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Volume 4, Number 5 – July 8, 2010 FATTY LIVER: The Epidemic Wolf in Sheep’s Clothing

Wednesday, August 4th, 2010

Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent liver disease in the United States, affecting all age groups.  It encompasses a spectrum of disease, ranging from simple steatosis, steatohepatitis (NASH), fibrosis and cirrhosis, to hepatocellular carcinoma.  (1)  This issue of The WCC Note examines the imaging avenues to diagnosis and quantify hepatic steatosis.

What does recent literature report about ultrasound imaging of hepatic steatosis?
1.   The gray scale findings include the following:                          
a.  The diagnosis of fatty liver can be made if:
i.    The liver is more echogenic than
the renal cortex and spleen.
ii.   Ultrasound wave attenuation is present.
iii.  The diaphragm loses definition.
iv.  The intrahepatic architecture has poor
delineation.
v.   There should be more than just one or
two of the above present. (2)
b.  A 2008 review reported ultrasound sensitivity
ranged 67-84% and specificity 77-100% for
severe fatty liver (more than 30% fat by weight).
It has been reported as poor at diagnosing
lesser degrees of steatosis. (3)
c.  Subjective visual assessment of fatty liver at
ultrasound has marked observer variability. (4)
d.  A 2009 study reported that a hepatorenal sono-
graphic index of 1.49 (the ratio between the
mean brightness levels in a region of interest in
the liver and spleen) predicted steatosis of >5%
with a sensitivity of 90%, specificity 90%.  Steato-
sis of >60%; specificity 93%). (5)
2.   Elastography
  a. A significant positive correlation was reported between
median acoustic radiation force
impulse elastography (ARFI) and liver fibrosis in patients
with NAFLD. (6)

What are some updates on CT of hepatic steatosis?                        
1.    Hepatic steatosis can be diagnosed on
CT if:
a.  Noncontract
i.   Liver attenuation is at least
10 Hounsfield units (HU) less
than the spleen.
ii. The liver attenuation is<48
HU (7, 8, 9); or <40 HU when
lipid is about 30% . (9, 10)
b. With contrast:
i.    The comparison of the liver
and spleen HU is not as reliable. (2)
ii.   Fatty liver can be diagnosed if liver
attenuation is less than 40 HU. (2)
2.   Then if the liver is <40 HU, is that spe-
cific for liver steatosis?
a.   No. Ischemic or mucinous metasta-
ses, or abscesses can have this
attenustion.  Clinical laboratory, and
other imaging features need consid-
eration. (2)
3.    Lipid quantification can be preformed by
the following methods:
a.  Hepatic attenuation measurement
i.  A value of 40 HU is reported
to represent fetty change of
approximately 30%. (9, 10)
b.  Hepatic attenuation index
i.  A ratio of hepatic HU to splenic
HU less than 0.8 is reported as
highly specific for moderate to
severe (>30%) macrovesicular
steatosis.  (11, 9)
c.  Hepatic attenuation difference at
dual-energy CT
i.  Ma et al note, in review, that
while there is a paucity of literature
to validate its use, an increase in fatty
content associates with desreased HU at low
energy;  when the energy level increases, the
fat attenuation increases. (9)
4.    Unenhanced CT studies have reported:
a.  Visual grading and liver attentuation index were shown reliable and similarly accurate for
diagnosis of 30% or higher macrovesicular steatosis in living hepatic donor candidates.  (12)
b.  Moderate to severe macrovesicular steatosis (i.e. >30%) can be accurately diagnosed in
the living hepatic donor, avoiding biopsy, but biopsy is still needed if the CT calculates
<30% fat.  Coexistent fatty liver and hemosiderin or occult liver disease would be possible.
(13, 14, 15)
c.  Low dose unenhanced CT detected hepatic steatosis in asymptomatic patients, while
clinical risk factor profiles proved unreliable. (16)

What MRI methods are used to evaluate hepatic steatosis?
1.  Spectroscopy
a.   This technique uses the frquency position along the x-axis to separate and character-
ize chemicals within voxels.  (17)
b.  Localized or single-voxel MRI.  Sequences include:
i.   Point-resolved spectroscopy  (PRESS)
ii.  Stimulated echo acquisition mode  (STEAM)
iii. A reconfigured STEAM sequence has been reported with breath-hold acquisition of
TZ-corrected lipid measurement.  (18)
iv. A disadvantage is that a large, single voxel is studied.  (19)
c.    The summation of individual lipid peaks calculates the total liver triglyceride content.  (9)

