Rheumatol Int DOI 10.1007/s00296-013-2923-9
Original Article
Intraarticular corticosteroids in refractory childhood Lyme arthritis S. Nimmrich · I. Becker · G. Horneff
Received: 11 August 2013 / Accepted: 14 December 2013 © Springer-Verlag Berlin Heidelberg 2014
Abstract Lyme arthritis caused by infection with Borrelia burgdorferi is a common late manifestation of Lyme borreliosis. Current treatment recommendations include at least one oral or intravenous antibiotic course, followed by antirheumatic therapy in case of refractory arthritis. We reviewed the course of 31 children with Lyme arthritis who had received antibiotic treatment and assessed outcome and requirement of antirheumatic therapy. Of a total of 31 patients, 23 (74 %) showed complete resolution of arthritis after one or two courses of antibiotics, whereas in 8 patients (28 %), steroid injections had been performed due to relapsing or remaining symptoms. All of these 8 patients showed immediate resolution of symptoms after intraarticular steroid injections. Four of them (50 %) remained asymptomatic so far with a follow-up period between five up to 40 months. In two cases, multiple intraarticular corticosteroid injections were required; three patients received additional or consecutive treatment with systemic antirheumatic treatment. Patients with antibiotic refractory arthritis showed a higher rate of positivity of the IgG p58 and OspC immunoblot bands (p = 0.05) at presentation. Antibodies against OspA, an indicator of later stage infection, occurred more frequently in the refractory group without reaching significant level. No clinical marker as indicator for severe or prolonged course of Lyme arthritis was identifiable. A quarter of childhood Lyme arthritis patients were refractory S. Nimmrich (*) · G. Horneff Centre of Paediatric Rheumatology, Department of General Paediatrics, Asklepios Clinic Sankt Augustin, Sankt Augustin, Germany e-mail: [email protected] I. Becker Institute of Medical Statistics, Informatics and Epidemiology, University of Cologne, Cologne, Germany
to antibiotics and required antirheumatic treatment. Intraarticular steroid injections in childhood Lyme arthritis refractory to antibiotics can lead to marked clinical improvement. Keywords Lyme arthritis · Borreliosis · Intraarticular corticosteroids
Introduction Lyme borreliosis [1], named after a town in New England in the United States, is caused by different genotypes of Borrelia burgdorferi. In Europe, 12 types of Borrelia burgdorferi sensu lato (Bbsl) are described of which 4 are pathogenic for humans: Borrelia burgdorferi sensu stricto, B. garinii, B. afzelii, B. spielmanii. In contrast to Europe, in America, B. burgdorferi sensu stricto is the only existing species [2]. This issue leads to the fact that clinical studies from North America are not automatically applicable to conditions in Europe. The spirochetes are transmitted by the tick Ixodes ricinus. In Germany, approximately 5–35 % are infected depending on the geographic region and the stage of development of the tick [1]. The range of seroconversion after a tick bite varies between 3 and 6 % [1]. Lyme arthritis is a late manifestation occurring several months after infection. Most individuals infected with Borrelia burgdorferi show no clinical signs. The most frequent early manifestation is erythema migrans. Treatment of early manifestations prevents progression to late manifestations. Arthritis is typically characterized by a relapsing–remitting or chronic course, and the knee joint is involved in 85 %, by far the most frequently affected joint [3], followed by ankle, elbow and hip joints. Generally, long-term outcome in children with Lyme arthritis and adequate treatment is excellent. Bentas et al.
