- Email: [email protected]
A report of 21 cases of rheumatoid arthritis following Chikungunya fever. A mean follow-up of two years
Joint Bone Spine 76 (2009) 654–657
Original article
A report of 21 cases of rheumatoid arthritis following Chikungunya fever. A mean follow-up of two years Éric Bouquillard a , Bernard Combe b,∗ b
a Service de rhumatologie, 39, rue du Four-à-Chaux, 97410 Saint-Pierre, France Service d’immunorhumatologie, CHU Lapeyronie, université Montpellier I, 371, avenue du Doyen-Gaston-Giraud, 34295 Montpellier cedex 5, France
Accepted 12 August 2009 Available online 27 November 2009
Abstract Objective: In 2005, after an epidemic infection of Chikungunya fever in islands in the Indian Ocean, infected patients exhibited severe musculoskeletal disorders. We report 21 cases of rheumatoid arthritis (RA) after Chikungunya infection that were diagnosed at a rheumatological centre in Reunion Island. Methods: Patients were examined by the same rheumatologist from February 2006 to July 2007. Inclusion criteria were (1) Chikungunya infection confirmed by IgM and IgG antibodies, (2) RA according to ACR criteria, (3) no other definite diagnosis of arthritis and (4) persistent arthritis symptoms from the onset of viral infection to RA diagnosis. Results: Twenty-one patients (13 females; mean age, 57 ± 12 years) fulfilled the inclusion criteria. Eighteen patients (85.7%) had symmetric polyarthritis and three had oligoarthritis. The mean symptom duration was 10 months (range 4–18). The mean ESR was 40.7 ± 28.1 mm/hr and C-reactive protein level 37 ± 41 mg/l; 12 patients were positive for rheumatoid factor (57.1%), and six had anti-CCP antibodies (28.6%) and 14 HLA DRB1*04 or 01 alleles (66.6%). Radiographs of hands and feet of 12 patients showed erosions and/or joint space narrowing (JSN). During a mean follow-up of 27.6 ± 6.4 months, all patients were treated with DMARDs including methotrexate (n = 19) and TNF blockers (n = 6). Structural damage progressed, with 17 cases of erosion and/or JSN at follow-up. Conclusion: We diagnosed RA in 21 patients with Chikungunya fever. The first symptoms occurred at the time of viral infection. Outcome was severe in most of the cases despite low rate of anti-CCP antibodies. These cases suggest a role of viral infection in RA initiation. © 2009 Published by Elsevier Masson SAS on behalf of the Société Française de Rhumatologie. Keywords: Rheumatoid arthritis; Chikungunya fever; Viral arthropathy; Alphavirus
In 2005 and 2006, more than 1.5 million people in the islands of Comoros, Madagascar, Mayotte, Reunion, Mauritius, and Seychelles in the overheated Indian Ocean were infected with Chikungunya (CHIK) fever. In Reunion Island, 38.3% of the population, about 300,000 people, were infected [1]. The peak outbreak occurred between December 2005 and February 2006. Only 6% of the cases were asymptomatic, and the sex-ratio was approximately 1:1. CHIK fever is a viral infection transmitted to humans by Aedes mosquitoes infected with CHIK virus, a member of the alphavirus genus of the Togaviridae family [2,3]. Cases of CHIK fever are geographically distributed from Africa through Southeast Asia and South America, but cases have increasingly
∗
Corresponding author. E-mail address: [email protected] (B. Combe).
been reported in Europe and in North America, mainly in travellers [4,5]. CHIK infection usually causes a syndrome characterized by fever, headaches, chills, conjunctivitis, rash, myalgia and severe joint pain with or without swelling [6–10]. Peripheral joint symptoms vary from polyarthralgia to symmetrical polyarthritis, the most commonly involved joints being wrists, metacarpal and interphalangeal joints, elbows, ankles, knees and metatarsalphalangeal joints. The outcome is usually benign, but persistent joint pain and stiffness may occur. More than 10% of patients retain residual joint symptoms three years after infection [6,7,11]. Symptoms mimicking rheumatoid arthritis (RA) have been described [12,13], at least two cases showing bony erosions. We have followed 21 cases of patients with RA after CHIK infection that were diagnosed at a rheumatological center in Reunion Island. A preliminary report has been recently published [14].