2.  Chemical shift imaging:  Fat and water protons precess at different frequencies in a magnetic
field.  Exploiting this allows for detection and quantification of fatty infiltration.  Multiple
sequences have been developed on this basis.  These are:
a.  Two-point Dixion MRI
i.   This techniques offsets the rephasing pulse in a spin echo (SE) sequence to create
out -of-phase images, with the unmodified SE images used as in-phase.  Summation
and subtration of these images yields water-only and fat-only images to quantify fat,
but magnetic field inhomogeneity and longer scan times limit its use  (9)

ii.   A recent study  at 3T reported a 2D decomposition technique to identify distinct
in-phase/opposed and fat/water ratios for in vitro steatosis, iron overload, and
combined disease.  (20)
b.  Three-point Dixon MRI
i.      Developed to overcome the field inhomogeneity, it uses a third image with phase
correction but increases scan time.  (9)
c.  Modified Dixon
i.      When faast gradient echo (GRE) was developed, this methodused shorter TEs and
TRs to decrease scan time and allow breath hold images.
ii.     As reviewed by Ma et al, it can detect mild hepatic fat of 10% or more.  (9)
d.  Triple-echo chemical shift GRE
i.      This breath-hold low flip angle technique with correction for T2* was reported to
accurately quantify hepatic fat.  (21)

e.   Opposed-phase T1
i.    When fat and water proton magnetization are in phase, their signal is additive.
when out-of-phase, signal intensity decreases.
ii.  Dual echo fast GRE sequences decrease scan time, allow breath hold imaging,
and minimize T2* when shorter TEs are used.
iii. Opposed-phase T1-weighted images showed signal intensity loss that could be
used to grade the severity of liver steatosis.  (22)
iv.  A relative signal decrease of less than 20% allowed correst prediction of liver
donation appropriateness in 53 of 57 patients.  (23)
v.    Using MR spectroscopy as the referenceee standard, in-and out-of-phase imaging
rapidly estimated liver fat content.  A cutoff value of 5.1% discriminated between
normal and elevated liver fat.  (24)
vi.   Potential pitfall include:
1.  The presence of liver iron, which can cause signal intensity loss on in-
phase images.  (25)
2.  Fat fractions>50%, which cannot be reliably assessed (26)
3.  Fat is spectrally complex.  (26)

3.  MR elastography
a.  This technique employs three phases.  Mechanical waves are generated in tissue.  The
micron-level displacements are imaged using motion-sensitizing gradients.  Wave images
are processed to generate quantitative maps.  (26)
b.  MR 7T elastography detected early steatohepatitis in rats by showing increased elasticity.
(27, 28)
4.   Low-flip-angle multiecho GRE
a.    This is reported to provide high diagnostic and fat-grading accuracy in NAFLD.  (29)
b.    According to O’Regan et al., it can provide fat measurement without acquiring a separate
T2* map (unlike dual echo) and correlates highly with T2-corrected proton MR spectro-
scopy.  (30)
5.   Fast spin echo (FSE)
a.  T2-weighted fat saturated FSE images are compared to T2-weighted non-fat-saturated
FSE images.  A decrease in signal intensity on the fat-saturated images suggests fatty
infiltration.
b.  This method avoids the T2* effect signal loss of liver iron in the cirrhotic patient, which
can be problematic in GRE sequences.  (31, 9)

What are the patterns of hepatic fat deposition?
1.   Diffuse fatty infiltration is most common.  (2)
2.   Focal depostion or diffuse fatty infiltration with focal sparing shows:
a.   No mass effect,
b.   Geographic shape,
c.   Poorly defined margins,
d.   Positioning adjacent to the porta hepatis, gallbladder fossa, ligamentum venosum, or
falciformm ligament (perhaps because of variant venous circulation), and
e.   Contrast enhancement similar to or less than normal liver.  (2)
3.   Multifocal depostition:
a.    Is an uncommon pattern with multiple fat foci an atypical locations,
b.    May be round or oval,
c.    Is a difficult diagnosis,
d.    Must have microscopic fat,
e.    Chemical shift GRE may be helpful, and
d.    May be seen with regenerative nodules in cirrhosis.  (2)
4.   Perivascular:
a.     Has fat halos around hepatic and/or portal veins;
b.     Has an unknown pathogenesis.  (2)
5.   Subcapsular:
a.     This distribution occurs in insulin-dependent diabetics on peritoneal dialysis who get
insulin added to the peritoneal dialysate.
b.     The etiology is thought to be due to direct exposure of that region to a higher
concentration of insulin.  (2)
6.    Patients with fatty liver and concomitant focal liver lesions may display peritumoral sparing of
the fat, leading to atypical imaging appearances.  (32)

