Rheumatic manifestations in patients with Chikungunya infection.
Key words: Chikungunya virus, Arthritis, Treatment, Corticosteroids, Disease modifying anti-rheumatic drugs
La infeccion por el virus del chikungunya (CHIKV) es una causa comun de artritis febril. Las manifestaciones mas comunes de la infeccion aguda son fiebre, poliartralgias o poliartritis simetrica, mialgias y erupcion maculopapular en la piel. Hasta un 80% de los pacientes desarrollan manifestaciones musculoesqueleticas que persisten por mas de 3 meses, afectando la calidad de vida. Las manifestaciones cronicas mas comunes son poliartralgias, poliartritis y mialgias las cuales pueden ser persistentes o fluctuantes. Los dedos de las manos y los pies, las munecas, las rodillas y los tobillos son los mas afectados pero envolvimiento de las articulaciones proximales y axiales puede ocurrir en la etapa cronica. Las manifestaciones cronicas de CHIKV pueden parecerse a algunas enfermedades reumaticas de tejido conectivo. En adicion, CHIKV puede causar crioglobulinemia y podria inducir artritis reumatoide y espondiloartropatia seronegativa en pacientes con predisposicion genetica. Los Centros para el Control y Prevencion de Enfermedades recomiendan acetaminofen y antiinflamatorios no esteroideos para tratar las manifestaciones reumaticas agudas del CHIKV. Sin embargo, algunos estudios demuestran que el tratamiento por 1-2 meses con dosis bajas de corticosteroides es efectivo para aliviar los sintomas reumaticos agudos. Por otro lado, la hidroxicloroquina combinada con corticosteroides o con otros antirreumaticos modificadores de la enfermedad (DMARDs, por sus siglas en ingles) ha sido efectiva para el tratamiento de las manifestaciones reumaticas cronicas de CHIKV. Metotrexato y sulfasalazina (por si solos o en combinacion) tambien han sido beneficiosos para tratar la artritis cronica. Los pacientes afectados con CHIKV deben ser vigilados continuamente para identificar aquellos con artritis cronica que podrian beneficiarse de una evaluacion reumatologica y de tratamiento temprano con DMARDs.
Chikungunya virus (CHIKV) is a single-stranded RNA alphavirus transmitted to humans by the Aedes mosquitoes (1). It causes an acute febrile illness with polyarthralgias which are often severe and debilitating (2-5). After its discovery in 1952 in Tanzania, few sporadic outbreaks were described in Africa and Asia (2). In 2005, the virus underwent a mutation that enabled transmission through Aedes albopticus, a widely distributed mosquito (2, 4, 5). Since then, numerous CHIKV epidemics have been reported in Africa, South East Asia, the Indian Ocean islands, and Europe. More recently, in 2013, CHIKV transmission was described for the first time in the Caribbean. Since then, CHIKV has spread through the Antilles and is currently causing an epidemic in the Caribbean islands of Saint Martin, US Virgin Islands, Puerto Rico, and Dominican Republic, among others (6, 7).
Acute CHIKV infection is characterized by high fever and severe polyarthralgias, after an incubation period that lasts from 2 to 7 days (2, 3, 8-11). A retrospective cohort study in La Reunion reported that 96% of patients with acute CHIKV infection presented with arthralgias involving more than one joint, 73% had symmetrical joint involvement, and 32% had associated joint swelling (3). Distal joints such as fingers, wrists, knees, ankles and, toes are the most frequently involved (3, 10-13). Although some reports have described involvement of temporomandibular joints, elbows, shoulders, neck, lower back and hips, this appears to occur less frequently (11, 13, 14). Muscle manifestations are also common in CHIKV infection. Myalgias have been reported in up to 81% of patients (8). Although uncommon, myositis with elevation of creatinine phosphokinase has been described in one series and animal experimental models (15, 16). Additional reported symptoms include fatigue/general malaise (43-45%), gastrointestinal symptoms (nausea, vomiting, diarrhea; 47%), and rash (17-40%) (2, 3, 8, 9, ll). The most common skin lesion is a maculopapular eruption involving the face, trunk, and limbs occurring during the first week of illness. Pruritus is reported in 4% to 20% of patients and bullous skin lesions in 3% of patients with skin manifestations (2, 3, 11, 17).