13
[4] showed an excellent outcome with only 10 days of treatment. In contrast, predominantly in children, more serious manifestations of infection were described [5]. The majority of patients show an antibiotic responding course of Lyme arthritis. Beside, these chronic antibiotic refractory manifestations are frequent [6]. Generally, a higher frequency of episodic arthritis is described for Lyme arthritis compared to other forms of arthritis [7]. Persistent synovitis beyond 6 months from initiation of treatment was shown in up to 39 % of children with Lyme arthritis and 13 % even remain with synovitis 12 months after treatment [8]. Equally it was shown that prolonged antibiotic treatment with intravenous ceftriaxone for 30 days followed by an additional 60 days of oral antibiotic therapy is not justified as demonstrated in a controlled trial [9, 10]. Mild residual joint swelling after first antibiotic course also resolved without further therapy compared to additional course with oral antibiotic for another 30 days [3]. Rates of antibiotic therapy failure in later stages of disease are substantially higher than in early stages [11–13]. Even repeated therapy cycles showed considerably high rates of failure even in high dosage therapy [9, 14]. International consensus guidelines for treatment of Lyme borreliosis do not exist. Current treatment recommendations of the Infectious Diseases Society of America for children are amoxicillin, cefuroxime axetil, or from the age of 8 years doxycycline in case of early localized or early Lyme disease associated with erythema migrans, in the absence of neurologic manifestations or advanced atrioventricular heart block [15]. Macrolide antibiotics are not recommended as first-line therapy for early stages. The guidelines for Lyme arthritis recommend the use of amoxicillin, cefuroxime axetil or doxycycline. For patients who have persistent or recurrent joint swelling after a course of oral antibiotic therapy, another 4-week course of oral antibiotics or with a 2–4-week course of ceftriaxone intravenously is recommended. Consecutive symptomatic therapy might consist of non-steroidal anti-inflammatory agents, intra-articular injections of corticosteroids or disease-modifying antirheumatic drugs (DMARDs), such as hydroxychloroquine [15]. The German Society for Paediatric Infectiology (Deutsche Gesellschaft für Pädiatrische Infektiologie, DGPI) [16] recommends a third-generation cephalosporine for treatment of Lyme arthritis. In case of treatment failure, antirheumatic medication should be started at earliest 3 months after first antibiotic course due to expected further improvement of symptoms. Whereas in the past benefit and risks of long-term antibiotic treatment as adequate treatment of chronic forms of Lyme arthritis were debated controversially, a prolonged antibiotic therapy is no part of current treatment
13
Rheumatol Int
recommendation. The longer the course of antibiotic therapy, the greater the risk of adverse events with described serious complications including sepsis [17] and in case of long-term antibiotic treatment Clostridium difficile colitis [18]. No benefit or benefit so moderate that any potential benefit is compensated by the risks associated with the treatment was observed [9, 14]. Treatment with intraarticular glucocorticoid injections is recommended for antibiotic refractory Lyme arthritis (ARLA). As far as corticosteroid injections in context of Lyme arthritis are concerned, current data are deficient. Only few studies relate to post-antibiotic steroid injections [4, 6, 19, 20]. Therefore, our pilot study investigates the improvement and outcome in patients who received intraarticular steroid injections into the affected joint in case of failing sustained remission.
Methods Patients We reviewed clinical and serological data of patients diagnosed with Lyme arthritis and treated with antibiotics at the Asklepios children’s clinic Sankt Augustin in Germany between January 2009 and September 2012. The following criteria were used for defining Lyme arthritis: arthritis defined by clinically detected joint swelling and/or joint effusion as well as serological confirmation by ELISA and positive immunoblot for IgG antibodies against Borrelia burgdorferi. The ELISA test for determination of IgM and IgG against Borrelia burgdorferi was used as a sensitive screening test, in case of a positive result immunoblots followed to confirm the finding more specifically. All laboratory diagnostics were assessed in the same laboratory. A positive result for Borrelia serology as inclusion criteria consisted of a positive IgG result with a positive IgG immunoblot. The following bands were assessed: P100, VlsE, P58, P39, OspA, OspC and P18. The number of positive bands required for a positive result depends on the specificity of the individual blot. The total number of positive blots as well as differences in regard to single blots was content of our analysis. In case of joint puncture, the presence of Borrelia DNA was determined by PCR in synovial fluid. Before the diagnosis of Lyme arthritis was concluded, several other differential diagnoses were assessed including reactive arthritis, septic or other infectious arthritis. Laboratory work-up included CRP, ANA, HLAB27, rheumatoid factor, antistreptolysin, anti-DNAse B, antibodies against Yersinia, Shigella, Salmonella, Mykoplasma, Chlamydia or viruses (Hepatitis B and C virus, Parvovirus B19).
