For reprint orders, please contact: REVIEW [email protected] Future management of septic arthritis Catherine J Mathews, Septic arthritis is a disease with a high morbidity and mortality. Antimicrobial therapy is not Vivienne C Weston, always sufficient to prevent joint damage and overwhelming sepsis. This review examines Gabrielle H Kingsley & the progress that has been made in understanding the molecular mechanisms underlying Gerald Coakley† joint sepsis. The results of this work suggest the basis for potential targets for adjunctive †Author for correspondence immunotherapy. Changing patterns in microbial etiology and sensitivities are also reviewed, Queen Elizabeth Hospital, and predictions made surrounding emerging causative organisms. Department of Rheumatology, Woolwich, London, SE18 4QH, UK Tel.: +44 208 836 5025; The presentation of a patient with one or more Pathogenic mechanisms in septic Fax: +44 208 836 4958; hot swollen joint(s) is a common medical emer- arthritis: mouse models [email protected] gency, which presents to a wide range of medical Bacterial septic arthritis continues to cause sig- practitioners. It has a broad differential diagno- nificant morbidity and mortality despite timely sis, the most serious of which is bacterial septic and appropriate antibiotic therapy. This implies arthritis. This is defined as inoculation of the that antimicrobial therapy alone is not always joint with pathogenic microorganisms, either sufficient as a management approach. Efforts to directly or, more commonly, by hematogenous develop improved therapeutic strategies rely spread. If left untreated, septic arthritis can cause principally on the use of animal models to eluci- rapid and irreversible joint destruction and sub- date the pathogenic mechanisms that underlie sequent disability [1]. In addition, the diagnosis disease progression [4]. There are inherent diffi- carries a mortality of up to 11% [2]. culties in translating results from animal findings Septic arthritis poses many clinical challenges. into human disease, as animal and human First, definitive diagnosis currently depends on immune mechanisms are not precisely compara- the level of clinical suspicion of an experienced ble. However, research on this subject in patients physician [3]. Although necessary to make an is made difficult by the ambiguity surrounding informed evaluation, neither laboratory investi- the timing of an immunological response follow- gations nor radiological imaging are sufficient to ing a septic insult, as well as ethical issues sur- clinch the diagnosis beyond reasonable doubt. In rounding host or bacterial manipulation. addition, the sensitivities of causative micro- The use of experimental mouse models has organisms vary hugely, depending on demo- several advantages in this area of study. First, the graphic and clinical risk factors, creating immune system in mice is well characterized and difficulty when choosing appropriate antimicro- bears many similarities to its human counter- bial therapy. The most common causative organ- part. Mouse strains are available in which gene ism, Staphylococcus aureus, may be antibiotic expression can be either attenuated or exagger- resistant in certain situations. In addition, anti- ated to evaluate the contribution made by spe- biotic therapy alone is not always sufficient to cific components of the immune system to control the progression of joint damage and, in disease pathogenesis. In addition, novel pharma- some cases, overwhelming sepsis. ceutical and genetic therapies can be evaluated In recent years, there have been significant on the basis of the information derived from the developments in the understanding of the patho- results of these studies. Two mouse models have genic mechanisms underlying septic arthritis. been extensively developed and studied. Keywords: animal models, These studies have been performed exclusively in bacteria, immunotherapy, animal models, but the results have suggested Experimental Staphylococcus novel therapies, septic aureus-mediated septic arthritis arthritis, staphylococcal directions in which human research could arthritis, streptococcal evolve. In this review, advances in the under- Tarkowski and colleagues developed an experi- arthritis standing of pathogenic mechanisms and man- mental mouse model of septic arthritis mediated agement of septic arthritis will be discussed, as by S. aureus [4]. S. aureus is the most common part of well as changing trends in the microbiological pathogen in human septic arthritis, accounting etiology of bacterial joint disease. for over 80% of cases [2]. In humans, it is 10.2217/17460816.3.1.43 © 2008 Future Medicine Ltd ISSN 1746-0816 Future Rheumatol. (2008) 3(1), 43–50 43 REVIEW – Mathews, Weston, Kingsley & Coakley associated with a mortality of up to 11%, as well inter-dependent events, it is possible to visual- as severe morbidity due to joint destruction. This ize how targeting one or more of the steps in murine model parallels human disease pathogen- the pathogenic process could generate novel esis closely in that the pathogen is introduced prophylactic or therapeutic strategies. hematogenously by intravenous injection. More This model has been extensively studied to than 90% of the mice develop septic arthritis identify factors that can be manipulated to within 24 h of inoculation, and their joints show change the progression of disease. In broad terms a severe degree of bone erosion, similar to the these factors can be divided into two categories: changes seen in the human septic joint. • Factors that determine bacterial virulence The pathogenesis of staphylococcal septic arthritis is highly simplified and depicted • Factors that determine the host response to a schematically in Figure 1. Seen as a series of bacterial insult Figure 1. Simplified schematic representation of the pathogenesis of staphylococcal septic arthritis, showing potential therapeutic targets. Complement B cell Staphylococcus aureus Macrophage Toxins and enzymes Bacterial cell wall proteins T cell Adhesins IL-1 IL-10 IL-1 IL-4 IL-10 IL-10 TNFα IL-12 Joint 44 Future Rheumatol. (2008) 3(1) futurefuture sciencescience groupgroup Future management of septic arthritis – REVIEW Bacterial virulence factors Host response factors One way in which individual components of the One of the most elegant ways of assessing the bacterial armamentarium can be isolated and host response to staphylococcal infection is to studied is through their genetic deletion. use genetically modified knockout mice. This S. aureus produces a large number of interacting method has shed light on the roles of multiple virulence factors, which include an array of components of the immune response. extracellular toxins, enzymes and other cell-asso- The genetic deletion of macrophage-derived ciated components [4]. The genetic coding for cytokines, including lymphotoxin-α, TNF-α these molecules, and their interactions, is also and the IL-1 receptor, have been shown to complex, and in most instances a number of reduce host protection in S. aureus sepsis, caus- genes are involved at each step. However, selec- ing increased morbidity and mortality [11,12]. tive silencing of factors through genetic deletion Similarly, the absence of the anti-inflammatory or mutation has been performed in the S. aureus cytokine IL-10 in IL-10 knockout mice appears model. For example, a strain mutant for two to increase the frequency and severity of staphy- gene regulators at the agr/hld locus, in which lococcal joint disease secondary to reduced clear- much lower levels of several extracellular toxins ance of pathogens [13]. By contrast, the IL-4 and enzymes are produced, is a much less viru- knockout mouse is associated with reduced inci- lent bacterial strain, with reduced erosive dence and mortality. It is suggested by the arthropathy in mouse recipients [5]. authors that this may reflect the role of IL-4 in The virulence of bacterial molecules can also enhancing bacterial growth and/or decreasing be studied by immunizing animals with puri- bacterial clearance from the joint space [14]. fied concentrates of bacterial components. Pas- IL-12 also appears to be critical for the survival sive immunization involves the transfer of of mice with S. aureus-induced arthritis [15]. antibodies directed against particular bacterial The protective role of neutrophils early on in components into the host. Active immuniza- the progression of S. aureus infection has been tion is achieved by challenging the host with shown by inoculating mice with granulocyte- antigen and the subsequent development by the depleting monoclonal antibody before being host of specific antibodies. Using these subjected to S. aureus. All depleted mice died of approaches, the initiation of S. aureus arthritis sepsis within 2–3 days whereas the control mice through adhesion of the bacteria to tissues survived [16]. within the joint has been studied. Specific By contrast, mice administered granulocyte- adhesins that facilitate S. aureus infection have macrophage colony-stimulating factor before been well characterized [6]. Inactivation of and after inoculation with S. aureus follow a adhesins through vaccination with recombinant similar clinical course to control animals. Thus, collagen adhesin confers a protective effect on despite the role that macrophages play in host mice subsequently challenged with intravenous protection, the upregulation of these cells does S. aureus [7]. Mice immunized with a recombi- not appear to confer