Chronic musculoskeletal manifestations
Patients with CHIKV infection may continue to experience musculoskeletal symptoms that persist for a long period of time causing severe impairment in their quality of life. Studies report that 40 to 80% of patients with CHIKV infection develop chronic rheumatic symptoms (8-10, 12, 18-21). A prospective cohort study of 203 CHIKV infected patients in India found that 46% experienced persistent joint pain 10 months after the acute infection (10). Similarly, Schilte et al. prospectively studied 76 patients with acute CHIKV infection in La Reunion and reported that 69% had persistent arthralgias after 36 months of follow-up (18). Of these patients, 45% reported continuous arthralgias and 24% had partial recovery with relapsing symptoms. Most of these patients (90%) reported symmetrical joint involvement, 63% had associated local joint swelling and 39% also had chronic myalgias (18).
The most frequently affected joints during the chronic stages are the knees, ankles, and small joints of the upper and lower extremities (10,12,18,19). However, some authors have noted greater involvement of proximal (elbows, shoulders, and hips) and axial joints (neck and sacroiliac joints) during the chronic stage of CHIKV infection compared to the predominant distal joint involvement in the acute stage (10, 14). Although arthralgia is the most common musculoskeletal manifestation, many authors have described the presence of inflammatory polyarthritis, tenosynovitis, enthesopathies, and bone erosions (10, 11, 14). Morning stiffness, myalgias and edema of upper and lower extremities have also been described several months after the acute infection (12, 18). Table 1 summarizes the most common musculoskeletal manifestations of CHIKV infection.
Other rheumatic disorders
Similar to other viral illnesses such as hepatitis C virus, CHIKV infection has been associated with a high prevalence of mixed cryoglobulinemia (22). A study by Oliver et al. found that 94% of travelers returning from the Indian Ocean islands with confirmed CHIKV infection had cryoglobulinemia at least once during a 14-month follow-up (22). Fifty-five percent of patients tested after one year of disease onset had persistent cryoglobulinemia. Authors noted that the presence of cryoglobulins coincided with persistent arthralgias. Interestingly, in this study, those with mixed cryoglobulinemia did not present with palpable purpura or other clinical manifestations of small vessel vasculitis.
While fever and arthralgia/arthritis are the most common symptoms of CHIKV infection, other clinical features have been reported. In a cohort study from La Reunion of 610 hospitalized patients with extraarticular CHIKV manifestations, 11% presented with encephalitis, 2% with meningoencephalitis, 2% with seizures, 1% with Guillain-Barre syndrome, 7% with hepatitis or hepatic insufficiency, and 6% with myocarditis (2). In addition, ophthalmologic involvement manifested as optic neuritis, retinitis, episcleritis, and iridocyclitis has been documented in few case series (23, 24). Other nonrheumatic manifestations that have a significant impact in the quality of life such as sleeping disorders (56%), depression (50%), memory impairment (44%), and cognitive disorders (39%) have been reported several months after infection (18).
Laboratory findings during acute CHIKV infection are non-specific. In a retrospective cohort study of 157 patients with CHIKV infection, lymphopenia (<1000 [10.sup.9]/L) was the most common laboratory abnormality; this was observed in 79% of patients (3). Severe lymphopenia (<500 [10.sup.9]/L) was seen in 39%. Forty-four percent of patients had thrombocytopenia (<150 [10.sup.9]/L), 55% had hypocalcemia, and 10% had a two-fold increase in transaminases. Inflammatory markers such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are frequently elevated during the acute infection and may remain elevated in patients with chronic musculoskeletal symptoms (8, 10, 14, 25).
A definitive diagnosis of CHIKV infection is made by detection of viral RNA in serum by reverse transcription-polymerase chain reaction (RT-PCR) or the detection of serum IgM and/or IgG antibodies by enzyme-linked immunosorbent assay (26, 27). CHIKV RNA may be detected in a patient's serum during the first 7 days of infection while serum antibodies usually appear by the end of the first week (26, 27). Panning et al. prospectively studied 63 patients with confirmed CHIKV infection and found 100% of patients evaluated during the first 4 days of illness had a positive RT-PCR and all had IgM antibodies after the first 5 days of illness (26). IgM antibodies may persist up to 36 months post infection (18, 28).
