Joint Bone Spine 81 (2014) 110–111

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Editorial

Chronic Lyme disease: Fact or fiction?

a r t i c l e

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Keyword: Lyme disease

Lyme disease is a tick-borne bacterial infection that is very common in the Northern hemisphere. The causal agent is a spirochete belonging to the Borrelia family. In North America, Borrelia burgdorferi sensu stricto is the only species that is pathogenic for humans, whereas three pathogenic species have been identified in Europe, B. burgdorferi sensu stricto, B. afzelii, and B. garinii. Lyme disease can produce a vast spectrum of manifestations, involving the skin, joints, heart, and central and peripheral nervous systems. Primary Lyme disease is the early localized phase of the infection that manifests as erythema migrans, an erythematous skin lesion that enlarges centrifugally around the tick bite until it measures more than 5 cm in diameter. In some patients, the disease then progresses to the early disseminated phase characterized by joint symptoms, such as arthralgia or, less often, arthritis; lymphocytoma cutis; and neurological manifestations, such as meningoradiculitis. Finally, the late phase produces symptoms, such as acrodermatitis chronica atrophicans, chronic encephalomyelitis, and chronic arthritis. Antibiotic therapy is the cornerstone for the management of Lyme disease [1]. Antibiotics are effective in halting the progression of the infection and ensuring a full recovery. Nevertheless, a minority of patients report symptoms, such as fatigue, muscle and/or joint pain, impaired memory, or difficulties with concentration. These symptoms are often reported to persist after completion of the course of antibiotics and are sometimes designated by the term “chronic Lyme disease”. However, this term suggests the persistence of a chronic infection. Whether the symptoms are indeed ascribable to persistent infection or to another condition is open to discussion. In addition, the optimal means of diagnosing and managing chronic Lyme disease must be defined. The term “chronic Lyme disease” is widely used by physicians. In some cases, it designates the late phase of Lyme disease characterized, for instance, by chronic arthritis (< 10% in the USA, incidence unknown in France and other European countries). However, it is also often used to designate a wide variety of ill-defined clinical pictures for which there are no established criteria. Most of the cases described as chronic Lyme disease have been reviewed by Feder et al. [2], who described several highly heterogeneous populations of patients: • patients living in endemic areas and exhibiting non-specific symptoms consistent with Lyme disease (e.g., fatigue, myalgia,

arthralgia, or sleep disorders) but with negative standard serological tests for Borrelia antibodies, suggesting overdiagnosis; • patients with a history of documented Lyme disease (consistent clinical manifestation plus positive serological test) who subsequently develop non-specific symptoms (e.g., asthenia, cognitive disorders, or diffuse pain), suggesting post-Lyme syndrome. As Lyme disease is an infection, the term “chronic Lyme disease” suggests persistent infection. However, there is no evidence to date that Borrelia persists in patients believed to have “chronic Lyme disease”. A single study, by Philips et al. [3], recovered Borrelia from blood samples, using the MPM culture medium. Others have not been able to replicate this result. Another study found a high percentage of positive urine PCR tests among patients considered having “chronic Lyme disease”, but the test method used was not validated. There is no doubt that the laboratory tests available for everyday use have a number of limitations. Serological tests must be of excellent quality and cannot be distinguished between acute and remote infections or between active and inactive infections. The PCR test for Borrelia has less than ideal sensitivity, even when performed on tissues samples, such as the synovial membrane. Culturing Borrelia on a special medium (BSK) is difficult and cannot be performed in everyday practice. Thus, no ideal diagnostic tests are available for use in individual patients. In addition, a positive test (PCR or serology) neither indicates the date of the infection nor determines whether the infection is active or inactive. Thus, post-Lyme symptoms, such as arthralgia, myalgia, asthenia, sleep disorders, and concentration impairments are difficult to explain. Several hypotheses have been put forward, however: • persistent Borrelia infection is often suggested but not demonstrated, and very few documented cases have been reported [4,5]; • autoimmune mechanisms may be involved. For instance, certain immunogenic spirochete proteins share similarities with host tissue epitopes [6,7]. Higher anti-neurone antibody titers have been found in patients classified as having “post-Lyme disease” compared to healthy individuals. Although these results require confirmation, they may shed some light on the etiopathogenesis of this condition. Importantly, the antibody profile showed no changes after treatment with antibiotics, most notably ceftriaxone; • Borrelia infection may trigger immunological mechanisms related to the genetic background of the host. In one study, interferon-alpha levels were elevated in patients with postLyme disease compared not only to healthy individuals, but also to patients with a prior history of Lyme disease [8]. That

1297-319X/$ – see front matter © 2013 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. doi:10.1016/j.jbspin.2013.12.003