Rheumatol Int
To document the clinical presentation, we recorded data of the duration of signs and symptoms before presentation, the total number and type of affected joints, the presence of exudation at joint ultrasound (or clinical examination) and the pattern of joint involvement (symmetric vs. non-symmetric). We recorded the clinical outcome of patients with intraarticular steroid injection by subjective reports, physical examination and sonographic assessment of the joint in follow-up outpatient visits. Additionally, we compared the outcome and diagnostic or clinical parameters to clinical outcome of Lyme arthritis. Statistical methods Statistical analysis was performed by using SPSS Version 17.0. To assess differences between groups, we used descriptive statistics, chi-squared tests and t test for independent samples in cases of normal distribution or Mann– Whitney U tests was used. Statistical significance was set at p
Original Article
Intraarticular corticosteroids in refractory childhood Lyme arthritis S. Nimmrich · I. Becker · G. Horneff
Received: 11 August 2013 / Accepted: 14 December 2013 © Springer-Verlag Berlin Heidelberg 2014
Abstract Lyme arthritis caused by infection with Borrelia burgdorferi is a common late manifestation of Lyme borreliosis. Current treatment recommendations include at least one oral or intravenous antibiotic course, followed by antirheumatic therapy in case of refractory arthritis. We reviewed the course of 31 children with Lyme arthritis who had received antibiotic treatment and assessed outcome and requirement of antirheumatic therapy. Of a total of 31 patients, 23 (74 %) showed complete resolution of arthritis after one or two courses of antibiotics, whereas in 8 patients (28 %), steroid injections had been performed due to relapsing or remaining symptoms. All of these 8 patients showed immediate resolution of symptoms after intraarticular steroid injections. Four of them (50 %) remained asymptomatic so far with a follow-up period between five up to 40 months. In two cases, multiple intraarticular corticosteroid injections were required; three patients received additional or consecutive treatment with systemic antirheumatic treatment. Patients with antibiotic refractory arthritis showed a higher rate of positivity of the IgG p58 and OspC immunoblot bands (p = 0.05) at presentation. Antibodies against OspA, an indicator of later stage infection, occurred more frequently in the refractory group without reaching significant level. No clinical marker as indicator for severe or prolonged course of Lyme arthritis was identifiable. A quarter of childhood Lyme arthritis patients were refractory S. Nimmrich (*) · G. Horneff Centre of Paediatric Rheumatology, Department of General Paediatrics, Asklepios Clinic Sankt Augustin, Sankt Augustin, Germany e-mail: [email protected] I. Becker Institute of Medical Statistics, Informatics and Epidemiology, University of Cologne, Cologne, Germany
to antibiotics and required antirheumatic treatment. Intraarticular steroid injections in childhood Lyme arthritis refractory to antibiotics can lead to marked clinical improvement. Keywords Lyme arthritis · Borreliosis · Intraarticular corticosteroids
Introduction Lyme borreliosis [1], named after a town in New England in the United States, is caused by different genotypes of Borrelia burgdorferi. In Europe, 12 types of Borrelia burgdorferi sensu lato (Bbsl) are described of which 4 are pathogenic for humans: Borrelia burgdorferi sensu stricto, B. garinii, B. afzelii, B. spielmanii. In contrast to Europe, in America, B. burgdorferi sensu stricto is the only existing species [2]. This issue leads to the fact that clinical studies from North America are not automatically applicable to conditions in Europe. The spirochetes are transmitted by the tick Ixodes ricinus. In Germany, approximately 5–35 % are infected depending on the geographic region and the stage of development of the tick [1]. The range of seroconversion after a tick bite varies between 3 and 6 % [1]. Lyme arthritis is a late manifestation occurring several months after infection. Most individuals infected with Borrelia burgdorferi show no clinical signs. The most frequent early manifestation is erythema migrans. Treatment of early manifestations prevents progression to late manifestations. Arthritis is typically characterized by a relapsing–remitting or chronic course, and the knee joint is involved in 85 %, by far the most frequently affected joint [3], followed by ankle, elbow and hip joints. Generally, long-term outcome in children with Lyme arthritis and adequate treatment is excellent. Bentas et al.