1297-319X/$ – see front matter © 2009 Published by Elsevier Masson SAS on behalf of the Société Française de Rhumatologie. doi:10.1016/j.jbspin.2009.08.005
É. Bouquillard, B. Combe / Joint Bone Spine 76 (2009) 654–657
655
1. Patients and methods
Table 1 HLA-DR typing (microlymphocytotoxicity).
Following the CHIK fever outbreak in Reunion Island, numerous patients with chronic arthritis of more than three months were seen by a single rheumatologist (BE). Since some showed typical clinical symptoms of RA, they were included in a prospective follow-up study. Inclusion criteria of the 21 patients with possible RA after CHIK fever infection included a history of CHIK fever in 2005 and 2006, a positive CHIK test result for IgM or IgG antibodies, RA according to the 1987 American College of Rheumatology criteria [15], no other definite diagnosis of arthritis, and persistent arthritis symptoms from the onset of CHIK infection to the diagnosis of RA. At baseline, the selected patients underwent clinical examination and history taking; testing for erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, blood cell counts, liver enzyme activity, proteinuria and renal function, rheumatoid factor (ELISA or Waller-Rose reaction), anti-CCP antibodies (CCP2, ELISA, Inova), antinuclear antibodies, and HLA DR alleles (microlymphocytotoxicity); and radiographs of the hands and wrists and anteroposterior feet. In addition, six patients with normal plain-radiographs results underwent MRI of the hands. Patients were followed up clinically every six months and underwent hand and feet radiographs at six, 12 and 24 months.
Patients
HLA-DR antigens
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
04/07 01/13 01/15 02/04 01/15/14 12/07 11/13/01/12 17/04 04/07 01/14 04/07 17/13 04/07 02/11 01/13 07/01/11 04/07
2. Results 2.1. Clinical characteristics at the time of rheumatoid arthritis diagnosis Twenty-one patients (13 females [61.9%]; mean age 57.3 ± 12.2 years) fulfilled the inclusion criteria. None had a personal or family history of inflammatory arthritis. Three patients had a history of smoking. At presentation, 18 patients (85.7%) had symmetric polyarthritis and three (14.3%) had oligoarthritis (≤ five swollen joints). The mean delay between CHIK fever onset and RA diagnosis was 10 months (range 4–18).
2.2. Baseline biological data Laboratory tests for the 21 patients suggested significant systemic inflammation, with mean ESR 40.7 ± 28.1 mm/hr and mean CRP level 37.3 ± 41.1 mg/l (normally < 5 mg/l). Sixteen patients (78.2%) had an abnormal CRP level. Twelve patients (57.1%) were positive for rheumatoid factor, and antiCCP2 antibodies were detected in only six patients (28.6%); 14 patients (66.6%) were positive for rheumatoid factor or anti-CCP antibodies. Two patients had antinuclear antibodies without anti-DNA or anti-ENA antibodies. Fourteen patients (66.6%) were positive for HLA DRB1*04 or DRB1*01 alleles (Table 1).
2.3. Baseline radiography Despite the relatively short disease duration, baseline radiographs of hands and feed were normal for only nine of 21 patients (42.9%) (Table 2). Other patients had typical bone erosions (n = 5) or joint space narrowing (n = 12). For five of six patients with normal radiographs, MRI revealed erosions in the hands. 2.4. Treatment and outcome Patients with a diagnosis of RA received classical disease-modifying antirheumatic drug (DMARD) therapy with methotrexate (n = 19), sulfasalazine (n = 3), leflunomide (n = 2), or hydroxychloroquine (n = 2). One patient was lost to followup after four months. In six patients, after inadequate response to methotrexate, treatment was successful with TNF blockers (etanercept = 4, adalimumab = 2). Fifteen patients (71.4%) received low-dose prednisone (≤ 10 mg/day). After a mean follow-up of 27.6 ± 6.4 months (range 4–21 months) for all patients, radiographs revealed five additional patients with joint space narrowing and 12 more with erosions, despite the use of DMARDs (Table 2). Only four Table 2 Radiographic analysis of hands and feet of 21 patients with RA after Chikungunya fever infection.