What tumors are pitfalls and can contain microscopic fat?
1.     Hepatic adenomas may contain microscopic fat.
Hepatocellular carcinoooooomas, angiomyolipoma, and nodular hyperplasia may contain
microscopic fat and soft tissue.  (2, 33)

Conclusion:  Noncontrast CT can accurately diagnose moderate to severe hepatic steatosis (>30%)
but is not accurate at lower levels.  MRI techniques to detect and quantify hepatic steatosis currently
emphasize chemical shift imaging, with spectroscopy as the gold standard.  Ultrasound suffers from
subjectivity and inability to diagnose lesser degrees of hepatic fat, though a recent study of hepatorenal index  was encouraging.  

Research and reporting by Margaret D. Phillips, M.D.

Reviewer and publisher: Stephen J. Pomeranz, M.D. 

For full sources and credit, please download the PDF copy of the newsletter here

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Knee Osteoarthritis: MRI in the Landscape of Current and Potential Treatment – Vol. 3, Number 10

Thursday, December 3rd, 2009

Like trying to mend broken glass in the hope that it will shine clearly again, repairing the destruction of knee osteoarthritis (OA) looms as an arduous and complex task – if it can ever be accomplished.

Where is current science, then, on the path to one day preventing, arresting, or reversing this debilitating crippler of joints?  This issue of The WCC Note continues our series on knee OA by examining current literature on treatment and prospective cures, and how MRI is poised to aid monitoring the disease.

As outlined in previous issues of this newsletter, the enormity of knee OA as a population problem – the scope of its occurrence, pathogenesis, and heterogeneity – confounds a simplistic approach to therapy.  Rather than a single disease-modifying drug, surgery, or physical therapy procedure, the idea that multiple influences lead to a common endpoint of joint destruction means that this multi-dimensional disease will, in most cases, always require a multi-faceted treatment approach.

While this can seem like a frustrating and daunting process, it helps to step back and tease apart the fundamental questions at hand, imposing structure on the analysis of this most labyrinthine of common disorders.

TREATMENT

What Treatment Approaches to Knee OA Are Currently Practiced?

  1. At 2008 overview of knee osteoarthritis management in Rheumatic Disease Clinics of North America called for conservative treatment, outlining recommendations from the Task Force of Standing Committee for International Clinical Studies including Therapeutic Trials (ESCISIT).  In summary, the guidelines were:
    a.  Combination nonpharmacologic and phamacologic treatment
    b.  Treatment tailored according to risk factors, such as obesity and activity, age, level of pain, signs of inflammation,and location and extent of structural damage
    c.  Education, exercise, use of appliances, and weight reduction
    d.  Paracetamol (acetaminophen) as the first analgesic used and the preferred long-term choice if efficacy is established
    e.  Topical NSAIDs and capsaicin are efficacious and safe
    f.  NSAIDs can be considered in patients for whom paracetamol is not helpful.  Nonselective NSAIDs or COX-2 inhibitors play a role for a subset of patients
    g.  Opioid analgesics, with or without paracetamol, can be useful in patients for whom NSAIDs are contraindicated or do not work
    h.  Symptomatic, slow-acting drugs such as avocad-soybean unsaponifiables may be of benefit
    i.  Intra-articular injection of long-acting corticosteroids may be useful in settings of pain flare
    j.  Joint replacement becomes a consideration for patients with refractory pain and disability
  2. In the September 2009 Journal of the American Academy of Orthopedic Surgery, authors from The New England Baptist Hospital in Boston reported practice guidelines for knee OA that were developed explicitly aside from knee replacement (arthroplasty).  The authors recommend that patients participate in educational programs regarding self-management, weight loss, exercise, and quadriceps strengthening.  The guidelines recommend taping for short-term pain relief, analgesics, and intra-articular corticosteroids.  The report advises against free-floating interpositional devices and lateral heel wedges for medial compartment knee OA.  The authors note that the group did not come to a recommendation in regards to the use of braces with valgus- or varus-directing forces.