13
[4] showed an excellent outcome with only 10 days of treatment. In contrast, predominantly in children, more serious manifestations of infection were described [5]. The majority of patients show an antibiotic responding course of Lyme arthritis. Beside, these chronic antibiotic refractory manifestations are frequent [6]. Generally, a higher frequency of episodic arthritis is described for Lyme arthritis compared to other forms of arthritis [7]. Persistent synovitis beyond 6 months from initiation of treatment was shown in up to 39 % of children with Lyme arthritis and 13 % even remain with synovitis 12 months after treatment [8]. Equally it was shown that prolonged antibiotic treatment with intravenous ceftriaxone for 30 days followed by an additional 60 days of oral antibiotic therapy is not justified as demonstrated in a controlled trial [9, 10]. Mild residual joint swelling after first antibiotic course also resolved without further therapy compared to additional course with oral antibiotic for another 30 days [3]. Rates of antibiotic therapy failure in later stages of disease are substantially higher than in early stages [11–13]. Even repeated therapy cycles showed considerably high rates of failure even in high dosage therapy [9, 14]. International consensus guidelines for treatment of Lyme borreliosis do not exist. Current treatment recommendations of the Infectious Diseases Society of America for children are amoxicillin, cefuroxime axetil, or from the age of 8 years doxycycline in case of early localized or early Lyme disease associated with erythema migrans, in the absence of neurologic manifestations or advanced atrioventricular heart block [15]. Macrolide antibiotics are not recommended as first-line therapy for early stages. The guidelines for Lyme arthritis recommend the use of amoxicillin, cefuroxime axetil or doxycycline. For patients who have persistent or recurrent joint swelling after a course of oral antibiotic therapy, another 4-week course of oral antibiotics or with a 2–4-week course of ceftriaxone intravenously is recommended. Consecutive symptomatic therapy might consist of non-steroidal anti-inflammatory agents, intra-articular injections of corticosteroids or disease-modifying antirheumatic drugs (DMARDs), such as hydroxychloroquine [15]. The German Society for Paediatric Infectiology (Deutsche Gesellschaft für Pädiatrische Infektiologie, DGPI) [16] recommends a third-generation cephalosporine for treatment of Lyme arthritis. In case of treatment failure, antirheumatic medication should be started at earliest 3 months after first antibiotic course due to expected further improvement of symptoms. Whereas in the past benefit and risks of long-term antibiotic treatment as adequate treatment of chronic forms of Lyme arthritis were debated controversially, a prolonged antibiotic therapy is no part of current treatment
13
Rheumatol Int
recommendation. The longer the course of antibiotic therapy, the greater the risk of adverse events with described serious complications including sepsis [17] and in case of long-term antibiotic treatment Clostridium difficile colitis [18]. No benefit or benefit so moderate that any potential benefit is compensated by the risks associated with the treatment was observed [9, 14]. Treatment with intraarticular glucocorticoid injections is recommended for antibiotic refractory Lyme arthritis (ARLA). As far as corticosteroid injections in context of Lyme arthritis are concerned, current data are deficient. Only few studies relate to post-antibiotic steroid injections [4, 6, 19, 20]. Therefore, our pilot study investigates the improvement and outcome in patients who received intraarticular steroid injections into the affected joint in case of failing sustained remission.
Methods Patients We reviewed clinical and serological data of patients diagnosed with Lyme arthritis and treated with antibiotics at the Asklepios children’s clinic Sankt Augustin in Germany between January 2009 and September 2012. The following criteria were used for defining Lyme arthritis: arthritis defined by clinically detected joint swelling and/or joint effusion as well as serological confirmation by ELISA and positive immunoblot for IgG antibodies against Borrelia burgdorferi. The ELISA test for determination of IgM and IgG against Borrelia burgdorferi was used as a sensitive screening test, in case of a positive result immunoblots followed to confirm the finding more specifically. All laboratory diagnostics were assessed in the same laboratory. A positive result for Borrelia serology as inclusion criteria consisted of a positive IgG result with a positive IgG immunoblot. The following bands were assessed: P100, VlsE, P58, P39, OspA, OspC and P18. The number of positive bands required for a positive result depends on the specificity of the individual blot. The total number of positive blots as well as differences in regard to single blots was content of our analysis. In case of joint puncture, the presence of Borrelia DNA was determined by PCR in synovial fluid. Before the diagnosis of Lyme arthritis was concluded, several other differential diagnoses were assessed including reactive arthritis, septic or other infectious arthritis. Laboratory work-up included CRP, ANA, HLAB27, rheumatoid factor, antistreptolysin, anti-DNAse B, antibodies against Yersinia, Shigella, Salmonella, Mykoplasma, Chlamydia or viruses (Hepatitis B and C virus, Parvovirus B19).
Rheumatol Int
To document the clinical presentation, we recorded data of the duration of signs and symptoms before presentation, the total number and type of affected joints, the presence of exudation at joint ultrasound (or clinical examination) and the pattern of joint involvement (symmetric vs. non-symmetric). We recorded the clinical outcome of patients with intraarticular steroid injection by subjective reports, physical examination and sonographic assessment of the joint in follow-up outpatient visits. Additionally, we compared the outcome and diagnostic or clinical parameters to clinical outcome of Lyme arthritis. Statistical methods Statistical analysis was performed by using SPSS Version 17.0. To assess differences between groups, we used descriptive statistics, chi-squared tests and t test for independent samples in cases of normal distribution or Mann– Whitney U tests was used. Statistical significance was set at p