Erosions Joint space narrowing Normal radiographs
At diagnosis
At ∼24 months’ follow-up
5 (23.8%) 12 (57.1%) 9 (42.9%)
17 (81.0%) 17 (81.0%) 4 (19.0%)
656
É. Bouquillard, B. Combe / Joint Bone Spine 76 (2009) 654–657
patients (19%) had normal radiographs for hands and feet. Seven patients (33.3%) were still receiving long-term steroids. 3. Discussion We report 21 cases of active and destructive RA following CHIK fever outbreak during 2005 and 2006 in Reunion Island in the Indian Ocean. All patients showed persistent arthritis symptoms from the onset of viral infection to the diagnosis of RA. RA was severe; 80% of patients had radiographic evidence of joint damage and six (29.0%) required therapy with TNF blockers. Our observations raise the questions of how to diagnose RA in the context of viral infection and the role of CHIK fever infection in RA development. Musculoskeletal disorders are common features of CHIK fever. Diffuse joint and muscular pain are usual in the acute phase of the infection, with a resolution of symptoms in most cases in a few days or weeks. Persistent polyarthralgia and arthritis have been reported in 10 to 20% of patients at 20 to 36 months [7,12]. In a retrospective study, three years after the onset of CHIK fever infection, 12% of 107 patients still complained of joint symptoms, and 5.6% had nonerosive arthritis [7]. Clinical features of RA with joint destruction and rheumatoid factor positivity have been described in a limited number of cases after CHIK fever [12,13]. The diagnosis of RA is usually delayed by several months, as we observed in our cohort (10.7 ± 3.9 months). This delay could be explained by the difficulty in differentiating between onset of early RA and persistent arthritis secondary to CHIK fever, an outcome reported in 10 to 20% of patients [6,7,11]. The immunologic profile may help in diagnosis, since two-thirds of our patients were positive for rheumatoid factor and/or anti-CCP antibodies. The positivity for rheumatoid factor in our cases (57.1%) was similar to that for cases in European countries. However, the proportion of patients with anti-CCP antibodies (28.6%) and to lesser extent RA-associated HLA-DR alleles (66.6%) was lower than that for European cases. Currently, no data exist on anti-CCP antibodies in RA patients from Reunion Island; however, we have observed anti-CCP positivity in 52% of our own RA patients from an African origin (unpublished data). As well, HLA-DRB1*01 and DRB1*04 alleles have been associated with RA in African European patients [16], which is consistent with our report. The severity of our cases is of interest. Only nine patients at baseline and four after two years of follow-up had normal plain-radiograph images of hands and feet. In addition, six patients required therapy with TNF blockers because of inadequate response to classical DMARDs, including methotrexate and seven were receiving lont-term steroids. RA development after CHIK infection has been reported in only a limited number of cases [12,13], and it is not possible to rule out that our observed cases are only due to chance. There are no valid data to explore if during this period, incidence of RA was increased in the infected patients compared to the normal population. Anyway, a preliminary cross-sectional study [17] and incidence data from the French social security system (http://www.amelie.fr) support the fact that RA could have occured more frequently following the recent outbreak in the Indian Ocean.