The differential diagnosis of CHIKV infection is dependent on the geographical area and the patient's travel and exposure history. Dengue virus, transmitted by the Aedes mosquitoes and thus prevalent in similar geographical areas as CHIKV, should be considered. While dengue shares several clinical manifestations with CHIKV, other features including retroorbital pain, petechiae, hemorrhage and severe thrombocytopenia are more common in dengue (27). Parvovirus B19, transmitted by respiratory aerosol secretions, also causes fever with symmetrical polyarthritis in adults; however outbreaks tend to occur in a seasonal pattern (late winter) and patients have a history of exposure to an infected individual (usually infants and children) (29). Other causes of acute febrile illness such as leptospirosis, adenovirus, enterovirus, measles, and rubella should also be considered. Moreover, patients with persistent arthralgias, and particularly those with arthritis, should be followed closely and examined for other serious causes of chronic arthritis including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), spondyloarthritis, and vasculitis, among others.
Chikungunya and autoimmune connective tissue diseases
The clinical manifestations in acute and chronic CHIKV infection, such as arthralgias, arthritis, myalgias, and rash, may resemble those of some autoimmune connective tissue diseases such as RA, seronegative arthritis and SLE (10, 20). In fact, a longitudinal cohort of CHIKV-infected patients in India, reported that 36% of patients with persistent arthralgias met the American College of Rheumatology (ACR) classification for RA 10 months post-infection (10, 30). Moreover, several authors have reported the development of RA after CHIKV infection (10,14,25,31). Rheumatoid factor (RF) and anti-citrullinated protein (CCP) antibodies were documented in many of these patients as well as radiographic findings common to RA such as joint space narrowing, effusions, and bone erosions (10, 14, 25, 28, 31). However, other authors have not noted any structural joint damage in patients with post-CHIKV RA (14, 31). Interestingly, Boquillard et al. described that 14 of 21 (66%) patients with post-CHIKV RA were HLA DRB1*01 or DRB1*04 positive, alleles known to be associated with RA (25). In addition, seronegative spondyloarthropathies (psoriatic arthritis and ankylosing spondylitis), have also been reported after CHIKV infection, particularly in those with positive HLA B27 (14,28,31). These findings suggest CHIKV infection may induce autoimmunity in susceptible individuals, a concept that has been well established for autoimmune rheumatic conditions (32, 33).
The clinical course of CHIKV infection in patients with pre-existing autoimmune rheumatic diseases has not been thoroughly examined. Chopra et al. described 2 patients with psoriatic arthritis and one with reactive arthritis, previously in clinical remission, who experienced a relapse of their disease after CHIKV infection (14). Reactivation and worsening of psoriatic skin disease has also been reported (17).
Pathophysiology of articular involvement
The exact pathophysiology for CHIKV-induced joint disease remains uncertain. Most data are based on several animal (mouse and macaque) model studies and few human studies (34-40). It is not entirely clear whether joint damage is caused by direct viral effect or by viral activation of the immune system and its associated inflammatory reactions. Viral RNA was found in muscles, lymph nodes, spleen, liver, and joints of CHIKV inoculated mice and macaques (34-36). In addition, viral RNA has been found in synovial biopsies of patients with acute and chronic CHIKV infection along with cellular infiltrates consisting of activated macrophages, natural killer cells and T cells (35). Several studies have shown that macrophages seem to have a major role in joint injury (34,36, 37). Experimental mouse models with depleted macrophages do not develop joint disease when inoculated with CHIKV (34, 36, 37). In addition, the most commonly described cytokines in animal experimental models and few human studies of CHIKV infection are IL-1[beta], IL-6, IL-8, IL-12, INF-[alpha], and MCP-1; all of which are associated with macrophage activity (34, 35, 37-40).
The mechanism behind the development of persistent CHIKV arthralgia/arthritis has not been clearly established. Scant data suggest viral persistence in joint tissues and thus perpetuation of chronic inflammation (35,40). A rapid humoral response seems to be important in eliminating the virus and protecting from chronic disease. Kam et al. noted a higher viremia was associated with more severe illness, early CHIKV IgG production, and complete clinical recovery in a cohort of 30 CHIKV-infected patients (41). Conversely, some authors have noted a higher viral load during the acute phase creates stronger cellular and molecular innate immune activity, and higher cytokine levels; thus, causing greater joint damage (35,38). High levels of IL-1[beta], IL-6, IL-12, and IL-17 have been described in patients with persistent CHIKV symptoms (8, 35, 38). Most of these cytokines are produced by activated macrophages in response to antigenic stimuli, further denoting the pathological role of macrophages in CHIKV infection.