Editorial / Joint Bone Spine 81 (2014) 110–111

interferon-alpha elevation is associated with cognitive impairments has been established in both animal models and humans. One hypothesis is that persistently high interferon-alpha activity in patients with post-Lyme disease may be related to genetic susceptibility factors, as occurs in lupus with the IRF5 polymorphism. To date, no convincing data have been reported; • fatigue is a common symptom after infectious diseases, as described for instance, after brucellosis. In a study of patients with erythema migrans, the percentage of patients with persistent symptoms was 34% after 3 weeks, 24% after 3 months, and 17% after 1 year [9]. Post-infective fatigue syndrome may occur after Lyme disease. Among 250 patients with viral infections or Q fever, 35% reported fatigue after 6 weeks, 37% after 3 months, and 9% after 1 year [10], which are similar proportions to those seen after Lyme disease. The severity of the infection may predict the severity of the post-infective fatigue syndrome. The time to the response to antibiotic therapy is generally accepted to be longer in patients with late manifestations compared to those with early manifestations; • fibromyalgia or chronic fatigue syndrome may develop after Lyme disease. These conditions are relatively common in the general population. Among 3664 individuals older than 25 years of age, 44.4% reported musculoskeletal pain of more than 3 months’ duration in at least one joint (knee, neck, shoulder, or low back), 15.6% reported chronic pain in at least two or three joints, and 5.2% reported chronic diffuse pain [11,12]. Repeated treatment for “post-Lyme disease” has been evaluated in several studies [13–15]. However, repeated courses of antibiotics did not significantly modify the clinical manifestations. In this situation, priority should be given to symptomatic treatments. The term “chronic Lyme disease” is probably inappropriate, as it suggests a chronic infection similar, for instance, to chronic viral hepatitis. Studies done over the last decade have failed to obtain any proof of chronic infection in patients described as having chronic Lyme disease. The term “post-Lyme syndrome” is probably preferable, despite the absence of evidence on the underlying pathophysiological mechanisms. Nevertheless, the possibility that dysimmunity is involved, which deserve evaluation. In practice, it may be wise to inform patients, particularly, those at the early disseminated or late phase of Lyme disease, that they may experience persistent symptoms (e.g., asthenia, joint and muscle pain, and impaired concentration) for a few months after the infection, while downplaying their significance. Repeated serological testing is useless, and repeated courses of antibiotics must be avoided at all cost, given the absence of proof of efficacy. According to the consensus conference [1], re-treatment of patients with post-Lyme disease is indicated only when the proper conduct of the initial treatment is in doubt. In this situation, there may be a role for additional antibiotic therapy, possibly with a different antibiotic class than used initially.

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Disclosure of interest The author declares that she has no conflicts of interest concerning this article. References [1] Société francaise de pathologie infectieuse de langue franc¸aise.16e conférence de consensus en thérapeutique anti-infectieuse. Borréliose de Lyme : démarches diagnostiques thérapeutiques et préventives. 2006. [2] Feder Jr HM, Johnson BJ, O’Connell S, et al. A critical appraisal of “chronic Lyme disease”. N Engl J Med 2007;357:1422–30. [3] Philips SE, Mattman LH, Hulinska D, et al. A proposal for the reliable culture of Borrelia burgdorferi from patients with chronic Lyme disease, even from those previously aggressively treated. Infection 1998;26:364–7. [4] Limbach FX, Jaulhac B, Puechal X, et al. Treatment resistant Lyme arthritis caused by Borrelia garinii. Ann Rheum Dis 2001;60:284–6. [5] Frey M, Jaulhac B, Piemont Y, et al. Detection of Borrelia burgdorferi DNA in muscle of patients with chronic myalgia related to Lyme disease. Am J Med 1998;104:591–4. [6] Chandra A, Latov N, Wormser GP, et al. Epitope mapping of antibodies to VlsE protein of Borrelia burgdorferi in post-Lyme disease syndrome. Clin Immunol 2011;141:103–10. [7] Chandra A, Wormser GP, Klempner MS, et al. Anti-neural antibody reactivity in patients with a history of Lyme borreliosis and persistent symptoms. Brain Behav Immun 2010;24:1018–24. [8] Jacek E, Fallon BA, Chandra A, et al. Increased IFN␣ activity and differential antibody response in patients with a history of Lyme disease and persistent cognitive deficits. J Neuroimmunol 2013;255:85–91. [9] Wormser GP, Ramanathan R, Nowakowski J, et al. Duration of antibiotic therapy for early Lyme disease. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2003;138:697–704. [10] Hickie I, Davenport T, Wakefield D, et al. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. BMJ 2006;333:575. [11] Picavet HS, Schouten JS. Musculoskeletal pain in the Netherlands: prevalences, consequences and risk groups, the DMC(3)-study. Pain 2003;102:167–78. [12] Aggarwal VR, Mc Bethj J, Zakrzawska JM, et al. The epidemiology of chronic syndromes that are frequently unexplained: do they have common associated factors? Int J Epidemiol 2006;35:468–76. [13] Krupp LB, Hylan LG, Grimson R, et al. Study and treatment of post Lyme disease (STOP-LD): a randomized double masked clinical trial. Neurology 2003;60:1923–30. [14] Fallon BA, Keilp JG, Corbera KM, et al. A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy. Neurology 2008;70:992–1003. [15] Klempner MS, Hu LT, Evans J, Schmid CH, et al. Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. N Engl J Med 2001;345:85–92.

Christelle Sordet ∗ Service de rhumatologie, CHU Hautepierre, 1, avenue Molière, 67098 Strasbourg, France ∗ Tel.:

+33 3 88 12 81 16; fax: +33 3 88 12 82 53. E-mail address: [email protected] Accepted 19 November 2013 Available online24 February 2014

Chronic Lyme disease: fact or fiction?

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