Other alphaviruses, including Ross River virus, O’nyongnyong virus or Sindbis virus, can induce rheumatic manifestations such as persistent arthritis [3]. These viruses seem to be able to enter quickly into macrophages and synovial cells and persist inside the cells, thus preventing immune reactions [18]. Chemokines such as monocyte chemoattractant protein 1, produced by infected cells, could play a role in the recruitment and activation of inflammatory cells in the synovium and in the development of chronic joint inflammation. The possible role of viruses in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus, Sjögren syndrome or RA has been suggested but never clearly demonstrated [19]. Epstein Barr virus, parvovirus B19 [20] and other viruses have been associated with the development of RA. Viral DNA in the synovium of patients with RA and the onset of classically defined RA after such acute viral infections has been reported. Viruses could play the role of superantigens in mediating T- and B-cell interactions and inducting an autoimmune response in susceptible patients. In conclusion, we diagnosed RA in 21 patients after CHIK fever infection in Reunion Island. The first symptoms occurred at the time of viral infection. Outcome was severe in most cases, despite low rate of anti-CCP antibodies and rheumatoid factor and required early treatment with methotrexate in most cases and TNF blockers in four. These cases suggest a role of viral infection in RA initiation. Conflicts of interest None of the authors has any conflicts of interest to declare. References [1] Paquet C, Quatresous I, Solet JL, et al. Chikungunya outbreak in Reunion: epidemiology and surveillance, 2005 to early January 2006. Euro Surveill 2006;11:E060202.3. [2] Jeandel P, Josse R, Durand JP, et al. Exotic viral arthritis: role of alphavirus. Med Trop 2004;64:81–8. [3] Colin de Verdiere N, Molina JM. Rheumatoid manifestations caused by tropical viruses. Joint Bone Spine 2007;74:410–3. [4] Taubitz W, Cramer JP, Kapaun A, et al. Chikungunya fever in travellers: clinical presentation and course. Clin Infect Dis 2007;45:e1–4. [5] Simon F, Parola P, Grandadam M, et al. Chikungunya infection: an emerging rheumatism among travellers returned from Indian Ocean islands. Report of 47 cases. Medicine (Baltimore) 2007;86:123–37. [6] Kennedy AC, Fleming J, Solomon L. Chikungunya viral arthropathy: a clinical description. J Rheumatol 1980;7:231–6. [7] Brighton SW, Prozesky OW, de la Harpe AL. Chikungunya virus infection. A retrospective study of 107 cases. S Afr Med J 1983;63: 313–5. [8] Volpe A, Caramaschi P, Angheben A, et al. Chikungunya outbreak: remember the arthropathy. Rheumatology (Oxford) 2006;45:1449–50. [9] Yazdani R, Kaushik VV. Chikungunya fever. Rheumatology (Oxford) 2007;46:1214–5. [10] Carmona RJ, Shaikh S, Khalidi NA. Chikungunya viral polyarthritis. J Rheumatol 2008;35:935–6. [11] Calabrese J. Emerging viral infections and arthritis: the role of the rheumatologist. Nat Clin Pract Rheumatol 2008;4:2–3. [12] Fourie ED, Morrison JG. Rheumatoid arthritic syndrome after Chikungunya fever. S Afr Med J 1979;56:130–2.
É. Bouquillard, B. Combe / Joint Bone Spine 76 (2009) 654–657 [13] Brighton SW, Simson IW. A destructive arthropathy following Chikungunya virus arthritis: a possible association. Clin Rheumatol 1984;3:253–8. [14] Bouquillard E, Combe B. Rheumatoid arthritis after chikhungunya fever. Ann Rheum Dis 2009;68:1505–6. [15] Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315–24. [16] Hughes LB, Morrison D, Kelley JM, et al. The HLA-DRB1 shared epitope is associated with susceptibility to rheumatoid arthritis in African Americans through European genetic admixture. Arthritis Rheum 2008;58:335–7.
657
[17] Ribera A, Jaffar Bandjee M, Mohy F, et al. Emerging chronic rheumatologic demonstrations post-Chikungunya in La Reunion. EULAR 2008, Paris, Abstract OP-0222. [18] Suhrbier A, La Linn M. Clinical and pathologic aspects of arthritis due to Ross River virus and other alphaviruses. Curr Opin Rheumatol 2004;16:374–9. [19] Vaughan JH. Viruses and autoimmune disease. J Rheumatol 1996;23:1831–3. [20] Kerr JR. Pathogenesis of human parvovirus B19 in rheumatic disease. Ann Rheum Dis 2000;59:672–83.