Risk factors for chronic musculoskeletal involvement
Risk factors for developing chronic rheumatic symptoms after CHIKV infection have not been clearly established and reports have yielded inconsistent data. Few small prospective studies have depicted associations between development of chronic symptoms and female gender, older age, comorbid conditions and severity of symptoms at onset of infection (9, 12, 14, 18, 20,42). Arterial hypertension, diabetes mellitus, osteoarthritis and dyslipidemia have been associated with the development of chronic arthralgias in several longitudinal studies (12, 18, 42). Gerardin et al. noted that patients with two or more comorbid conditions were more likely to experience long-lasting musculoskeletal symptoms after CHIKV infection (42). These findings are not surprising as these comorbid conditions are linked to increased morbidity in other infectious disorders. In addition, severe rheumatic involvement and joint pain during the acute phase of CHIKV infection have been associated with chronic rheumatic symptoms (42). However, other authors have not found associations between indicators of disease severity such as number of joints affected, viral load, hospitalizations and the development of persistent symptoms (9, 18, 21).
Anti inflammatory drugs
There are no established evidence-based treatment guidelines for acute CHIKV infection, causing uncertainty among clinicians and heterogeneity of treatment in the community. The Centers for Disease Control and Prevention (CDC) recommends supportive treatment that includes rest, adequate hydration with fluids, and acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) for fever and joint pains (7).
Data regarding the role of corticosteroids are controversial. In a small randomized control trial, Padmakumar et al. found that patients treated with aceclofenac (a diclofenac analog [200 mg/day]), hydroxychloroquine (400 mg/day) and prednisone (10 mg/day) and those treated with aceclofenac and prednisone (same doses) during the first 6 weeks ot CHIKV infection had a greater reduction in the perception of pain (using a visual analog scale) and improvement in activities of daily living scores compared to patients receiving aceclofenac and hydroxychloroquine or aceclofenac alone (43). Symptoms returned in all groups after discontinuation of therapy 6 weeks later. Simon et al. observed dramatic improvement of acute and chronic rheumatic symptoms in CHIKV infected travelers treated with corticosteroids (44). However, corticosteroid doses were not described in detail. These data suggest that a low-dose corticosteroid treatment can be beneficial in relieving the acute rheumatic symptoms of CHIKV infection and in improving quality of life. However, a prolonged course (1-2 months) with slow tapering may be required to prevent rebound symptoms (22, 43, 44). Sissoko et al. noted that 76% of patients who received treatment with corticosteroids reported being satisfied with their therapy compared to 35% of patients who received NSAIDs and acetaminophen alone (12).
Corticosteroids have also been used successfully to treat other uncommon but serious complications of CHIKV infection such as optic neuritis and encephalitis (24, 45). Rose et al. reported that 9 out of 10 patients who developed acute optic neuritis during CHIKV infection experienced an improvement in visual acuity after treatment with pulse doses of intravenous methylprednisolone followed by oral prednisone tapper over one month (24). In addition, Gauri et al. reported a patient with demyelinating encephalitis presenting with vertigo, dysarthria, and ataxia who improved with intravenous steroid therapy (45).
