BOSTON, Mass—A new report highlights effective postantibiotic strategies for treating antibiotic-refractory Lyme arthritis and helps to identify risk factors for this rare, but vexing condition.

Lyme arthritis patients with proliferative synovitis following a 1-month course of oral antibiotics may benefit from 2 grams a day of intravenous ceftriaxone for an additional month, and if their polymerase chain reaction (PCR)  tests are still positive, retreatment with one course of oral antibiotics can be effective, write Allen C. Steere, MD, and Sherilyn M. Angelis, MD, of Massachusetts General Hospital, in Boston, in Arthritis & Rheumatism.¹

Patients with a negative PCR test, however, may benefit from nonsteroidal anti-inflammatory drugs (NSAIDs) or hydroxyquinolone. If the arthritis persists for longer than 1 year, arthroscopic synovectomy is an option.

"Although chronic Lyme arthritis may cause functional disability with erosion of cartilage and bone, it eventually resolves in all patients," they conclude.

They compared characteristics and treatments among 117 Lyme arthritis patients, including 67 with signs of antibiotic-resistant arthritis (defined as persistent joint swelling for 3 or more months after the start of at least 4 weeks of IV antibiotic therapy or at least 8 weeks of oral antibiotic therapy or both).

After antibiotic therapy, patients received nonsteroidal antinflammatory drugs (NSAIDs) or intraarticular steroids, and if the arthritis persisted for two years, they underwent arthroscopic synovectomy (strategy 1). Strategy 2 added disease modifying antirheumatic drugs (DMARDs), namely hydroxychloroquine, for patients with negative PCR tests and persistent arthritis. If synovitis persisted, researchers tried methotrexate (MTX) or infliximab, when it became available.

Most patients treated with either strategy received NSAIDs or one or two injections of intraarticular steroids. The overall rate of arthritis resolution was similar in both groups and the longest duration of arthritis was about 3.5 years. Specifically, all patients treated by strategy 1 showed resolution of their arthritis within 14 months after the start of antibiotic therapy, while arthritis persisted for about 9 months after the start of antibiotic therapy among those treated with by strategy 2.

When it comes to antibiotic use, longer is not necessarily better, the researchers point out. Several of the patients received oral antibiotics for 6 months to 1 year or IV antibiotics for 6 to 8 weeks, but the elongated treatment regimens had no bearing on joint swelling. In addition, the longer the course of the antibiotics, the greater the risk of adverse events, including IV line sepsis.

Risk Factors for Antibiotic-Refractory Lyme Arthritis

Risk factors for antibiotic-refractory arthritis include specific HLA-DRB1 alleles, greater immune reactivity with an epitope of Borrelia burgdorferi outer-surface protein A (OspA) and, potentially, treatment with intraarticular steroids prior to antibiotic therapy, according to the new report.

"Intraarticular corticosteroids given prior to antibiotics may be a risk factor for persistent Lyme arthritis and, in animal models, are associated with higher spirochetal burdens and longer persistence or spirochetal DNA," they write. "Thus intraarticular corticosteroids should not be given prior to antibiotic therapy and we now rarely use them in the postantibiotic period."

New Strategies Make Sense

"Antibiotic-refractory Lyme arthritis is a very uncommon feature overall in Lyme disease, since it occurs in about 10% of patients with Lyme arthritis and Lyme arthritis is no longer very common (relative to how common Lyme disease is) since it can be prevented by appropriate treatment of Lyme disease in its early stages," explained Arthur Weinstein, MD, a  professor of medicine at Georgetown University Medical Center in Washington, DC.

"Lyme arthritis, even with appropriate antibiotic therapy, often takes some months to resolve so I believe Dr. Steere's recommendation to wait for 1 to 2 months after the second course of antibiotics is appropriately conservative," he told CIAOMed.

"My approach in the past has had elements of both strategy 1 and 2 and is similar to his current recommendations," he said.  "If a patient does not respond to a 1-month course of oral doxycycline and persists with inflammatory synovitis, I give another 1-month course of therapy— generally intravenous ceftriaxone and not oral doxycycline," he said. "Most patients gradually improve after this, and even if there is some joint swelling, aspiration reveals only mildly or noninflammatory fluid."

"Patients who have persistent or recurrent inflammatory synovitis with negative PCR receive anti-inflammatory therapy (NSAIDs, intraarticular corticosteroids), and if it persists, they will receive a course of Plaquenil® or sulfasalazine," he said.

"I have not gone on to give stronger DMARD therapy at this juncture, but rather go to arthroscopic synovectomy," Dr. Weinstein said. "I have given MTX only in those few patients for whom synovectomy did not lead to a durable remission, [and] I have not seen significant joint damage (cartilage/bone erosion) in these patients, but have not routinely done magnetic resonance imaging (MRI)."

"Slow Resolution" Arthritis, a Better Descriptive Term?

"We don't see very much Lyme arthritis, and most people who get treated are cured, so emphasizing refractory Lyme arthritis is doing somewhat of a disservice," said Raymond Dattwyler, MD, professor of medicine and microbiology, chief of immunology, and chief of a new division of allergy, immunology and rheumatology at New York Medical College in Valhalla.

Dr. Dattwytler prefers the term 'slow-resolution arthritis' as most of these patients do get better. "Even in referral centers, the incidence of slow resolution is really uncommon," he said. In the new report, refractory could be as little as 4months after being on an antibiotic.  "I always tell patients to 'be patient' and if someone is resolving slowly, it's okay."

When it comes to treatment after antibiotics, "I think we need to weigh the risks and benefits of therapy," he said. "NSAIDS and intraarticular steroids are OK, but if we start to use MTX or RemicadeR, what do we gain if everyone is getting better anyway?"

Aggrecanase 1 Plays Causal Role in Lyme Arthritis

Related research sheds light on how infection with Borrelia burgdorferi results in Lyme arthritis. B burgdorferi infection induces aggrecanase 1 or ADAMTS-4 in human chondrocyte cell cultures, mice with arthritism and patients with Lyme arthritis, but Aggrecanase 2 or ADAMTS-5 does not, according to a report in Arthritis & Rheumatism. ²

In vitro and ex vivo studies show that ADAMTS-4 is processed and found in its most active form within the joint. The researchers suspect that ADAMTS-4 cleaves aggrecan and exposes the joints' collagen matrix, allowing it to be processed by matrix metalloproteinases (MMPs) and resulting in cartilage degradation and destruction. Aggrecanases, not MMPs, seem to mediate the cleavage of aggrecan, according to bovine cartilage explants of this disease.

The "use of selective aggrecanase inhibitors may impart cartilage protection by preventing aggrecan degradation without some of the negative responses associated with more broad-spectrum MMP inhibitors," the study authors conclude.

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