Editorial Commentary: What Constitutes Appropriate Treatment of Post-Lyme Disease Symptoms and Other Pain and Fatigue Syndromes?

Lyme disease, which is caused by the tickborne spirochete Borrelia burgdorferi, is estimated to cause over 300 000 cases annually in the United States, primarily in northeastern and mid-Atlantic States [1]. In untreated patients, the infection typically occurs in stages with different manifestations at each stage [2]. It usually begins during summer with an expanding skin lesion, erythema migrans, sometimes followed weeks later by neurologic or cardiac abnormalities, and often followed months later by arthritis, or rarely a subtle encephalopathy or polyneuropathy. With late stage abnormalities, patients often have few, if any, systemic symptoms. Most patients respond well to appropriate antibiotic regimens for the stage of disease, as recommended by the Infectious Diseases Society of America (IDSA) [3]. However, despite antibiotic therapy, some patients experience post-infectious signs or symptoms, which can be quite disabling. The only post-infectious picture with a well-defined pathologic correlate (proliferative synovitis) is antibiotic-refractory Lyme arthritis [4]. In such patients, inflammatory arthritis persists for months or several years after apparent spirochetal killing with oral and intravenous (IV) antibiotics. Excessive inflammation, immune dysregulation, and infectioninduced autoimmunity are thought to play a role in this disease outcome [5]. After antibiotic therapy, treatment with disease modifying antirheumatic drugs, such as methotrexate or synovectomy, is often beneficial [4]. However, the term post-Lyme disease symptoms or syndrome usually refers to subjective pain, neurocognitive, or fatigue symptoms that persist after antibiotic therapy. At one end of the spectrum, one or a few subjective symptoms such as malaise and fatigue or minor joint symptoms may persist for several months after antibiotic treatment of erythema migrans [6]. In a recent study, a subgroup of such patients had persistently high levels of interleukin 23, suggesting that hyperactive Th17 immune responses may have a role in their delayed recovery from the disease [7]. At the other end of the spectrum, and often after a gap of several months after treatment of the infection, patients may develop chronic, disabling joint and muscle pain, neurocognitive difficulties, and incapacitating fatigue that persist for years after antibiotic treatment for Lyme disease [8]. This chronic pain and fatigue syndrome may have different pathogenic mechanisms than those involved when symptoms resolve rather soon after antibiotic therapy. This chronic syndrome, which sometimes meets criteria for fibromyalgia or chronic fatigue syndrome, is not specific for Lyme disease [8]. Such symptoms may follow other infections or physical or emotional trauma, or the inciting cause may not be apparent. Moreover, using the serologic criteria of the Centers for Disease Control and Prevention [9],most patients with the diagnosis of “chronic Lyme disease” have little or no evidence of past or present B. burgdorferi infection [8]. Thus, in general usage, the term “chronic Lyme disease” has come to have a different and broader meaning than evidencebased descriptions of B. burgdorferi infection, and only a minority of patients with this diagnosis has evidence of preceding B. burgdorferi infection. Received 23 February 2014; accepted 25 February 2015; electronically published 6 April 2015. Correspondence: Allen C. Steere, MD, Massachusetts General Hospital, CNY 149/8301, 55 Fruit St, Boston, MA 02114 (asteere@mgh.harvard.edu). Clinical Infectious Diseases 2015;60(12):1783–5 © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com. DOI: 10.1093/cid/civ187