Comment
will affect future burdens of bacterial infections and resistance. Once all this work and a wealth of further high-quality research has been done, there is still the task of assessing the new knowledge that has emerged and the translation of that knowledge into implementation strategies that will be appropriate, feasible, and socially and politically acceptable in high-income, middle-income, and lowincome countries. The world has to be in it for the long haul. Good luck, one and all. We’ll need it. Michael G Head Research Department of Infection and Population Health, Farr Institute, University College London, London NW1 2DA, UK [email protected]
I declare no competing interests. 1
2 3
4
5
6
Braggington EC, Piddock LJV. UK and European Union public and charitable funding from 2008 to 2013 for bacteriology and antibiotic research in the UK: an observational study. Lancet Infect Dis 2014; published online July 25. http://dx.doi.org/10.1016/S1473-3099(14)70825-4. Head MG, Fitchett JR, Atun R. Investing in antimicrobial resistance research. Br J Hosp Med 2014; 75: 6–7. Head MG, Fitchett JR, Cooke MK, et al. Systematic analysis of funding awarded for antimicrobial resistance research to institutions in the UK, 1997–2010. J Antimicrob Chemother 2014; 69: 548–54. Davies SC, Fowler T, Watson J, Livermore DM, Walker D. Annual Report of the Chief Medical Officer: infection and the rise of antimicrobial resistance. Lancet 2013; 381: 1606–09. WHO. Antimicrobial resistance: global report on surveillance 2014. Geneva: World Health Organization, 2014. http://www.who.int/drugresistance/ documents/surveillancereport/en/ (accessed June 19, 2014). Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States, 2013. http://www.cdc.gov/drugresistance/threatreport-2013/ (accessed June 19, 2014).
Chikungunya virus and arthritic disease
www.thelancet.com/infection Vol 14 September 2014
cases had been reported by the Pan American Health Organization.2,3 Spread and establishment of the virus in new endemic regions will be dependent on availability of competent vectors and a source of the virus. Although establishment of the virus will require travellers with above-threshold viraemias and an overlap of seasons between the northern and southern hemispheres for vector activity, the potential exists for spread of this virus to both Europe and other regions of America. Bone-related disorders, such as osteoporosis, rheumatoid arthritis, or osteoarthritis, affect millions of people worldwide. Osteoporosis is a systemic disease characterised by declining bone density that results in bone fractures, whereas autoimmune rheumatoid arthritis and degenerative osteoarthritis lead to chronic joint arthralgia and bone destruction. Bone homeostasis is maintained by the coordinated action of bone-forming osteoblasts and boneresorbing osteoclasts. Osteoclastogenesis is regulated by osteoblastic and non-osteoblastic cells such as T cells through receptor activator of nuclear factor κB ligand (RANKL) and osteoprotegerin, a soluble decoy receptor for RANKL. Changes in the ratio of RANKL to osteoprotegerin have been implicated in bone diseases including rheumatoid arthritis and osteoporosis.4 Weiqiang Chen5 and colleagues reported that RANKL expression by primary human
Sinclair Stammers/Science Photo Library
Chikungunya virus is a mosquito-borne alphavirus that has recently emerged in several explosive epidemics, causing febrile illness that can progress to painful and debilitating rheumatic disease. The virus continues to spread globally. Based on recent developments, we propose a potential link between chikungunya infection and other bone and joint diseases. Chikungunya virus, transmitted by Aedes spp mosquitoes, is widely distributed in tropical and subtropical regions of Africa, the Indian Ocean islands, and southeast Asia. Three distinct genotypes of the virus exist, with phenotypic differences that have facilitated adaptation of the virus to Aedes albopictus, a species with wider geographical distribution than Aedes aegypti. In 2004, the virus emerged in the coastal towns of Kenya resulting in an outbreak that spread rapidly through the Indian Ocean islands and India. Subsequently, seasonal outbreaks have been recorded in various countries. The first autochthonous transmission of the virus was recently confirmed in the Americas.1 The outbreak seems to have started in October, 2013, in Saint Martin Island and rapidly spread to countries and territories in the Americas. Local transmission of the virus has so far been confirmed in 27 countries or territories in the Caribbean, Central America, South America, and North America. By Aug 1, 2014, 4736 laboratoryconfirmed cases and more than 500 000 suspected
789
Comment