Disease modifying anti-rheumatic drugs
Data are also limited regarding the appropriate treatment for CHIKV-induced chronic arthritis. Because of the pathophysiological and clinical resemblance to inflammatory arthritides, several disease modifying anti-rheumatic drugs (DMARDs) have been studied. A small randomized-control trial comparing chloroquine to meloxicam found no statistical difference in symptom improvement between treatment groups (46). Evidence with hydroxychloroquine treatment in combination with NSAIDs has not been favorable (43). However, when used in combination with other DMARDs (methotrexate [MTX] and sulfasalazine) or steroids, the efficacy seems to increase (43,47). Many authors have reported chronic CHIKV arthritis effectively treated with methotrexate, alone or in combination with sulfasalazine (25, 28, 47, 48). Pandya et al. reported that 49% of patients who were treated with MTX (15-20 mg/weekly) and hydroxychloroquine (400 mg/day) achieved ACR 20 clinical response, 20% achieved ACR 50 response, and 5% ACR 70 response after 16 weeks of therapy (47). Ganu et al. also noted that treatment with MTX and sulfasalazine was beneficial in 71% of patients with persistent arthritis 3 months post CHIKV infection and 13% of patients responded to MTX alone (48). Tumor necrosis factor blockers were successful in 6 patients with RA diagnosed post-CHIKV infection who failed MTX therapy (25). However, caution should be exerted if considering biologic agents as etanercept was shown to aggravate articular disease in a mouse model inoculated with Ross River virus (an alphavirus similar to CHIKV) (49).
It is not clear when it is appropriate to initiate DMARD therapy for CHIKV-induced arthritis. However, immunosuppressive agents should be reserved for the chronic stages of CHIKV infection. Mouse models show early treatment with MTX may cause a more severe illness (49, 50). Ribera et al. found that patients with rheumatic symptoms persisting longer than 3 weeks were at increased risk for developing inflammatory polyarthritis and recommended rheumatologic evaluation at no longer than 3 months of symptoms persistence (51). Table 2 depicts treatment options for acute and chronic arthritis induced by CHIKV.
In summary, CHIKV infection can lead to chronic musculoskeletal manifestations. The most frequent are symmetrical polyarthralgias and polyarthritis. Myalgias may also persist several months following acute infection. The chronic manifestations of CHIKV may resemble those of an autoimmune inflammatory arthritis with or without associated joint damage. The CDC currently recommends treatment of acute CHIKV symptoms with acetaminophen and NSAIDs (7). However, some studies suggest that an extended course (1-2 months) of low-dose corticosteroids, started at the onset of disease, is successful in relieving the acute rheumatic symptoms of CHIKV and thus improving the patient's quality of life (22, 43, 44). Nonetheless, prospective longitudinal studies are needed to ascertain the duration of therapy and their role in preventing CHIKV-induced chronic arthritis. In addition, close follow-up of these patients is essential to evaluate chronic CHIKV manifestations and to screen those who would benefit from an evaluation by a rheumatologist and further treatment with DMARDs. Monitoring inflammatory markers (ESR, CRP) and examining autoantibodies (RF, anti-CCP, and antinuclear antibodies) should be considered in patients with chronic arthritis. Also, imaging studies such as plain radiographs, sonograms, or magnetic resonance should be performed when deemed appropriate to evaluate for erosive or inflammatory changes.
(1.) Staples JE, Breiman RE, Powers AM. Chikungunya fever: an epidemiological review of a re-emerging infectious disease. Clin Infect Dis 2009;49:942-948.
(2.) Economopoulou A, Dominguez M, Helynck B, et al. Atypical Chikungunya virus infections: clinical manifestations, mortality and risk factors for severe disease during the 2005-2006 outbreak on Reunion. Epidemiol Infect 2009;137:534-541.
(3.) Borgherini G, Poubeau P, Staikowsky F, et al. Outbreak of chikungunya on Reunion Island: early clinical and laboratory features in 157 adult patients. Clin Infect Dis 2007;44:1401-1477. Epub 2007 Apr 18.
(4.) Horcada ML, Diaz-Calderon C, Garrido L. Chikungunya fever. Rheumatic manifestations of an emerging disease in Europe. Reumatol Clin 2014;pii: S1699-258X(14) :00158-2.
(5.) Ali Ou Alla S, Combe B. Arthritis after infection with Chikungunya virus. Best Pract Res Clin Rheumatol 2011;25:337-46.
(6.) Rodriguez, A. Fiebre Chikungunya. Revista Puertorriquena de Medicina y Salud Publica 2014;44: 6-9.
(7.) Chikungunya virus. [Centers for Disease Control and Prevention Web site]. November 4, 2014. Available at: Url: http://www.cdc.gov/chikungunya. Accessed December 8, 2014.
(8.) Chopra A, Anuradha V, Ghorpade R, Saluja M. Acute Chikungunya and persistent musculoskeletal pain following the 2006 Indian epidemic: a 2-year prospective rural community study. Epidemiol Infect 2012; 140:842-850.