Original article
A report of 21 cases of rheumatoid arthritis following Chikungunya fever. A mean follow-up of two years Éric Bouquillard a , Bernard Combe b,∗ b
a Service de rhumatologie, 39, rue du Four-à-Chaux, 97410 Saint-Pierre, France Service d’immunorhumatologie, CHU Lapeyronie, université Montpellier I, 371, avenue du Doyen-Gaston-Giraud, 34295 Montpellier cedex 5, France
Accepted 12 August 2009 Available online 27 November 2009
Abstract Objective: In 2005, after an epidemic infection of Chikungunya fever in islands in the Indian Ocean, infected patients exhibited severe musculoskeletal disorders. We report 21 cases of rheumatoid arthritis (RA) after Chikungunya infection that were diagnosed at a rheumatological centre in Reunion Island. Methods: Patients were examined by the same rheumatologist from February 2006 to July 2007. Inclusion criteria were (1) Chikungunya infection confirmed by IgM and IgG antibodies, (2) RA according to ACR criteria, (3) no other definite diagnosis of arthritis and (4) persistent arthritis symptoms from the onset of viral infection to RA diagnosis. Results: Twenty-one patients (13 females; mean age, 57 ± 12 years) fulfilled the inclusion criteria. Eighteen patients (85.7%) had symmetric polyarthritis and three had oligoarthritis. The mean symptom duration was 10 months (range 4–18). The mean ESR was 40.7 ± 28.1 mm/hr and C-reactive protein level 37 ± 41 mg/l; 12 patients were positive for rheumatoid factor (57.1%), and six had anti-CCP antibodies (28.6%) and 14 HLA DRB1*04 or 01 alleles (66.6%). Radiographs of hands and feet of 12 patients showed erosions and/or joint space narrowing (JSN). During a mean follow-up of 27.6 ± 6.4 months, all patients were treated with DMARDs including methotrexate (n = 19) and TNF blockers (n = 6). Structural damage progressed, with 17 cases of erosion and/or JSN at follow-up. Conclusion: We diagnosed RA in 21 patients with Chikungunya fever. The first symptoms occurred at the time of viral infection. Outcome was severe in most of the cases despite low rate of anti-CCP antibodies. These cases suggest a role of viral infection in RA initiation. © 2009 Published by Elsevier Masson SAS on behalf of the Société Française de Rhumatologie. Keywords: Rheumatoid arthritis; Chikungunya fever; Viral arthropathy; Alphavirus
In 2005 and 2006, more than 1.5 million people in the islands of Comoros, Madagascar, Mayotte, Reunion, Mauritius, and Seychelles in the overheated Indian Ocean were infected with Chikungunya (CHIK) fever. In Reunion Island, 38.3% of the population, about 300,000 people, were infected [1]. The peak outbreak occurred between December 2005 and February 2006. Only 6% of the cases were asymptomatic, and the sex-ratio was approximately 1:1. CHIK fever is a viral infection transmitted to humans by Aedes mosquitoes infected with CHIK virus, a member of the alphavirus genus of the Togaviridae family [2,3]. Cases of CHIK fever are geographically distributed from Africa through Southeast Asia and South America, but cases have increasingly
∗
Corresponding author. E-mail address: [email protected] (B. Combe).
been reported in Europe and in North America, mainly in travellers [4,5]. CHIK infection usually causes a syndrome characterized by fever, headaches, chills, conjunctivitis, rash, myalgia and severe joint pain with or without swelling [6–10]. Peripheral joint symptoms vary from polyarthralgia to symmetrical polyarthritis, the most commonly involved joints being wrists, metacarpal and interphalangeal joints, elbows, ankles, knees and metatarsalphalangeal joints. The outcome is usually benign, but persistent joint pain and stiffness may occur. More than 10% of patients retain residual joint symptoms three years after infection [6,7,11]. Symptoms mimicking rheumatoid arthritis (RA) have been described [12,13], at least two cases showing bony erosions. We have followed 21 cases of patients with RA after CHIK infection that were diagnosed at a rheumatological center in Reunion Island. A preliminary report has been recently published [14].
