Chikungunya virus (CHIKV) is an enveloped positive-strand RNA alphavirus which can infect human epithelial and endothelial cells, fibroblasts or macrophages 12. A CHIKV epidemic recently occurred on islands of the Indian Ocean in 2005 345. CHIKV infection may cause an algoeruptive syndrome with disabling joint pain and recurrent rheumatic manifestations 678. Until now, it has been assumed that complete recovery occurs, even when symptoms are long lasting. Remarkably, despite the severity and duration of arthritis, articular destruction has been reported very rarely 9. We report the case of a patient with CHIKV infection presenting with severe chronic rheumatism accompanied by progressive destructive arthritis and dysregulated expression of inflammatory mediators.

In November 2005, a 60-year-old French man living in La Réunion experienced an acute influenza-like illness with diffuse arthralgia affecting bilaterally the distal inter-phalangeal joints of the fingers and the toes with hand tenosynovitis. His past medical history was unremarkable with no family history of inflammatory rheumatism.

Serology demonstrated the presence of anti-CHIKV IgM and confirmed the diagnosis of CHIKV infection. During the following months, the patient had persisting inflammatory arthralgia and joint stiffness which were not improved by symptomatic treatment. One year later, he developed refractory tenosynovitis in the wrists.

On February 15, 2007, the patient returned to France and consulted in our department. He complained of persistent symmetrical inflammatory arthritis of the wrists with fixed oedema of the two hands predominating on the right. Hand synovitis of the extensors and the flexors of wrists and fingers were noted. Lymphocyte immunophenotyping showed an increased CD4 T-cell count at 1,18 × 10⁹/L (63.5%) and an activated CD45/CD3 (-) T-cell count at 0.209 × 10⁹/L (11.3%), and CD45/CD3 (+) at 0,119 × 10⁹/L (6.4%). Serum immunoglobulin was normal, as were the C3 and C4 complement fractions. No markers of autoimmunity were found, notably anti-citrullin peptide antibodies, antinuclear antibodies or cryoglobulinemia. The HLA B27 gene was positive and HLA system class II genotyping revealed an HLA-DRB1.03.11 genotype.

At the time of the consultation, serologic status for CHIKV antibodies was reevaluated using IgM-capture and an IgG-capture enzyme-linked immunoabsorbent assay with inactivated cell-culture-ground chikungunya virus and mouse anti-chikungunya hyperimmune ascitic fluid (Institut Pasteur, Lyon, France). Persistent specific anti-CHIKV IgM was detected in this late stage serum sample, collected 18 months after the infection, with optical density (OD) values of 1.47 for IgG and 0.81 for IgM. Testing for CHIKV RNA was negative 10. Radiography of the hands and wrists showed a subchondral defect of the 2^nd and 3^rd right proximal interphalangeal finger joints as well as of the 3^rd, 4^th and 5^th left distal interphalangeal joints. Magnetic resonance imaging (MRI) of the hands and wrists revealed marked bilateral periostal inflammation and oedematous carpitis (Fig 1A and 1B), with carpis synovitis (1C) and bone destruction in the left hand (1D) accompanied by intra-articular swelling (1D). Bone scintigraphy revealed diffuse inflammation of several joints, prominent in the right wrist (3^rd metacarpo-phalangeal joint) (Fig 1E) and the left ankle (1F), as well as evolutive enthesopathy of the left calcaneum. Methotrexate (MTX) was initiated at the dose of 17.5 mg/week and four months later, dramatic improvement was observed in both the number and state of swollen and tender joints and in tendon involvement. At this time, MRI of the hands, wrists and feet showed reduced progression of erosion and a decrease in radiographic inflammation and oedematous damage compared to before treatment. Clinical and radiological improvement was maintained over 15 months. At this end-point, CHIKV antibody serology showed persistence of both specific IgM and IgG, with OD values of 0.60 and 0.32, respectively.

Chikungunya virus infection is usually a self-limiting disease characterized by arthralgia with late peripheral joint pain in the smaller joints 1112. A sole case of late articular destruction after decades of post CHIKV-chronic rheumatism has been reported with a questionable relationship to the CHIKV infection 9. Our case is remarkable for the clearly erosive arthritis pattern accompanied with enthesopathies, which developed within less than two years of the index CHIKV infection 13.

