Destructive arthritis in a patient with chikungunya virus infection with persistent specific IgM antibodies

Malvy, Denis; Ezzedine, Khaled; Mamani-Matsuda, Maria; Autran, Brigitte; Tolou, Hugues; Receveur, Marie‐Catherine; Pistone, Thierry; Rambert, Jérôme; Moynet, Daniel; Mossalayi, Djavad

doi:10.1186/1471-2334-9-200

Cited by 113 publications

(104 citation statements)

References 30 publications

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“…Following the 2005-2006 epidemic in Indian Ocean islands, radiographic evidence emerged of bone pathologies similar to those in rheumatoid arthritis (RA) in CHIKV-infected patients (5,6). Recently, bone pathologies in joints of CHIKV patients have been reported, providing clinical evidence that alphaviruses may also affect skeletal health (7).…”

mentioning

confidence: 98%

Bindarit, an Inhibitor of Monocyte Chemotactic Protein Synthesis, Protects against Bone Loss Induced by Chikungunya Virus Infection

Chen

Foo

Taylor

et al. 2015

J Virol

106

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The recent global resurgence of arthritogenic alphaviruses, in particular chikungunya virus (CHIKV), highlights an urgent need for the development of therapeutic intervention strategies. While there has been significant progress in defining the pathophysiology of alphaviral disease, relatively little is known about the mechanisms involved in CHIKV-induced arthritis or potential therapeutic options to treat the severe arthritic symptoms associated with infection. Here, we used microcomputed tomographic (CT) and histomorphometric analyses to provide previously undescribed evidence of reduced bone volume in the proximal tibial epiphysis of CHIKV-infected mice compared to the results for mock controls. This was associated with a significant increase in the receptor activator of nuclear factor-B ligand/osteoprotegerin (RANKL/OPG) ratio in infected murine joints and in the serum of CHIKV patients. The expression levels of the monocyte chemoattractant proteins (MCPs), including MCP-1/CCL2, MCP-2/CCL8, and MCP-3/CCL7, were also highly elevated in joints of CHIKV-infected mice, accompanied by increased cellularity within the bone marrow in tibial epiphysis and ankle joints. Both this effect and CHIKV-induced bone loss were significantly reduced by treatment with the MCP inhibitor bindarit. Collectively, these findings demonstrate a unique role for MCPs in promoting CHIKV-induced osteoclastogenesis and bone loss during disease and suggest that inhibition of MCPs with bindarit may be an effective therapy for patients affected with alphavirus-induced bone loss. IMPORTANCE Arthritogenic alphaviruses, including chikungunya virus (CHIKV) and Ross River virus (RRV), cause worldwide outbreaks of polyarthritis, which can persist in patients for months following infection. Previous studies have shown that host proinflammatory soluble factors are associated with CHIKV disease severity. Furthermore, it is established that chemokine (C-C motif) ligand 2 (CCL2/MCP-1) is important in cellular recruitment and inducing bone-resorbing osteoclast (OC) formation. Here, we show that CHIKV replicates in bone and triggers bone loss by increasing the RANKL/OPG ratio. CHIKV infection results in MCP-induced cellular infiltration in the inflamed joints, and bone loss can be ameliorated by treatment with an MCP-inhibiting drug, bindarit. Taken together, our data reveal a previously undescribed role for MCPs in CHIKV-induced bone loss: one of recruiting monocytes/OC precursors to joint sites and thereby favoring a pro-osteoclastic microenvironment. This suggests that bindarit may be an effective treatment for alphavirus-induced bone loss and arthritis in humans.

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confidence: 98%

Bindarit, an Inhibitor of Monocyte Chemotactic Protein Synthesis, Protects against Bone Loss Induced by Chikungunya Virus Infection

Chen

Foo

Taylor

et al. 2015

J Virol

106

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“…Persistent CHIKV infection also has been observed for weeks to months in experimentally infected mice (137,147) and NHPs (105,163), with vRNA detected in joint tissue (150), muscle, and spleen (105). In addition, persistent IgM levels have been detected in patients and animals experiencing chronic arthritis (8,105,126,153,164,165). These data suggest that persistent CHIKV antigen, or perhaps infection, in protected cellular reservoirs triggers inflammation that culminates in chronic CHIKV rheumatic disease (Figure 3).…”

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confidence: 70%

Chikungunya virus: epidemiology, replication, disease mechanisms, and prospective intervention strategies

Silva¹,

Dermody²

2017

Journal of Clinical Investigation

307

338

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“…19 Viral or antigen persistence also has been suggested as a possible mechanism for the prolonged production of IgM antibodies seen with other viruses, such as chikungunya, Japanese encephalitis, and rubella. [20][21][22] A third possible explanation for prolonged IgM antibody synthesis is an incomplete class switching either caused by alterations in the vaccine virus because of the attenuation process or potential interference of the vaccine virus in the regulation or recognition of molecules needed for class switching. 23,24 Finally, subsequent exposure to YF virus or a related flavivirus could have caused IgM antibodies to persist or reform after infection.…”

Section: Resultsmentioning

confidence: 99%

Detection of Anti-Yellow Fever Virus Immunoglobulin M Antibodies at 3–4 Years Following Yellow Fever Vaccination

Gibney¹,

Edupuganti²,

Panella³

et al. 2012

The American Journal of Tropical Medicine and Hygiene

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Destructive arthritis in a patient with chikungunya virus infection with persistent specific IgM antibodies

Abstract: Background: Chikungunya fever is an emerging arboviral disease characterized by an algoeruptive syndrome, inflammatory polyarthralgias, or tenosynovitis that can last for months to years. Up to now, the pathophysiology of the chronic stage is poorly understood.

Cited by 113 publications

References 30 publications

Bindarit, an Inhibitor of Monocyte Chemotactic Protein Synthesis, Protects against Bone Loss Induced by Chikungunya Virus Infection

Bindarit, an Inhibitor of Monocyte Chemotactic Protein Synthesis, Protects against Bone Loss Induced by Chikungunya Virus Infection

Chikungunya virus: epidemiology, replication, disease mechanisms, and prospective intervention strategies

Detection of Anti-Yellow Fever Virus Immunoglobulin M Antibodies at 3–4 Years Following Yellow Fever Vaccination

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