(9.) Win MK, Chow A, Dimatatac F, Go CJ, Leo YS. Chikungunya fever in Singapore: acute clinical and laboratory features, and factors associated with persistent arthralgia. J Clin Virol 2010;49:111-114.
(10.) Manimunda SP, Vijayachari P, Uppoor R, et al. Clinical progression of chikungunya fever during acute and chronic arthritic stages and the changes in joint morphology as revealed by imaging. Trans R Soc Trop Med Hyg 2010,104:392-399.
(11.) Simon F, Parola P, Grandadam M, et al. Chikungunya infection: an emerging rheumatism among travelers returned from Indian Ocean islands. Report of 47 cases. Medicine (Baltimore). 2007;86:123-137.
(12.) 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.
(13.) Lui NL, Leong HN, Thumboo J. Polyarthritis in four patients with chikungunya arthritis. Singapore MedJ. 2012 Apr;53(4):241-3.
(14.) Chopra A, Anuradha V, Lagoo-Joshi V, Kunjir V, Salvi S, Saluja M. Chikungunya virus aches and pains: an emerging challenge. Arthritis Rheum 2008;58:2921-2922.
(15.) Ozden S, Huerre M, Riviere JP, et al. Human muscle satellite cells as targets of Chikungunya virus infection. PLoS One 2007;2:e527.
(16.) Morrison TE, Oko L, Montgomery SA, et al. A mouse model of chikungunya virus-induced musculoskeletal inflammatory disease: evidence of arthritis, tenosynovitis, myositis, and persistence. Am J Pathol 2011; 178:32-40.
(17.) Bhat RM, Rai Y, Ramesh A, et al. Mucocutaneous manifestations of chikungunya Fever: a study from an epidemic in coastal karnataka. Indian J Dermatol 2011;56:290-294.
(18.) Schilte C, Staikowsky F, Couderc T, et al. Chikungunya virus-associated long-term arthralgia: a 36-month prospective longitudinal study. PLoS Negl Trop Dis 2013;7:e2137. Epub 2013 Mar 21.
(19.) Borgherini G, Poubeau P, Jossaume A, et al. Persistent arthralgia associated with chikungunya virus: a study of 88 adult patients on Reunion Island. Clin Infect Dis 2008;47:469-475.
(20.) Essackjee K, Goorah S, Ramchurn SK, Cheeneebash J, Walker-Bone K. Prevalence of and risk factors for chronic arthralgia and rheumatoid-like polyarthritis more than 2 years after infection with chikungunya virus. Postgrad MedJ 2013;89:440-447.
(21.) Larrieu S, Pouderoux N, Pistone T, et al. Factors associated with persistence of arthralgia among Chikungunya virus-infected travellers: report of 42 French cases. J Clin Virol 2010;47:85-88.
(22.) Oliver M, Grandadam M, Marimoutou C, et al. Persisting mixed cryoglobulinemia in Chikungunya infection. PLoS Negl Trop Dis 2009;3:e374.
(23.) Mahendradas P, Ranganna SK, Shetty R, et al. Ocular manifestations associated with chikungunya. Ophthalmology 2008; 115:287-291.
(24.) Rose N, Anoop TM, John AP, Jabbar PK, George KC. Acute optic neuritis following infection with chikungunya virus in southern rural India. Int J Infect Dis 2011;15:e147-150.
(25.) Bouquillard E, Combe B. A report of 21 cases of rheumatoid arthritis following Chikungunya fever. A mean follow-up of two years. Joint Bone Spine 2009;76:654-657.
(26.) Panning M, Grywna K, Van Esbroeck M, Emmerich P, Drosten C. Chikungunya fever in travelers returning to Europe from the Indian Ocean region, 2006. Emerg Infect Dis 2008; 14:416-422.
(27.) J. Erin Staples, Susan L. Hills, Ann M. Powers. Infectious Diseases Related to Travel. In: Gary W. Brunette, Editor in Chief. CDC Health Information for International Travel 2014. New York: Oxford University Press; 2014.
(28.) Malvy D, Ezzedine K, Mamani-Matsuda M, et al. Destructive arthritis in a patient with chikungunya virus infection with persistent specific IgM antibodies. BMC Infect Dis 2009;9:200.