The patient was positive for HLA B27 antigen although no clinical rheumatologic manifestations had been noted before the CHIKV infection. For this reason, we can conclude that he developed a form of spondylarthropathy. Concerning the acute phase, recent findings suggested that both classical and severe symptoms of chikungunya disease closely reflect CHIKV tissue tropism 14, with fibroblasts being the primary targets, as they are for other alphaviruses 115. The molecular basis of this tropism may combine specific interactions between virus and host cells and tissues, and an intrinsic lower ability of this cell type to control CHIKV infection 814.

The pathogenesis of persistent arthritis remains unclear although persistent infection of synovial macrophages has been documented for other alphaviruses 1617. Moreover, factors secreted by infected macrophages seem to play a pivotal role in joint inflammation 18. To date, the presence of CHIKV RNA in joints during the acute phase of infection has only been demonstrated in animal models 1419. CHIKV RNA has never been detected in joint tissues during the late phase, although it has been found in human muscle satellite cells three months after infection 2. Taken together with reports of the presence of long lasting IgM anti-CHIKV antibodies 20, these findings could indicate the persistence of CHIKV in certain host tissues or cells. However, there is no evidence that viral persistence is necessary to sustain chronic joint pathology after the infection. In our case, an antigen-specific immunopathology may underlie the development of chronic joint disease due to the presentation of specific autologous or microbial arthritogenic peptides 21. This would be consistent with the notion of an infectious trigger for immune activation derived from molecular mimicry which has been postulated as a potential pathogenic mechanism in autoimmunity 222324.

High levels of pro-inflammatory cytokines IL-1, IL-6 and IL-8 were detected in cell supernatants from the patient's lymphocytes and elevated expression of genes encoding a variety of cytokines and chemokines known to be implicated in the pathogenesis of arthritis were also observed 2526. In contrast, IFN-α, IL-4 and IL-5 were not detected in cell supernatants whereas IL-10 was increased. Of interest, the lymphocytes failed to express genes encoding IFN-α, IL-22 and CD40L, which are required for B cell differentiation, optimal immunoglobulin isotype switching and antiviral activity. Although the persistence of specific IgM antibodies has been documented after CHIKV infections 20, an association between these antibodies and disease severity has not been established. It is possible that antibody persistence may be determined by the persistence of virus in host tissues since, in acute arboviral infections, IgM are generally no longer detectable after 6-12 months. Unfortunately, in our case, it was not possible to perform RT-PCR for detection of CHIKV in synovial fluid or tissue

Viruses have evolved a number of mechanisms for suppressing host immune responses. In particular, viral proteins may suppress the retinoic acid-inducible gene I-like helicase and Toll-like receptor pathways important for the expression of type 1-IFNs, such as IFN-α isoforms, which play a crucial role in eliminating viral infections 14272829. Immunoglobulin class switching from IgM to IgG and IgA is central to immunity against viruses and requires the activation of B-cells by T-cells via cytokine interactions with CD154/CD40L. Mutations in the CD40L gene have been observed in cases of inherited hyper-IgM X-linked immunodeficiences 27. In this context, CHIKV may be able to evade T-cell dependent IgG and IgA responses by attenuating CD40L gene expression. Such a mechanism has been postulated previously to explain hyper IgM syndrome associated with various viral infections 303132.

We report here a case of CHIKV infection with joint and bone erosion and persistent specific IgM nearly two years following infection. Transcriptomic and protein analysis revealed individual genes which could be implicated in the pathogenesis of chronic arthritis; these genes have not been associated previously with alphavirus-induced arthritis.

The patient has provided written consent to the use of his history for publication

The authors declare that they have no competing interests.

DMa took care of the patient. DMa and KE drafted the manuscript. BA and HT performed immunoglobulin assays. MMM, DMoy, DMa, JR and DMos performed the immunological analyses and evaluation. All authors reviewed the manuscript, contributed to its finalisation and approved the submitted version.