OA & MENISCAL TEARS

Are Meniscal Tears Caused By, or a Result of, OA, And What Does Current Literature Advise About the Role of Surgery for Them?
It is well known that normal menisci are rare in osteoarthritic knees.  While meniscal lesions in healthy knees may result in osteoarthritis due to loss of meniscal function, osteoarthritis may itself lead to mensical tears, which subsequently accelerate the disease.  Proteolytic degradation and shear stress may lead to decreased meniscal tensile strength.  Meniscal tears may then result from teh compromised meniscus being unable to withstand loads and force transmitted during normal joint loading.

Meniscal resection is reported as the procedure most frequently performed by orthopaedic surgeons in the United States.  A recent review called for well-designed, randomized, controlled clinical trials to study the true effects of meniscal resection repair or transplant, or nonsurgical treatments, as compared with placebo or sham treatment.

Noting that a meniscal tear is an almost ubiquitous MRI finding in a person with knee arthritis and is not necessarily responsible for symptoms, Hunter and Low wrote in Rheumatic Disease Clinics of North America that the removal of menisci should not be preformed unless there is clinical locking or extension blockade, since strong evidence supports that even partial meniscectomy increases the risk for worsening osteoarthritis.

Allogenic, xenogenic, or artificial material meniscal replacements have been attempted in younger subjects post-total meniscectomy, but transplant survival is variable and long-term results prove lacking.

Individuals with initial asymptomatic meniscal lesions have a clinical course that shows an increased frequency of symptoms compared to those without meniscal lesions, though the pain and impairment remain of low severity.

MRI T2 measurements of cartilage in patients with osteoarthritis show them to be increased in patients with meniscal tears.  Friedrick, et al., note that this supports the theory of meniscal and hyaline cartilage damage occurring in the setting of osteoarthritis.

SURGERY FOR KNEE OA

What Surgical Approaches Exist, And What Does Recent Literature Report About Them?

  1. Lavage and Debridement: Arthroscopic lavage and debridement are not recommended for routine treatment, as they do not alter disease progression.  In a study involving 92 patients assigned to surgery (and six not undergoing surgery), as well as 86 controlled subjects who received only physical and medical therapy, arthroscopic surgery with surgical lavage and debridement failed to add additional benefit to patients with moderate to severe osteoarthritis over optimized physical and medical therapy.
  2. Microfracture: A technique for therapy of focal chondral defects, the microfracture surgical procedure involves subchondral drilling to crate 4mm-deep pits, into which multipotential stem cells migrate from the subjacent marrow to form fibrocartilaginous tissue repair.
  3. Cell-Based Cartilage Repair:
    a.  Autologous Chondrocyte Implantation (ACI):  In this procedure, chondrocytes are harvested from nonweight-bearing cartilage, cultured in vitro and subsequently reimplanted.  Elegant reviews of the technique geared towards imaging were published in Radiographics in 2007 and 2008.  MRI can depict the state of cartilage healing, as well as the subchondral bone and bone marrow.
    Noting that young individuals with early osteoarthritis who want to remain physically active have limited treatment options, ACI may offer benefit, according to Minas, et al., in a 2009 study.
    ACI can be performed using a polymer-based graft to repair cartilage defects.  While the ACI typically requires a rim of intact cartilage at the periphery of the defect, such a recent report states that a newer technique can allow cartilage repair even when such a rim is not present.  In general, the technique uses chondrocytes harvested from healthy cartilage in nonwweight-bearing regions of the knee and transplants them into areas of defect.  A report from 2009 states that chondrocytes cultivated in a three-dimensional matrix of bioresorbable material avoided the use of covering materials such as periosteum or collagen sheets.  The fibrin polymer matrix provided a scaffold to stabilize the graft.  The authors reported that improvements were still present four years after graft implementation for patients who had undergone the procedure.
    A 2009 study of symptomatic cartilage defects of the knee reported that chondrocyte implantation had better clinical outcomes at 36 months than the microfracture technique.
    b.  Autologous Osteochoncral Autograft Transplantation:  This technique harvests osteochondral plugs from the lateral femoral condyle or trochlear nonweight-bearing areas and transplants them into an area of articular defect.
    c.  Osteochondral Allograft Implantation:  Osteochondral allograft transplantation involves the harvesting of cadaveric bone cartilage.
  4. Osteotomy: Osteotomy can be considered for unicompartmental knee OA, with the intent to shift the weight load away from the damaged compartment.
  5. Arthroplasty (Joint Replacement):
    a.  Joint replacement surgery includes: unicompartmental athroplasty and patellofemoral replacement in selected patients with isolated meial or patellofemoral OA, and total knee arthroplasty for patients with severe OA.