(29.) Franssila R, Hedman K. Infection and musculoskeletal conditions: Viral causes of arthritis. Best Pract Res Clin Rheumatol 2006;20:1139-1157.
(30.) Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315-324.
(31.) Mathew AJ, Goyal V, George E, Thekkemuriyil DV, Jayakumar B, Chopra A; Trivandrum COPCORD Study Group. Rheumatic-musculoskeletal pain and disorders in a naive group of individuals 15 months following a Chikungunya viral epidemic in south India: a population based observational study. IntJ Clin Pract 2011 ;65:1306-1312.
(32.) Nelson P, Rylance P, Roden D, Trela M, Tugnet N. Viruses as potential pathogenic agents in systemic lupus erythematosus. Lupus 2014;23: 596-605.
(33.) Vaughan JH. Viruses and autoimmune disease. J Rheumatol 1996;23: 1831-1833.
(34.) Gardner J, Anraku I, Le TT, Larcher T, Major L, Roques P, Schroder WA, Higgs S, Suhrbier A. Chikungunya virus arthritis in adult wild-type mice. J Virol 2010;84:8021-8032.
(35.) Hoarau JJ, Jaffar Bandjee MC, Krejbich Trotot P, et al. Persistent chronic inflammation and infection by Chikungunya arthritogenic alphavirus in spite of a robust host immune response. J Immunol 2010; 184:5914-5927.
(36.) Labadie K, Larcher T, Joubert C, et al. Chikungunya disease in nonhuman primates involves long-term viral persistence in macrophages. J Clin Invest 2010;120:894-906.
(37.) Lidbury BA, Rulli NE, Suhrbier A, et al. Macrophage-derived proinflammatory factors contribute to the development of arthritis and myositis after infection with an arthrogenic alphavirus. J Infect Dis 2008,T97:1585-1593.
(38.) Chow A, Her Z, Ong EK, et al. Persistent arthralgia induced by Chikungunya virus infection is associated with interleukin-6 and granulocyte macrophage colony-stimulating factor. J Infect Dis 2011;203:149-157.
(39.) Chaaitanya IK, Muruganandam N, Sundaram SG, et al. Role of proinflammatory cytokines and chemokines in chronic arthropathy in CHIKV infection. Viral Immunol 2011;24:265-721.
(40.) Hawman DW, Stoermer KA, Montgomery SA, et al. Chronic joint disease caused by persistent Chikungunya virus infection is controlled by the adaptive immune response. J Virol 2013; 87: 13878-13888. doi: 10.1128/ JVI.02666-13. Epub 2013 Oct 16.
(41.) Kam YW, Simarmata D, Chow A, et al. Early appearance of neutralizing immunoglobulin G3 antibodies is associated with chikungunya virus clearance and long-term clinical protection. J Infect Dis 2012; 205: 114754. doi: 10.1093/infdis/jis033. Epub 2012 Mar 1.
(42.) Gerardin P, Fianu A, Michault A, et al. Predictors of Chikungunya rheumatism: a prognostic survey ancillary to the TELECHIK cohort study. Arthritis Res Ther 2013; 15: R9.
(43.) Padmakumar B, Jayan JB, Menon RMR, Krishnankutty B, Payippallil R, Nisha RS. Comparative evaluation of four therapeutic regimes in chikungunya arthritis: a prospective randomized parallel-group study. Indian Journal of Rheumatology 2009; 4; 94-101.
(44.) Simon F, Parola P, Grandadam M, et al. Chikungunya infection: an emerging rheumatism among travelers returned from Indian Ocean islands. Report of 47 cases. Medicine (Baltimore) 2007;86:123-137.
(45.) Gauri LA, Ranwa BL, Nagar K, Vyas A, Fatima Post chikungunya brain stem encephalitis. J Assoc Physicians India 2012; 60: 68-70.
(46.) Chopra A, Saluja M, Venugopalan A. Effectiveness of chloroquine and inflammatory cytokine response in patients with early persistent musculoskeletal pain and arthritis following chikungunya virus infection. Arthritis Rheumatol 2014; 66: 319-326.