1297-319X/$ – see front matter © 2009 Published by Elsevier Masson SAS on behalf of the Société Française de Rhumatologie. doi:10.1016/j.jbspin.2009.08.005
É. Bouquillard, B. Combe / Joint Bone Spine 76 (2009) 654–657
655
1. Patients and methods
Table 1 HLA-DR typing (microlymphocytotoxicity).
Following the CHIK fever outbreak in Reunion Island, numerous patients with chronic arthritis of more than three months were seen by a single rheumatologist (BE). Since some showed typical clinical symptoms of RA, they were included in a prospective follow-up study. Inclusion criteria of the 21 patients with possible RA after CHIK fever infection included a history of CHIK fever in 2005 and 2006, a positive CHIK test result for IgM or IgG antibodies, RA according to the 1987 American College of Rheumatology criteria [15], no other definite diagnosis of arthritis, and persistent arthritis symptoms from the onset of CHIK infection to the diagnosis of RA. At baseline, the selected patients underwent clinical examination and history taking; testing for erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, blood cell counts, liver enzyme activity, proteinuria and renal function, rheumatoid factor (ELISA or Waller-Rose reaction), anti-CCP antibodies (CCP2, ELISA, Inova), antinuclear antibodies, and HLA DR alleles (microlymphocytotoxicity); and radiographs of the hands and wrists and anteroposterior feet. In addition, six patients with normal plain-radiographs results underwent MRI of the hands. Patients were followed up clinically every six months and underwent hand and feet radiographs at six, 12 and 24 months.
Patients
HLA-DR antigens
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
04/07 01/13 01/15 02/04 01/15/14 12/07 11/13/01/12 17/04 04/07 01/14 04/07 17/13 04/07 02/11 01/13 07/01/11 04/07
2. Results 2.1. Clinical characteristics at the time of rheumatoid arthritis diagnosis Twenty-one patients (13 females [61.9%]; mean age 57.3 ± 12.2 years) fulfilled the inclusion criteria. None had a personal or family history of inflammatory arthritis. Three patients had a history of smoking. At presentation, 18 patients (85.7%) had symmetric polyarthritis and three (14.3%) had oligoarthritis (≤ five swollen joints). The mean delay between CHIK fever onset and RA diagnosis was 10 months (range 4–18).
2.2. Baseline biological data Laboratory tests for the 21 patients suggested significant systemic inflammation, with mean ESR 40.7 ± 28.1 mm/hr and mean CRP level 37.3 ± 41.1 mg/l (normally < 5 mg/l). Sixteen patients (78.2%) had an abnormal CRP level. Twelve patients (57.1%) were positive for rheumatoid factor, and antiCCP2 antibodies were detected in only six patients (28.6%); 14 patients (66.6%) were positive for rheumatoid factor or anti-CCP antibodies. Two patients had antinuclear antibodies without anti-DNA or anti-ENA antibodies. Fourteen patients (66.6%) were positive for HLA DRB1*04 or DRB1*01 alleles (Table 1).
2.3. Baseline radiography Despite the relatively short disease duration, baseline radiographs of hands and feed were normal for only nine of 21 patients (42.9%) (Table 2). Other patients had typical bone erosions (n = 5) or joint space narrowing (n = 12). For five of six patients with normal radiographs, MRI revealed erosions in the hands. 2.4. Treatment and outcome Patients with a diagnosis of RA received classical disease-modifying antirheumatic drug (DMARD) therapy with methotrexate (n = 19), sulfasalazine (n = 3), leflunomide (n = 2), or hydroxychloroquine (n = 2). One patient was lost to followup after four months. In six patients, after inadequate response to methotrexate, treatment was successful with TNF blockers (etanercept = 4, adalimumab = 2). Fifteen patients (71.4%) received low-dose prednisone (≤ 10 mg/day). After a mean follow-up of 27.6 ± 6.4 months (range 4–21 months) for all patients, radiographs revealed five additional patients with joint space narrowing and 12 more with erosions, despite the use of DMARDs (Table 2). Only four Table 2 Radiographic analysis of hands and feet of 21 patients with RA after Chikungunya fever infection.