GLUCOSAMINE AND CHONDROITIN

Do Glucosamine and Chondroitin Work?
Glucosamine and chondroitin sulfate, alone or in combination, failed to reduce pain effectively in a study of 1,583 patients with symptomatic knee osteoarthritis.  The analysis suggested that the combination of both medicines may be of benefit to a subgroup of individuals who have moderate to severe knee pain.  Glucosamine, but not ibuprofen, has been shown to alter cartilage turnover in patients with osteoarthritis undergoing physical training.

MRI AS BIOMARKER

How Can MRI Be Used to Grade the Impact of Therapies – Pharmaceutical, Operative, Physical Therapy, and Behavioral Interventions?

  1. MRI can provide semi-quantitative assessment in osteoarthritis because it can detail articular cartilage integrity; subchondral bone-marrow pathology; edema or cysts; subchondral bone attrition; marginally, centrally, and posteriorly positioned osteophytes; meniscal and ligament integrity; synovitis and effusion; and loose bodies.  Three commonly sued whole-joint MRI imaging assessments are:
    a.  Whole-organ MR imaging score (WORMS)
    b.  Knee osteoarthritis scoring system (KOSS)
    c.  Boston leads osteoarthritis knee score (BLOKS)
  2. Cartilage can be reproducibly and accurately measured by MRI.  Cartilage morphology and trabecular bone may be quantitatively measured in the research arena to provide baseline and follow-up monitoring of treatment in OA.  In a clinical trial, cartilage thickness can provide the same level of sensitivity as cartilage volume to estimate cartilage loss.
  3. MRI shows potential value as a biomarker, since studies have indicated that the presence of either bone-marrow lesions or meniscal disease is predictive of those OA patients at greater risk for disease progression.
  4. Very early changes in cartilage biochemistry, prior to joint damage or pain, may be able to be measured by experimental MRI methods of T1-rho and T2.
  5. Specialized research MRI protocols of T2 mapping, T1-rho, sodium MR, and delayed gadolinium-enhanced MRI imaging to assess the macromolecular status of cartilage may be useful in assessing disease-modifying strategies for OA.
  6. Molecular and functional techniques for imaging early osteoarthritis include charged-based methods such as delayed gadolinium-enhanced MRI of cartilage, which is based on teh negatively charged T1-shortening agent gadopentetate dimeglumine.  Hyaline cartilage has negatively charged molecules, similar in charge to gadolinium, and thereby repulses gadolinium when the cartilage is normal and intact.  Conversely, damaged cartilage lacks the negatively charged hydrophilic molecules, allowing the gadolinium into the cartilage proper.
  7. Sodium-23 MR spectroscopy also takes advantage of the negative-fixed charged density (FCD) of cartilage.  In this technique, sodium-23 atoms, which are positively charged, correlate directly with cartilage-fixed charged density.  Sodium-23, therefore, decreases in abnormal cartilage.
  8. In the research arena, cathepsin B-sensitive near-infared fluorescent probes have been used to image osteoarthritic knees in animals.  Since damaged cartilage may release proteases such as cathepsins, this method is used experimentally to image matrix-degrading enzymes.
  9. Since OA is widely thought to result from local mechanical factors in people with systemic susceptibility, the influence of biomechanics in osteoarthritis, and the imaging quantification of them, is both interesting and important.  Joint kinematics assessed with MRI imaging have been preformed with patients supine in the magnet, with some recent work attempted in open-configuration scanners with vertical gaps, which allow standing.

OA PROGRESSION

What Have We Learned About OA Progression from MRI?

  1. Patients with knee OA who display MRI evidence of meniscal damage or extrusion, as assessed by WORMS score, show association with cartilage loss over a 30-month period.
  2. In a 2009 study from the Multicenter Osteoarthritis Study Group (MOST), a longitudinal study of people with, or at high risk for, knee OA, those subjects who had minimal baseline cartilage damage but high body-mass index, meniscal damage, synovitis or effusion, or any baseline severe MRI lesion, had a strongly increased risk of fast cartilage loss.
  3. The finding of MRI-evident bone-marrow lesions (BMLS) shows association with change in knee cartilage over two years in asymptomatic subjects.  As the size of the BMLS increases, there is increased progression of cartilage defects.  The 2008 study included 271 healthy adults with no history of knee injury, knee pain, or clinical knee OA, who underwent knee MRI at baseline and two-year follow-up to study the relationship between presence of BMLS as baseline and cartilage change over two years.
  4. The role of alignment and biomechanics in osteoarthritis underwent review this year in Radiologic Clinics of North America.  Valgus and varus malalignment were reported as increasing risk for OA, with patellar malalignment asociated with patellofemoral OA progression.  MR imaging measurements of kinematics, and measurements of contact area, were both discussed.
  5. The incidence of degenerative cleavage trizonal body tears in patients with moderate to advanced osteoarthritis is over 50 percent in patients over age 50 (personal observation by Dr. Stephen J. Pomeranz).

