Department of Paediatrics and Child Health and 1 Department of Rheumatology, Nelson R. Mandela School of Medicine, University of KwaZulu Natal, Private Bag X7, Congella, 4013, South Africa.
Correspondence to: K. Chinniah, Department of Paediatrics and Child Health, Nelson R. Mandela School of Medicine, University of KwaZulu Natal, Private Bag X7, Congella, 4013, South Africa. E-mail: chinniahk2{at}ukzn.ac.za
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Abstract |
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Method. Retrospective review of 132 children with arthritis who were tested for HIV infection.
Results. Thirty-five (27%) of the children were HIV infected and the male to female ratio was 2.5:1 (P = 0.02). Arthritis was the presenting feature of HIV infection in 78% of these children. The remaining 97 (73%) were diagnosed as having juvenile idiopathic arthritis. Spondyloarthropathy-like features were found in 34% of HIV-infected children compared with 5% of uninfected children.
Conclusion. The high prevalence of HIV infection in 27% of children, the predominance of males and the increased prevalence of spondyloarthropathy-like features, supports a causal relationship between HIV infection and arthritis.
KEY WORDS: Arthritis, Juvenile idiopathic arthritis (JIA), Spondyloarthropathy (SPA), HIV infection, Children
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Introduction |
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Articular manifestations have been reported to occur at any stage of HIV infection but tend to be more prevalent in the late stages. The pathogenesis of arthritis in patients with HIV infection is not completely understood but is probably multifactorial and may involve direct viral invasion of joint tissue, indirect involvement via an activated immune system, genetic and environmental factors.
HIV disease has reached pandemic proportions with an estimated 40 million people worldwide living with AIDS of whom about 26.6 million are estimated to be residing in sub-Saharan Africa [20]. An antenatal survey in 2002, in KwaZulu-Natal, South Africa, documented an HIV prevalence rate of 37% in pregnant women [21]. The vertical transmission rate in Africa is estimated to be between 30 and 35% resulting in the majority of paediatric HIV/AIDS being due to vertical transmission [22]. It is estimated that in the absence of antiretroviral therapy only 50% of vertically infected children will survive to 2 yr and 40% to 5 yr with subsequent low mortality for an undetermined period [23]. The only data on HIV prevalence in South African children come from a recent Human Science Research Council Household Survey in 2002, of all population groups, which reported a 5.6% prevalence of HIV infection in children between the ages of 2 and 14 yr [24].
A review of published literature revealed only a few reports of children with HIV infection and arthritis. These reports include a study by Martinez-Rojano et al. [1] who examined 26 HIV-infected children for rheumatological manifestations and found two children with joint pathology, one with septic arthritis and the other with arthralgia; Smith et al. [2] detected HIV infection in three of 61 children with septic arthritis of the shoulder; Pappo et al. [3] reported HIV positivity in three of four children with septic arthritis in a survey of 139 children with haemophilia; Schlesinger et al. [4] noted a child with concomitant HIV infection and Lyme arthritis, and recently Ahuja et al. [5] reported a 5-yr-old boy with HIV infection and arthritis of the large joints.
From 1997 an increasing number of children referred to our clinic with arthritis of unknown origin were found to be HIV infected. Despite extensive investigations no other cause for the arthritis, except HIV infection, could be identified. This created a dilemma as to whether these children had JIA and coincidental HIV infection or whether HIV infection was causally related to the arthritis. Thus we undertook this study at our Paediatric Rheumatology Clinic to determine the prevalence of HIV infection in Black African children with arthritis of unknown origin, and to compare the pattern of arthritis in children who were HIV infected with those who were HIV uninfected with JIA.
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Patients and methods |
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An enzyme linked immunosorbent assay [HIV-1/2 ELISA, Abbott (USA), Axsym] for HIV-1 and -2 antibodies was performed in children in whom informed consent was obtained following appropriate pre-test counselling. A duplicate unlinked test for antibodies to HIV-1 and -2 using the HIV ELISA Abbott (USA) kit was performed on children with positive or indeterminate results. A diagnosis of HIV infection was made when two ELISA tests were positive in children over the age of 15 months and appropriate post-test counselling was undertaken. HIV/AIDS was classified according to the Centers for Disease Control (CDC) clinical criteria [26], and when available, the CD4 counts were measured to determine the CDC immunological stage of HIV disease. T-cell subsets were analysed using flow cytometry. HLA B27 was tested by polymerase chain reaction (PCR) using sequence-specific primers on DNA obtained from peripheral blood. Joint-related disability was graded according to the Steinbrocker functional class [27].
The children were divided into two categories based on whether they were HIV infected or HIV uninfected. The demographic data, clinical findings, laboratory investigations and management were analysed in these two groups of children. Laboratory results recorded (other than HIV testing) included a full blood count, erythrocyte sedimentation rate, rheumatoid factor, antinuclear factor, complement, blood culture, rubella, hepatitis B and parvovirus serology, tests for streptococcal infection, rheumatic fever, chest X-ray, tuberculin test and other relevant investigations based on the clinical findings (e.g. joint fluid aspiration, bone marrow aspirate, synovial biopsy, rickettsial serology and clotting profiles). None of the children received antiretroviral therapy as it was not available in public sector hospitals in South Africa during the period of review. Children with HIV-associated arthritis received non-steroidal anti-inflammatory drugs (ibuprofen, indometacin, diclofenac, naproxen) as first-line therapy. Chloroquine was the first disease-modifying agent added followed by sulphasalazine or penicillamine. Corticosteroids were given either orally or as intravenous pulse therapy to children with resistant disease. Methotrexate was not prescribed due to its immunosuppressive effects. Children with JIA received current recommended treatment except tumour necrosis factor antagonists.