Erosions Joint space narrowing Normal radiographs
At diagnosis
At ∼24 months’ follow-up
5 (23.8%) 12 (57.1%) 9 (42.9%)
17 (81.0%) 17 (81.0%) 4 (19.0%)
656
É. Bouquillard, B. Combe / Joint Bone Spine 76 (2009) 654–657
patients (19%) had normal radiographs for hands and feet. Seven patients (33.3%) were still receiving long-term steroids. 3. Discussion We report 21 cases of active and destructive RA following CHIK fever outbreak during 2005 and 2006 in Reunion Island in the Indian Ocean. All patients showed persistent arthritis symptoms from the onset of viral infection to the diagnosis of RA. RA was severe; 80% of patients had radiographic evidence of joint damage and six (29.0%) required therapy with TNF blockers. Our observations raise the questions of how to diagnose RA in the context of viral infection and the role of CHIK fever infection in RA development. Musculoskeletal disorders are common features of CHIK fever. Diffuse joint and muscular pain are usual in the acute phase of the infection, with a resolution of symptoms in most cases in a few days or weeks. Persistent polyarthralgia and arthritis have been reported in 10 to 20% of patients at 20 to 36 months [7,12]. In a retrospective study, three years after the onset of CHIK fever infection, 12% of 107 patients still complained of joint symptoms, and 5.6% had nonerosive arthritis [7]. Clinical features of RA with joint destruction and rheumatoid factor positivity have been described in a limited number of cases after CHIK fever [12,13]. The diagnosis of RA is usually delayed by several months, as we observed in our cohort (10.7 ± 3.9 months). This delay could be explained by the difficulty in differentiating between onset of early RA and persistent arthritis secondary to CHIK fever, an outcome reported in 10 to 20% of patients [6,7,11]. The immunologic profile may help in diagnosis, since two-thirds of our patients were positive for rheumatoid factor and/or anti-CCP antibodies. The positivity for rheumatoid factor in our cases (57.1%) was similar to that for cases in European countries. However, the proportion of patients with anti-CCP antibodies (28.6%) and to lesser extent RA-associated HLA-DR alleles (66.6%) was lower than that for European cases. Currently, no data exist on anti-CCP antibodies in RA patients from Reunion Island; however, we have observed anti-CCP positivity in 52% of our own RA patients from an African origin (unpublished data). As well, HLA-DRB1*01 and DRB1*04 alleles have been associated with RA in African European patients [16], which is consistent with our report. The severity of our cases is of interest. Only nine patients at baseline and four after two years of follow-up had normal plain-radiograph images of hands and feet. In addition, six patients required therapy with TNF blockers because of inadequate response to classical DMARDs, including methotrexate and seven were receiving lont-term steroids. RA development after CHIK infection has been reported in only a limited number of cases [12,13], and it is not possible to rule out that our observed cases are only due to chance. There are no valid data to explore if during this period, incidence of RA was increased in the infected patients compared to the normal population. Anyway, a preliminary cross-sectional study [17] and incidence data from the French social security system (http://www.amelie.fr) support the fact that RA could have occured more frequently following the recent outbreak in the Indian Ocean.