MRI IN OA CLINICAL TRIALS

What Are Some Examples Where MRI Played a Biomarker Role in OA Clinical Pharmaceutical Trials?

  1. In patients with knee pain on efficacious doses of NSAIDs or acetaminophen, a decrease in effusion volume (quantified by gadolinium-enhanced T1 imaging) was observed and rapidly reversed when treatment was withdrawn.
  2. In a placebo-controlled, double-blind study of 377 knee OA patients, changes in MRI assessment of subchondral bone marrow abnormalities were observed within three months of treatment and were positively correlated with type II collagen degradation (determined by urinary CTX-II).

MRI imaging is a sensitive and early marker of OA that can correlate with drug efficacy. (Contributed by Rick Walovitch, Ph.D., WorldCare Clinical)

CONCLUSION

The complexity of knee osteoarthritis etiologies complicates the search for a single disease modifying therapeutic approach.  Current treatment emphasizes conservative management including mechanical joint preservation measures.  MRI depicts the whole joint nature of the disease and serves as a barometer of its time course.

Research and reporting by Margaret D. Phillips, M.D.
Reviewer and publisher: Stephen J. Pomeranz, M.D.

For full sources and credit, please download the PDF copy of the newsletter here

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Osteoarthritis
Vol. 3, Number 9

Wednesday, September 16th, 2009

Osteoarthritis: “The Malady of the Masses Re-Examined”
Like the common cold and taxes, osteoarthritis (OA) sweeps so ubiquitously over humanity, and looms so complex in its etiology and cure, that it can seem to drop off the analytical radar.  Not trendy or exotic, and taking a back seat to more mortal diseases, it nevertheless presents a scourge to a large percentage of the population.

This issue of The WCC Note discusses the prevalence and pathology of osteoarthritis, with specific emphasis on its most common focus of affliction – the knee.

OA: THE NUMBERS

How many people are afflicted with OA?

  1. OA afflicts 13.9% of all people 25 years old and older and 33.6% of all people 65 years old and older.
  2. In 2005, a conservative estimate of U.S. adults with OA numbered 26.9 million.
  3. In 2006, an estimated 11.7 million ambulatory care visits were made for OA and allied disorders.
  4. Knee OA accounts for 1 of 5 primary factors of disability in non-institutionalized adults.
  5. Lifetime risk estimates project that nearly half of adults in a longitudinal osteoarthritis project in rural North Carolina will develop symptomatic knee OA by age 85.
  6. The estimated annual U.S., expenditure for OA treatment and lost work is more than $33 billion.

OA RISK FACTORS

Who gets OA? What risk factors are associated with OA?
Both avoidable and nonmodifiable factors influence the development of OA, as outlined below.

  1. Modifiable risk factors:
    a.  Excess weight, especially with knee OA.  For some women, weight loss of as few as 11 pounds can decrease the risk of developing knee OA by 50%
    b.  Joint injury (including occupational and sports-related)
    c.  Occupation – excess mechanical stress or repetitive injury
    d.  Muscle weakness or structural malalignment
  2. Nonmodifiable risk factors:
    a.  Gender (female risk is higher)
    b.  Advancing age
    c.  Race (risk lower in some Asian populations)
    d.  Genetic predisposition

OA GENETICS

What is the genetic component of OA?