osteoblasts infected with the arthritogenic alphavirus Ross River virus is elevated and that the increased RANKL to OPG ratio favours osteoclastogenesis, which might lead to severe bone pathologies. C57BL/6 wild-type mice infected with Ross River virus had an increased ratio of RANKL to osteoprotegerin, accompanied by severe bone loss in knee joints and vertebrae.5 These findings strongly suggest a mechanism involving direct infection of osteoblasts to explain the arthritis and arthralgia during infection with arthritogenic alphaviruses such as Ross River virus and chikungunya virus. The bone pathology and inflammatory response in chikungunya infection shares similarities with other forms of arthritis. In particular, the inflammatory response during alphavirus infection in the joint is very similar to that in rheumatoid arthritis, with a similar pattern of leucocyte infiltration, cytokine production, and complement activation.6–8 Several of the shared cytokines such as tumour necrosis factor, interleukin 1, interleukin 6, and interleukin 17 are established therapeutic targets during rheumatoid arthritis, showing their importance in pathogenesis. Based on these similarities, we predict that chikungunya infection might lead to exacerbation of (or increased susceptibility to) underlying rheumatoid arthritis and other joint pathologies. The at-risk population is potentially very large because of the relatively high incidence of bone diseases in the general population. This hypothesis has not yet been analysed in detail. Little is known about the outcome of alphavirus infection in patients with joint pathologies. Preexisting arthritis (including rheumatoid arthritis and osteoarthritis) has been associated with prolonged rheumatic symptoms after infection with Ross River virus, chikungunya virus, or the related alphavirus Pogosta virus.9,10 These observations suggest that arthritogenic virus infection can exacerbate preexisting joint pathology. Large-scale studies are needed to probe the link between viral arthritis and underlying bone disease. Mechanistic examination of this disease interaction in human studies will be difficult. To this end, we have established a mouse model of rheumatoid arthritis exacerbation by alphavirus infection and are analysing the immune mechanisms at the interface between these diseases. 790
Underlying rheumatic disorders might affect the incidence of alphaviral arthritis. The risk of infection in patients with rheumatoid arthritis is twice as high as it is in the normal population, which is partly due to the immunosuppressive effects of rheumatoid arthritis drugs, but is also due to immunoregulatory abnormalities in rheumatoid arthritis.7 This increased susceptibility includes infections in the joint: individuals with rheumatoid arthritis are predisposed to septic arthritis.11 From the enhanced incidence of septic arthritis and increased severity of alphaviral infection in patients with rheumatoid arthritis, we speculate that population studies will identify an increased incidence of alphaviral arthritis in these patients. *Felicity Burt, Weiqiang Chen, Suresh Mahalingam Department of Medical Microbiology and Virology, National Health Laboratory Services, Universitas and Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa (FB); and Emerging Viruses and Inflammation Research Group, Institute for Glycomics, Griffith University, Gold Coast, QLD, Australia (WC, SM) [email protected] We declare no competing interests. 1
2
3
4
5
6 7 8
9
10
11
Van Bortel W, Dorleans F, Rosine J, et al. Chikungunya outbreak in the Caribbean region, December 2013 to March 2014, and the significance for Europe. Euro Surveill 2014; 19: 20759. US Centers for Disease Control and Prevention. Chikungunya in the Americas. http://www.cdc.gov/chikungunya/geo/americas.html (accessed Aug 4, 2014). Pan American Health Organization. Chikungunya. Number of reported cases of chikungunya fever in the Americas EW 31. http://www.paho. org/hq/index.php?option=com_topics&view=article&id=343&Item id=40931 (accessed Aug 4, 2014). Hofbauer LC, Schoppet M. Clinical implications of the osteoprotegerin/ RANKL/RANK system for bone and vascular diseases. JAMA 2004; 292: 490–95. Chen W, Foo SS, Rulli NE, et al. Arthritogenic alphaviral infection perturbs osteoblast function and triggers pathologic bone loss. Proc Natl Acad Sci USA 2014; 111: 6040–45. Burt FJ, Rolph MS, Rulli NE, Mahalingam S, Heise MT. Chikungunya: a re-emerging virus. Lancet 2012; 379: 662–71. Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet 2010; 376: 1094–108. Nakaya HI, Gardner J, Poo YS, Major L, Pulendran B, Suhrbier A. Gene profiling of Chikungunya virus arthritis in a mouse model reveals significant overlap with rheumatoid arthritis. Arthritis Rheum 2012; 64: 3553–63. Mylonas AD, Brown AM, Carthew TL, et al. Natural history of Ross River virus-induced epidemic polyarthritis. Med J Aust 2002; 177: 356–60. Sissoko D, Malvy D, Ezzedine K, et al. Post-epidemic Chikungunya disease on Reunion Island: course of rheumatic manifestations and associated factors over a 15-month period. PLoS Negl Trop Dis 2009; 3: e389. Edwards CJ, Cooper C, Fisher D, Field M, van Staa TP, Arden NK. The importance of the disease process and disease-modifying antirheumatic drug treatment in the development of septic arthritis in patients with rheumatoid arthritis. Arthritis Rheum 2007; 57: 1151–57.
