Mar. 6, 2008 Researchers have learned more about how a leading drug prevents certain types of arthritis from eating away at bone, according to a study published in the March edition of the Annals of the Rheumatic Diseases. The findings may soon enable physicians to tell patients quickly whether or not they will respond to current therapies. In addition, the findings may help with the design of new drugs that prevent arthritis-related bone loss, but with fewer side effects.
Psoriatric arthritis (PsA), like rheumatoid arthritis, is an autoimmune disease, where the body mistakes its own tissues for an infection and attacks them. The attack comes in the form of inflammation, the unleashing of attack cells, chemicals and fluids meant to remove bacteria or viruses, but that also destroy human cells and tissues in too high amounts. Psoriatic arthritis affects about six percent of those suffering from the autoimmune skin condition psoriasis, and can severely damage joints and bones. One study found that, within two years of first diagnosis, almost half of PsA patients experience holes in their bones, visible on X-ray scans, that define erosive arthritis.
While traditional PsA treatments include NSAIDs or steroids to stop inflammation, the recent focus has been on newer drugs that interfere with tumor necrosis factor (TNF), an inflammatory chemical central to both normal immune function and autoimmune disease. Such drugs go beyond reducing inflammation to prevent bone damage, but how they do so has remained unclear. A better understanding is important because, although newer drugs suppress immune attack on joints, they also leave patients vulnerable to infection. The hope is that the next generation of treatments will not.
In the current study, researchers examined the molecular effects of etanercept (Enbrel), a genetically engineered drug produced by Amgen and approved by the U.S. Food and Drug Administration in 1998. Going into the study, researchers knew that Enbrel attaches to TNF and removes it from joints and the bloodstream, reducing inflammation, tenderness and pain. The current study suggests that anti-TNF therapy may work in another way as well.
Human bone must continually recycle itself to maintain its strength. Under the control of signaling molecules, two paired cell types make recycling possible in a careful balance. Osteoclasts "eat" or excavate aging bone to make way for new bone, while osteoblasts build new bone.
"In erosive psoriatic arthritis, mistaken immune signals tell osteoclasts to keep digging, as if they were trying to get at an infection buried inside the bone," said Edward M. Schwarz, Ph.D., professor of Orthopaedics within the Center for Musculoskeletal Research at the University of Rochester Medical Center, and an author of the study. "Our study confirms that we have two ways of measuring this process, and provides the first clues about how to prevent it."
As it does with many cell types, the body keeps pools of osteoclast precursors on hand, inactive until needed. In past studies, Schwarz and his team found an increased frequency of osteoclast precursor in the peripheral blood of patients with PsA. Past work has also shown that TNF plays a role in the formation of osteoclast precursors, and that TNF blockers decrease osteoclast precursor frequency.
In 2003, Schwarz and team guessed that osteoclast precursors must come from the bone marrow near affected joints. In the human embryo, one layer of stem cells develops into the common source of cells making up bone marrow, blood and immune cells. One particular stem cell line goes on to form macrophages, immune cells that dissolve any bacteria they encounter. A related stem line becomes osteoclasts, which dissolve any bone they encounter. Something in the bone marrow of PsA patients, an inflammatory signaling molecule perhaps, is directing cells, which would otherwise become macrophages, to turn instead into pockets osteoclast precursors, researchers said.
The current study confirmed their guess by capturing images of another factor closely tied with erosive arthritis: bone marrow edema. Decades ago, using relatively crude imaging technologies, researchers first recognized what looked like water deposits in the otherwise fatty bone marrow near affected joints. The pockets, mistaken for fluid, at that time were labeled edema, another word for swelling. The current study, with access to modern imaging technologies, has proven is that the watery bone marrow pockets seen in PsA patients are filled with, not water, but instead osteoclast precursors, which like most cells, are made mostly of water.
Researchers are excited by the possibility that watery pockets of macrophage-related osteoclast precursors might be taken out of commission by a precise treatment before they start damaging bone. The current work takes advantage of new image analysis technology, developed by Rochester, N.Y.-based VirtualScopics Inc., to show for the first time that the high level of osteoclast precursors seen in erosive arthritis originates in bone marrow lesions near affected joints. The team has started the search for a molecule or mechanism in bone marrow, which they believe must exist, that converts its normal fatty content into osteoclast precursor cell lesions at the behest of inflammatory signaling.
Twenty patients with erosive psoriatic arthritis were enrolled to receive etanercept twice weekly for 24 weeks. Biomarkers were measured and clinical assessments performed at baseline, 2, 12 and 24 weeks. Gadolinium-enhanced magnetic resonance images were obtained at baseline and 24 weeks to measure bone marrow edema. All patients were given subcutaneous injections of etanercept, 25 mg twice weekly for 6 months. This study was approved by the Institutional Review Board at the University of Rochester Medical Center, and informed consent was obtained from all patients.
The study found that patients saw improvement in the 68 joints analyzed, including less swelling and pain, according to standard measures of joint function. Secondly, patients treated with anti-TNF therapy saw a dramatic drop in the median level of osteoclastic precursor cells (OCP) in patients' blood, from 24.5 OCP per million white blood cells to 7 (p = 0.006) after 6 months of treatment. The rapid decline in OCPs after anti-TNF therapy provides one explanation for the anti-erosive effects of TNF blockade in PsA.
A second, related explanation may be seen in the bone marrow edema results, albeit with limitations. Past studies have suggested that bone marrow edema predicts regions where severe bone erosions are soon to develop. To address this hypothesis, Schwarz and colleagues designed a study to assess the impact of anti-TNF therapy on the edema using gadolinium enhanced MR images. The longitudinal images provided researchers with an "unparalleled view" of the psoriatic joint, and the ability to accurately measure the borders of edema lesions in the bone marrow surrounding each joint.
The study found that edema volume decreased in 47 joints, indicating that the inflamed bone marrow was returning to its normal fatty content following therapy. However, the analysis also revealed an increase in edema-like lesions in 31 joints at 6 months. The team believes that those signals were caused by as yet unidentified changes in the bone marrow not related to bone marrow edema and osteoclast precursors, but further studies will be needed to confirm that.
"A simple blood test can determine a person's osteoclast precursor levels," Schwarz said. "That should soon change medical practice as we can tell by OCP levels if a person has erosive disease. If those levels fail to drop immediately with anti-TNF therapy, that person is likely among the 30 percent of people who don't respond to etanercept. We can spare them the side effects and perhaps switch them to drugs like rituximab or abatacept, which are approved for rheumatoid arthritis patients that do not respond to anti-TNF therapy. While the blood test can tell you if you have PsA, it cannot tell which joints are affected. That feat has been achieved in this study for the first time with new MRI technology, which shows which joints have pre-erosive, osteoclast precursor lesions forming in the nearby bone marrow. These two tests, done in serial fashion, should allow for earlier diagnosis and more precise treatment of psoriatic erosive arthritis."
The work was also presented at the annual meeting of the Orthopaedic Research Society in San Francisco.
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