(47.) Pandya S. Methotrexate and hydroxychloroquine combination therapy in chronic chikungunya arthritis: a 16 week study. Indian Journal of Rheumatology 2008;3:93-97.
(48.) Ganu MA, Ganu AS. Post-chikungunya chronic arthritis-our experience with DMARDs over two year follow up. J Assoc Physicians India 2011;59:83-86.
(49.) Zaid A, Rulli NE, Rolph MS, Suhrbier A, Mahalingam S. Disease exacerbation by etanercept in a mouse model of alphaviral arthritis and myositis. Arthritis Rheum 2011;63:488-491.
(50.) Taylor A, Sheng KC, Herrero LJ, Chen W, Rulli NE, Mahalingam S. Methotrexate treatment causes early onset of disease in a mouse model of Ross River virus-induced inflammatory disease through increased monocyte production. PLoS One 2013;8:e71146.
(51.) Ribera A, Degasne I, Jaffar-Bandjee MC, Gasque P. [Chronic rheumatic manifestations following chikungunya virus infection: clinical description and therapeutic considerations]. Med Trop (Mars) 2012;72:83-85. French.
Mariangeli Arroyo-Avila, MD; Luis M. Vila, MD
Division of Rheumatology, Department of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, PR
Supported in part by an unrestricted educational grant from Abbvie. The authors have no conflicts of interest to disclose.
Address correspondence to: Luis M. Vila, MD, Division of Rheumatology, University of Puerto Rico Medical Sciences Campus, PO Box 365067, San Juan, PR 00936-5067. E-mail: firstname.lastname@example.org
Table 1. Musculoskeletal manifestations of chikungunya infection. Features Comments Acute manifestations Polyarthralgias/arthritis Fingers, wrists, knees, ankles and toes are the most frequently involved. Symmetrical pattern is common (3,10-13). Myalgias Very common (8) Myositis Uncommon, rhabdomyolysis is rare (15,16). Cryoglobulinemia Common but manifestations of vasculitis are rare (22). Chronic manifestations Polyarthralgias/arthritis Fingers, wrists, knees, ankles and toes are the most frequently involved. Occasionally, elbows, shoulders, neck, sacroiliacs and hips are affected (10,12,14,18,19). Symptoms may be persistent or remitting-relapsing (17). Myalgias Very common (12,18) Tenosynovitis/enthesopathies Rare (10,11,14) Bone erosions Rare (10,14, 25) Cryoglobulinemia Common but manifestations of vasculitis are rare (22). Table 2. Treatment of acute and chronic arthritis induced by chikungunya infection. Drug Comments Acute treatment Acetaminophen For relief of fever and pain per CDC NSAIDs recommendations (7) Corticosteroids Combination therapy with prednisone 10 mg/ day (or equivalent) and NSAIDs wlth/ wlthout hydroxychloroquine was superior to other combinations without prednisone (43). Chronic treatment (> 3 months) NSAIDs No differences between meloxicam and chloroquine treatment groups (46) Chloroquine Hydroxychloroquine Effective in combination with corticosteroids or other DMARDs (methotrexate/sulfasalazine) (43, 47). No studies have been conducted with hydroxychloroquine alone. Methotrexate Methotrexate (15/20 mg/weekly) in combination with hydroxychloroquine (400 mg/daily) was effective after 16 weeks of therapy (47). Not recommended during early CHIKV infection (49, 50). Sulfasalazine Beneficial in combination with methotrexate in 71% of patients with persistent CHIKV arthritis > 3 months (48). Monotherapy has been successful in few case reports (25). TNF-[alpha] blockers Successful in 6 patients (etanercept = 4, adalimubab = 2) who failed methotrexate therapy in one case series (25). NSAIDs: nonsteroidal anti-inflammatory drugs; CDC: Centers for Disease Control and Prevention; DMARDs: disease modifying anti-rheumatic drugs; TNF: tumor necrosis factor
|Printer friendly Cite/link Email Feedback|
|Author:||Arroyo-Avila, Mariangeli; Vila, Luis M.|
|Publication:||Puerto Rico Health Sciences Journal|
|Date:||Jun 1, 2015|
|Previous Article:||Recent advances in dengue: relevance to Puerto Rico.|
|Next Article:||Number and type of meals consumed by children in a subset of schools in San Juan, Puerto Rico.|