www.thelancet.com/infection Vol 14 September 2014
will affect future burdens of bacterial infections and resistance. Once all this work and a wealth of further high-quality research has been done, there is still the task of assessing the new knowledge that has emerged and the translation of that knowledge into implementation strategies that will be appropriate, feasible, and socially and politically acceptable in high-income, middle-income, and lowincome countries. The world has to be in it for the long haul. Good luck, one and all. We’ll need it. Michael G Head Research Department of Infection and Population Health, Farr Institute, University College London, London NW1 2DA, UK [email protected]
I declare no competing interests. 1
2 3
4
5
6
Braggington EC, Piddock LJV. UK and European Union public and charitable funding from 2008 to 2013 for bacteriology and antibiotic research in the UK: an observational study. Lancet Infect Dis 2014; published online July 25. http://dx.doi.org/10.1016/S1473-3099(14)70825-4. Head MG, Fitchett JR, Atun R. Investing in antimicrobial resistance research. Br J Hosp Med 2014; 75: 6–7. Head MG, Fitchett JR, Cooke MK, et al. Systematic analysis of funding awarded for antimicrobial resistance research to institutions in the UK, 1997–2010. J Antimicrob Chemother 2014; 69: 548–54. Davies SC, Fowler T, Watson J, Livermore DM, Walker D. Annual Report of the Chief Medical Officer: infection and the rise of antimicrobial resistance. Lancet 2013; 381: 1606–09. WHO. Antimicrobial resistance: global report on surveillance 2014. Geneva: World Health Organization, 2014. http://www.who.int/drugresistance/ documents/surveillancereport/en/ (accessed June 19, 2014). Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States, 2013. http://www.cdc.gov/drugresistance/threatreport-2013/ (accessed June 19, 2014).
Chikungunya virus and arthritic disease
www.thelancet.com/infection Vol 14 September 2014
cases had been reported by the Pan American Health Organization.2,3 Spread and establishment of the virus in new endemic regions will be dependent on availability of competent vectors and a source of the virus. Although establishment of the virus will require travellers with above-threshold viraemias and an overlap of seasons between the northern and southern hemispheres for vector activity, the potential exists for spread of this virus to both Europe and other regions of America. Bone-related disorders, such as osteoporosis, rheumatoid arthritis, or osteoarthritis, affect millions of people worldwide. Osteoporosis is a systemic disease characterised by declining bone density that results in bone fractures, whereas autoimmune rheumatoid arthritis and degenerative osteoarthritis lead to chronic joint arthralgia and bone destruction. Bone homeostasis is maintained by the coordinated action of bone-forming osteoblasts and boneresorbing osteoclasts. Osteoclastogenesis is regulated by osteoblastic and non-osteoblastic cells such as T cells through receptor activator of nuclear factor κB ligand (RANKL) and osteoprotegerin, a soluble decoy receptor for RANKL. Changes in the ratio of RANKL to osteoprotegerin have been implicated in bone diseases including rheumatoid arthritis and osteoporosis.4 Weiqiang Chen5 and colleagues reported that RANKL expression by primary human
Sinclair Stammers/Science Photo Library
Chikungunya virus is a mosquito-borne alphavirus that has recently emerged in several explosive epidemics, causing febrile illness that can progress to painful and debilitating rheumatic disease. The virus continues to spread globally. Based on recent developments, we propose a potential link between chikungunya infection and other bone and joint diseases. Chikungunya virus, transmitted by Aedes spp mosquitoes, is widely distributed in tropical and subtropical regions of Africa, the Indian Ocean islands, and southeast Asia. Three distinct genotypes of the virus exist, with phenotypic differences that have facilitated adaptation of the virus to Aedes albopictus, a species with wider geographical distribution than Aedes aegypti. In 2004, the virus emerged in the coastal towns of Kenya resulting in an outbreak that spread rapidly through the Indian Ocean islands and India. Subsequently, seasonal outbreaks have been recorded in various countries. The first autochthonous transmission of the virus was recently confirmed in the Americas.1 The outbreak seems to have started in October, 2013, in Saint Martin Island and rapidly spread to countries and territories in the Americas. Local transmission of the virus has so far been confirmed in 27 countries or territories in the Caribbean, Central America, South America, and North America. By Aug 1, 2014, 4736 laboratoryconfirmed cases and more than 500 000 suspected
789
Comment
