Our Understanding
Rheumatoid arthritis (RA) afflicts 1.3 million Americans.  A systemic disease, it affects the joints, skin, blood vessels, heart, lungs, and muscles.  While most prevalent between ages 40 to 70, it occurs at all ages, afflicting women two to three times more than men.  The ability of MRI to depict soft tissue and bone marrow has widened our perception of the disease and made MRI a modality of choice for RA diagnosis, assessment, and subsequently, clinical trial evauation.

The joint pathology occurs in stages:

1. Synovium swells and becomes hyperplastic.
2. Inflammatory cells infiltrate synovium.
3. Vascularity increases from vasodilatation and angiogenesis.
4. Organized fibrin covers some synovium and releases into the joint as rice bodies.
5. Osteoclastic activity occurs in subjacent bone, with erosions, cysts, and osteoporosis developing.
6. Masses of synovium, inflammatory cells, granulation, and fibroblasts, called pannus, occur.
7. Inflamed cells release enzymes that destroy cartilage and bone.

This issue of The WCC Note continues our series outlining some of the recent literature on RA.  This week’s articles address searches to elucidate the etiology of rheumatoid arthritis, since understanding its pathogenesis is requisite to optimally preventing or arresting joint destruction.

PATHOGENESIS FACTORS

The Components of Pathogenesis
General theory holds RA to be an autoimmune disease incited by an arthritogenic antigen in a genetically susceptible person.  Each of these factors – genetic susceptibility, antigen, and autoimmune reaction – plays a role.

1. Genetic susceptibility
   a.  Genetic factors predispose to RA, though their overall contribution is estimated at 50 percent or less.  Other nongenetic but gene-regulating factors may influence a person’s susceptibility to RA and disease severity.  Called epigenetic factors, these are heritable alterations in gene expression without changes in nucleotide sequences – in other words, changes not encoded directly by DNA sequence of the specific gene, but instead such entities as DNA methylation or noncoding RNAs.  Strieholt, et al., reviewed such epigenetic processes in RA.  The authors note that epigenetic modifications, while not fixed in DNA code, can be stable during a person’s life or can be altered by individual lifestyle differences.  Environmental triggers are hypothesized to participate in the RA by causing epigenetic modifications, which are thought to play a major role in RA’s development.
2. Autoimmune reaction
   a.  Reviewing what MRI has told us about the pathogenesis of RA, McGonagle and Tan report that MRI-demonstrated synovitis shows high correlation to histological grades of synovitis and tissue vascularity, and appears to confirm RA as primarily a disease of synovium.  They state their studies show erosions occur secondarily due to synovitis, with sites of joint compression possibly more prone to erosion, and that effective treatment of synovitis is crucial to successful therapy.
   b.  To determine the cellular components of MRI bone edema in RA, Dalbeth, et al., examine 11 patients with RA who were undergoing orthopedic surgery.  They found an increased number of osteoclasts, RANKL (Receptor Activator for Nuclear factor KappaB Ligand), macrophages, and plasma cells in samples with MRI bone edema, concluding that RA bone erosions result from activitation of local bone resorption of subchondral bone as well as synovial invasion.
   c.  Histopathological studies depict lymphocytes and osteoclasts in subchondral bone that could mediate erosions from the marrow toward the joint, according to a report from the Department of Molecular Medicine and Pathology at the University of Auckland, New Zealand.  The authors state that animal models show evidence that this cellular infiltrate corresponds to MRI bone edema, supporting the notion that bone-marrow pathology helps drive joint damage.
   d.  Macrophages of RA patients possess signaling pathways that drive continued production of pro-inflammatory mediators in effected joints.  Noting that current pharmaceuticals are biological agents blocking a cytokine (tumor necrosis factor) produced predominantly from macrophages, authors from Imperial College of Science, Technology and Medicine in London, U.K., discuss the various signaling mechanisms in innate immune cells.

Conclusion:  Several recent studies advance our understanding of the origin of rheumatoid arthritis, theorized to be an autoimmune disease triggered in a genetically susceptible person by an inciting antigen.  Areas under continued scrutiny include patient epigenetic factors, the dominant role of synovitis, and evolving evidence that bone-marrow pathology participates in joint damage.  Research documents the cornerstone role magnetic resonance imaging has played in furthering out knowledge about the disease.