Other alphaviruses, including Ross River virus, O’nyongnyong virus or Sindbis virus, can induce rheumatic manifestations such as persistent arthritis [3]. These viruses seem to be able to enter quickly into macrophages and synovial cells and persist inside the cells, thus preventing immune reactions [18]. Chemokines such as monocyte chemoattractant protein 1, produced by infected cells, could play a role in the recruitment and activation of inflammatory cells in the synovium and in the development of chronic joint inflammation. The possible role of viruses in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus, Sjögren syndrome or RA has been suggested but never clearly demonstrated [19]. Epstein Barr virus, parvovirus B19 [20] and other viruses have been associated with the development of RA. Viral DNA in the synovium of patients with RA and the onset of classically defined RA after such acute viral infections has been reported. Viruses could play the role of superantigens in mediating T- and B-cell interactions and inducting an autoimmune response in susceptible patients. In conclusion, we diagnosed RA in 21 patients after CHIK fever infection in Reunion Island. The first symptoms occurred at the time of viral infection. Outcome was severe in most cases, despite low rate of anti-CCP antibodies and rheumatoid factor and required early treatment with methotrexate in most cases and TNF blockers in four. These cases suggest a role of viral infection in RA initiation. Conflicts of interest None of the authors has any conflicts of interest to declare. References [1] Paquet C, Quatresous I, Solet JL, et al. Chikungunya outbreak in Reunion: epidemiology and surveillance, 2005 to early January 2006. Euro Surveill 2006;11:E060202.3. [2] Jeandel P, Josse R, Durand JP, et al. Exotic viral arthritis: role of alphavirus. Med Trop 2004;64:81–8. [3] Colin de Verdiere N, Molina JM. Rheumatoid manifestations caused by tropical viruses. Joint Bone Spine 2007;74:410–3. [4] Taubitz W, Cramer JP, Kapaun A, et al. Chikungunya fever in travellers: clinical presentation and course. Clin Infect Dis 2007;45:e1–4. [5] Simon F, Parola P, Grandadam M, et al. Chikungunya infection: an emerging rheumatism among travellers returned from Indian Ocean islands. Report of 47 cases. Medicine (Baltimore) 2007;86:123–37. [6] Kennedy AC, Fleming J, Solomon L. Chikungunya viral arthropathy: a clinical description. J Rheumatol 1980;7:231–6. [7] Brighton SW, Prozesky OW, de la Harpe AL. Chikungunya virus infection. A retrospective study of 107 cases. S Afr Med J 1983;63: 313–5. [8] Volpe A, Caramaschi P, Angheben A, et al. Chikungunya outbreak: remember the arthropathy. Rheumatology (Oxford) 2006;45:1449–50. [9] Yazdani R, Kaushik VV. Chikungunya fever. Rheumatology (Oxford) 2007;46:1214–5. [10] Carmona RJ, Shaikh S, Khalidi NA. Chikungunya viral polyarthritis. J Rheumatol 2008;35:935–6. [11] Calabrese J. Emerging viral infections and arthritis: the role of the rheumatologist. Nat Clin Pract Rheumatol 2008;4:2–3. [12] Fourie ED, Morrison JG. Rheumatoid arthritic syndrome after Chikungunya fever. S Afr Med J 1979;56:130–2.
É. Bouquillard, B. Combe / Joint Bone Spine 76 (2009) 654–657 [13] Brighton SW, Simson IW. A destructive arthropathy following Chikungunya virus arthritis: a possible association. Clin Rheumatol 1984;3:253–8. [14] Bouquillard E, Combe B. Rheumatoid arthritis after chikhungunya fever. Ann Rheum Dis 2009;68:1505–6. [15] Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315–24. [16] Hughes LB, Morrison D, Kelley JM, et al. The HLA-DRB1 shared epitope is associated with susceptibility to rheumatoid arthritis in African Americans through European genetic admixture. Arthritis Rheum 2008;58:335–7.
657
[17] Ribera A, Jaffar Bandjee M, Mohy F, et al. Emerging chronic rheumatologic demonstrations post-Chikungunya in La Reunion. EULAR 2008, Paris, Abstract OP-0222. [18] Suhrbier A, La Linn M. Clinical and pathologic aspects of arthritis due to Ross River virus and other alphaviruses. Curr Opin Rheumatol 2004;16:374–9. [19] Vaughan JH. Viruses and autoimmune disease. J Rheumatol 1996;23:1831–3. [20] Kerr JR. Pathogenesis of human parvovirus B19 in rheumatic disease. Ann Rheum Dis 2000;59:672–83.