osteoblasts infected with the arthritogenic alphavirus Ross River virus is elevated and that the increased RANKL to OPG ratio favours osteoclastogenesis, which might lead to severe bone pathologies. C57BL/6 wild-type mice infected with Ross River virus had an increased ratio of RANKL to osteoprotegerin, accompanied by severe bone loss in knee joints and vertebrae.5 These findings strongly suggest a mechanism involving direct infection of osteoblasts to explain the arthritis and arthralgia during infection with arthritogenic alphaviruses such as Ross River virus and chikungunya virus. The bone pathology and inflammatory response in chikungunya infection shares similarities with other forms of arthritis. In particular, the inflammatory response during alphavirus infection in the joint is very similar to that in rheumatoid arthritis, with a similar pattern of leucocyte infiltration, cytokine production, and complement activation.6–8 Several of the shared cytokines such as tumour necrosis factor, interleukin 1, interleukin 6, and interleukin 17 are established therapeutic targets during rheumatoid arthritis, showing their importance in pathogenesis. Based on these similarities, we predict that chikungunya infection might lead to exacerbation of (or increased susceptibility to) underlying rheumatoid arthritis and other joint pathologies. The at-risk population is potentially very large because of the relatively high incidence of bone diseases in the general population. This hypothesis has not yet been analysed in detail. Little is known about the outcome of alphavirus infection in patients with joint pathologies. Preexisting arthritis (including rheumatoid arthritis and osteoarthritis) has been associated with prolonged rheumatic symptoms after infection with Ross River virus, chikungunya virus, or the related alphavirus Pogosta virus.9,10 These observations suggest that arthritogenic virus infection can exacerbate preexisting joint pathology. Large-scale studies are needed to probe the link between viral arthritis and underlying bone disease. Mechanistic examination of this disease interaction in human studies will be difficult. To this end, we have established a mouse model of rheumatoid arthritis exacerbation by alphavirus infection and are analysing the immune mechanisms at the interface between these diseases. 790
Underlying rheumatic disorders might affect the incidence of alphaviral arthritis. The risk of infection in patients with rheumatoid arthritis is twice as high as it is in the normal population, which is partly due to the immunosuppressive effects of rheumatoid arthritis drugs, but is also due to immunoregulatory abnormalities in rheumatoid arthritis.7 This increased susceptibility includes infections in the joint: individuals with rheumatoid arthritis are predisposed to septic arthritis.11 From the enhanced incidence of septic arthritis and increased severity of alphaviral infection in patients with rheumatoid arthritis, we speculate that population studies will identify an increased incidence of alphaviral arthritis in these patients. *Felicity Burt, Weiqiang Chen, Suresh Mahalingam Department of Medical Microbiology and Virology, National Health Laboratory Services, Universitas and Faculty of Health Sciences, University of the Free State, Bloemfontein, South Africa (FB); and Emerging Viruses and Inflammation Research Group, Institute for Glycomics, Griffith University, Gold Coast, QLD, Australia (WC, SM) [email protected] We declare no competing interests. 1
2
3
4
5
6 7 8
9
10
11
Van Bortel W, Dorleans F, Rosine J, et al. Chikungunya outbreak in the Caribbean region, December 2013 to March 2014, and the significance for Europe. Euro Surveill 2014; 19: 20759. US Centers for Disease Control and Prevention. Chikungunya in the Americas. http://www.cdc.gov/chikungunya/geo/americas.html (accessed Aug 4, 2014). Pan American Health Organization. Chikungunya. Number of reported cases of chikungunya fever in the Americas EW 31. http://www.paho. org/hq/index.php?option=com_topics&view=article&id=343&Item id=40931 (accessed Aug 4, 2014). Hofbauer LC, Schoppet M. Clinical implications of the osteoprotegerin/ RANKL/RANK system for bone and vascular diseases. JAMA 2004; 292: 490–95. Chen W, Foo SS, Rulli NE, et al. Arthritogenic alphaviral infection perturbs osteoblast function and triggers pathologic bone loss. Proc Natl Acad Sci USA 2014; 111: 6040–45. Burt FJ, Rolph MS, Rulli NE, Mahalingam S, Heise MT. Chikungunya: a re-emerging virus. Lancet 2012; 379: 662–71. Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet 2010; 376: 1094–108. Nakaya HI, Gardner J, Poo YS, Major L, Pulendran B, Suhrbier A. Gene profiling of Chikungunya virus arthritis in a mouse model reveals significant overlap with rheumatoid arthritis. Arthritis Rheum 2012; 64: 3553–63. Mylonas AD, Brown AM, Carthew TL, et al. Natural history of Ross River virus-induced epidemic polyarthritis. Med J Aust 2002; 177: 356–60. Sissoko D, Malvy D, Ezzedine K, et al. Post-epidemic Chikungunya disease on Reunion Island: course of rheumatic manifestations and associated factors over a 15-month period. PLoS Negl Trop Dis 2009; 3: e389. Edwards CJ, Cooper C, Fisher D, Field M, van Staa TP, Arden NK. The importance of the disease process and disease-modifying antirheumatic drug treatment in the development of septic arthritis in patients with rheumatoid arthritis. Arthritis Rheum 2007; 57: 1151–57.
www.thelancet.com/infection Vol 14 September 2014