  1. A clear genetic component has been apparent since it was first reported by Kellgren in 1963, who found that nodal OA was twice as likely to occur in first-degree relatives than in control subjects.
  2. The genetic basis fails to follow typical Mendelian inheritance patterns, and multiple genetic alterations probably underlie the disease.
  3. The polygenic nature of OA, with its strong hereditary component, is supported by evidence from familial aggregation and classic twin studies.  Traits associated with OA, such as cartilage volume changes, also come under genetic control.
  4. The complex, multifactorial genetic basis has been partially revealed by genome-wide linkage scans.  Thus far, implicated genes include:
    a.  Interleukin I gene cluster at chromosome 2q11.2-q13
    b.  Matrilin 3 gene at 2p24.1
    c.  IL-4 receptor alpha-chain gene at 16p12.1
    d.  Secreted frizzled-related protein 3 gene at 2q32.1
    e.  Metalloproteinase gene ADAM12 at 10q26.2
    f.  Asporin gene at 9q22.31
    g.  Growth differentiation factor 5
    h.  DVWA gene on human chromosome 3p24.3, found in OA in Japanese and Chinese patients
  5. A recent review of the science of OA by Aramson and Attur describes the following:
    a.  Coexisting individual genes may give rise to an additive affect.
    b.  Some genes that encode extracellular matrix articular cartilage proteins have links to early OA.
    c.  Mutations in several genes expressed in cartilage and point mutations in type II collagen may cause inherited OA.
    d.  Genetically linked abnormal subchondral bone can cause OA in mice.

OA PATHOGENESIS

What is the pathogenesis of OA?
Abnormal biochemical processes occur in the cartilage, bone, and synovium, instigated by the risk factors delineated above.  Progressive cartilage damage occurs, with accompanying osteophyte formation, meniscal degeneration, bone-marrow and subchondrial lesions, synovial proliferation, and effusion.

The following list outlines the proposed mechanisms causing OA, segregated by risk factor – a subject elegantly reviewed by Abramson and Attur.

  1. Obesity
    a.  Increased mechanic force: Obese individuals commonly exhibit varus knee malalignment, increasing forces in the medial compartment.
    b.  Adipocytes play roles regulating cells in bone, cartilage, and joint tissue.
    c.  Adipocyte-derived factors may encourage catabolism for chondrocytes.
  2. Joint Injury
    a. Chondrocytes act as mechano-sensors and osmo-sensors, changing their metabolism depending upon local physical and chemical alterations.
    b.  Response to mechanical stress can change gene expression, resulting in increased formation of inflammatory cytokines and matrix-degrading enzymes.
    c.  A focal cartilage injury can result in matrix disruption and chondrocyte apoptosis, or both, which begins a vicious cycle.  Trauma can cause chondrocyte death by two mechanisms: via mechanical load or via disruption of extracellular matrix leading to chondrocyte physical isolation.  Detached chondrocytes undergo apoptosis (programmed cell death) and injured areas make degradative enzymes.  Load transfer to normal peripheral regions then undergo abnormal forces, resulting in their apoptosis.
    d.  An enzyme called Smurf2 (Smad Ubiquitination Regulatory Factors) controls whether a chondrocyte matures and calcifies and, in the setting of cartilage injury, may cause a chain reaction that deteriorates cartilage.
  3. Joint malalignment
    a.  This is debated as an etiological factor, but altered joint geometry may interfere with cartilage nutrition or change load distribution.  Knee malalignment may be a marker of disease, and the literature is conflicting about is role as an OA instigator.
  4. Gender
    a.  Estrogen receptors exist in joint chondrocytes.
    b.  It has been hypothesized that the markedly increased risk of knee OA in women after age 50 is due to estrogen insufficiency, though this is actually poorly understood and evidence for such a relation is reported as inconsistent.
  5. Age
    a.  This factor may alter mechanical stress on cartilage because of changes in muscles, gait, etc.
    b.  Aging probably decreases chondrocytes’ ability to maintain and repair tissue, as they sustain “decreased responsiveness to anabolic growth factors, and synthesize smaller and less uniform large aggregating proteoglycans and fewer functional link proteins.”
    c.  Aging predisposes chondrocytes to apoptosis.
    d.  Deviant chondrocyte behavior in age-related cartilage destruction has recently been found to be associated with altered signaling via LK1.
  6. Genetic predisposition
    a.  The newly identified DVWA genetic link to OA, found in certain populations, has been further revealed as the human gene encoding for collage VI alpha4 chain.
  7. Inflammation and angiogenesis
    a.  Challenging the notion that osteoarthritis is primarily a disease of the cartilage, newer findings relating to inflammation and angiogenesis postulate that these factors modulate chondrocyte function and contribute to abnormal tissue growth and perfusion, ossification, and endochondral bone development.
  8. Diet
    a.  Increased fatty acid consumption may increase the risk of developing bone-marrow lesions.

OA ANATOMY & PATHOLOGY

What is the gross anatomic and cellular pathology of OA?
The morphology of OA initially shows that:

  • Chondrocytes proliferate with increased water and decreased proteoglycans.
  • Then, vertical and horizontal fibrillation and matrix cracks occur.
  • Next, full-thickness cartilage areas are lost.
  • Friction smooths exposed bone (bone eburnation).
  • Sclerosis and rebuttressing of underlying bone happens
  • Small fractures of subjacent bone lead to dislodged pieces (loose bodies).
  • Synovial fluid is forced through the fractures into subchondral bone.
  • The fluid forms subchondral cysts with fibrous walls.
  • Bone outgrowths grow at articular margins (osteophytes).
  • Synovium becomes congested and fibrotic, and may have inflammatory cells.

Further details include:

  1. Cartilage:
    a.  Normal articular cartilage contains water (75% by weight), collagen (predominantly type II; 20% by weight), aggrecan (5% by weight), and other extracellular matrix molecules, all maintained by chondrocytes.  As reviwed by Biswal, et al., collagen provides tensile strength, while aggrecan (glycosaminoglycan molecules) affords compressive strength.
    b.  In OA, articular cartilage loss occurs due to proteolytic enzymes that destroy proteoglycans and collagen.  Increased cartilage degradation occurs with insufficient repair.
    c.  OA cartilage shows the presence of hypertrophic chondrocyte phenotype, leading to type II collagen degradation, endochronal ossification, and chondrocyte apoptosis.
    d.  Normal cartilage extracellular matrix has two main constituents: a type II, collagen-rich network providing tensile strength; and aggrecan, a cartilage-specific proteoglycan that is highly hydrated and helps cartilage resist compressive loads.  In OA, the degeneration of extracellular matrix outpaces its creation, leading to exposure of cartilage and, subsequently, bone.
    e.  In early OA, cartilage degenerates and contains increased water and decreased proteoglycans.  The collagen network weakens, due to decreased synthesis of type II collage and increased preexisiting collagen breakdown.  Apoptosis decreases functional chondrocytes.
  2. Inflammation
    a.  Inflammatory mediators like IL-1beta and tumor necrosis factor induce chondrocytes to make proteases, chemokines, nitric oxide, prostaglandins, and leukotrienes, which drive catabolism, impair cartilage substance generation, and encourage cell death.  Oxygen and nitrogen-derived free radicals promote chondrocyte cell death, probably by mitochondrial dysfunction.
  3. Abnormal bone
    a.  Osteophytes are theorized to develop from penetration of blood vessels into degenerating cartilage basal layers, or from the abnormal healing of stress fractures at the joint margins with subchondral bone.
    b.  Subchondral bone sclerosis may arise from excessive loads leading to microfractures in the trabeculae that go on to heal with callus and remodeling.
    c.  The histopathology of bone-marrow lesions in OA is unclear, by microfractures, cysts, and avascular necrosis may give rise to findings appreciable by MRI.
  4. Synovial proliferation and inflammation
    a.  Synovial hypertrophy and hyperplasia have been noted by arthroscopic studies in up to 50% of OA patients.
    b.  Cartilage breakdown products from mechanically or enzymatically destroyed cartilage can provoke release of collagenase and other enzymes from synovial cells and macrophages, lead to mononuclear cell infiltration and vascular hyperplasia in synovium, and induce synovial IL-1beta and tumor necrosis factor that continue the cascade of degredation.
  5. Meniscal tears
    a.  Degenerative meniscal tears may signal the first symptom of OA.  When an isolated meniscal tear has undergone limited meniscectomy treatment, there is a high risk of tibiofemoral OA at 16-year follow-up.
    b.  Meniscal damage without surgery is also a high-risk factor for subsequent OA.

CONCLUSION

Osteoarthritis currently seems inevitable and unavoidable for a large swath of the population.  Its etiology relates to a strong, but complex, non-Mendelian genetic basis, combined with mechanical and metabolic factors that cause molecular alterations – the end results of which affect the whole joint.

The next issue of The WCC Note will continue this three-part series with a discussion of the MRI appearance of OA.  The third and final article will review available treatments, clinical trials, and research developments.

Research and reporting by Margaret D. Phillips, M.D.
Reviewer and publisher: Stephen J. Pomeranz, M.D.

For full sources and credit, please download the PDF copy of the newsletter here

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Rhematoid Arthritis: MRI’s Role in Diagnosis and Management (Part II) – Vol. 3, Number 5

Monday, March 30th, 2009

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.

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Rhematoid Arthritis: MRI’s Role in Diagnosis and Management – Vol. 3, Number 4

Monday, March 9th, 2009

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.

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