JIA was classified according to the 1997 International League Against Rheumatism (ILAR) subgroups of JIA, namely systemic onset juvenile idiopathic arthritis (SOJIA), polyarthritis, oligoarthritis and enthesitis-related arthritis (ERA) [28]. HIV arthritis was classified as oligoarthritis (fewer than five joints involved), polyarthritis (five or more joints involved) or spondyloarthropathy-like disorder.
The term SPA like is used to emphasize the diversity of disorders that comprise this group and the fact that some children only partially fulfilled the criteria set out by the European Spondyloarthropathy Study Group (ESSG) for SPA [29]. SPA-like disorder comprises children with arthritis and enthesitis, children with arthritis and extra-articular features suggestive of reactive arthritis (ReA), like urethritis, acute diarrhoea and conjunctivitis, and children with extra-articular infections associated with ReA (Salmonella, Yersinia). Ethics approval for the study was obtained from the Biomedical Research Ethics Committee of the Nelson R. Mandela School of Medicine, University of KwaZulu-Natal.
Statistical analysis
The 2 test and the odds ratios were used to compare the findings in HIV-infected and HIV-uninfected children with arthritis. A P value of <0.05 and confidence interval of 95% defined statistical significance. Analysis was performed using SAS software (SAS revision 6, SASA Institute, USA).
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Results |
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A comparison of the demographic data, non-articular manifestations, coexistent diseases and serological findings in HIV-infected and HIV-uninfected children is shown in Table 1. The total study population included 71 males (25 of whom were HIV infected) and 61 females (10 of whom were HIV infected) with a male to female ratio of 1.2:1. There was a significantly higher prevalence of males 2.5:1 in HIV infected children than in HIV uninfected children [P = 0.02; confidence interval (CI) 1.124.11]. Although the mean age of onset of arthritis in HIV-infected children was 5.5 yr (range 211 yr) and 7.8 yr (range 8 months12 yr) in HIV-uninfected children, the difference was not statistically significant.
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There was no significant difference in the prevalence of fever or eye involvement in HIV-infected children compared with HIV-uninfected children. The ocular manifestations in the five HIV-infected children included anterior uveitis in three, bilateral conjunctivitis in one and chorioretinitis in the remaining patient. All four (4%) of the HIV-uninfected children had anterior uveitis. There was a significant increase in pulmonary tuberculosis in HIV-infected children. The mean haemoglobin and erythrocyte sedimentation rate were similar in both groups.
Comparison of the pattern of arthritis in HIV-infected and HIV-uninfected children (Table 2)
The 97 HIV-uninfected children fulfilled the ILAR criteria for JIA. All these children had had active arthritis for more than 6 weeks and no other cause for the arthritis could be identified despite extensive investigations. These 97 children were classified according to the ILAR criteria for JIA, namely SOJIA (16%), oligoarthritis (39%), polyarthritis (39%) and ERA (5%). None of the children had psoriatic arthritis. Rheumatoid factor (RF) was present in 9% of children with polyarthritis. Children with RF-positive polyarthritis had persistent and aggressive disease. Antinuclear antibody (ANA) was present in 14% of children with JIA, but none of these children had uveitis. There was no significant relationship between ANA, oligoarthritis and uveitis.
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The prevalence of SPA-like features was 34% in HIV-infected children, compared with 5% in HIV-uninfected children; these results were statistically significant (P<0.001; CI 2.7537.56). When the data in Table 2 are analysed according to the pattern of arthritis we note that 12 (71%) of the 17 children with SPA-like features were HIV infected compared with 5 (21%) who were uninfected (P<0.001; 2 = 24.03).
The records of the patients with HIV infection were further analysed with respect to the pattern of joint involvement, clinical stage of HIV infection, Steinbrocker functional assessment [27] at presentation, duration of arthritis, and the clinical course of the disease (Table 3). Tests for CD4 counts were performed on 20 of the 35 children (Table 4).
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The mean number of affected joints was 2 (range 14). Three children (33%) had monoarthritis. The joints most frequently involved were the knees (66%), ankles (55%) and the small joints of the foot (22%). The synovial fluid was examined in three children, and showed few pus cells but the culture was sterile. Synovial biopsies examined in two children showed non-specific synovial inflammation. The HLA B27 antigen was negative in the five children who were tested. ANA were present in one child but eye involvement was absent in this group. Early signs of HIV infection (CDC clinical category A), were present in 77% of these children. Seven (77%) were in Steinbrocker functional class 2.
The median duration of arthritis, until last follow-up, was 12 months (range 184 months). The records of the clinical course of the disease were available for seven children (77%) who were followed up for a mean period of 12 months (range 336 months). The arthritis resolved within 6 months in four (57%) of the children (one within 6 weeks), two had persistent arthritis and one had recurrent episodes of arthritis despite treatment.
HIV-associated polyarthritis (Table 3)
There was no significant difference in the ratio of males and females in this group. The mean number of affected joints was 7 (range 513). The joints of both upper and lower limbs were frequently involved; knees 12 (85%), ankles 10 (71%), wrists 8 (61%), elbows 7 (54%) and small joints of the hands in 8 (57%). The hips and sacroiliac joints were each clinically involved in three children (23%). One child had a synovial biopsy which showed chronic non-specific inflammation. Rheumatoid factor was positive in two children. The HLA B27 antigen was negative in the five children tested. Moderate to severe HIV disease (CDC clinical category B/C) was present in 71% of children with polyarthritis. Ten children (77%) had significant disability (Steinbrocker class 3 and 4).
The median duration of arthritis until last follow up was 17 months (range 356 months). Records of the clinical course of the disease were available for nine (64%) of the children who were followed up for a mean period of 26 months (range 260 months). Four children (44%) resolved within 6 months, three had persistent arthritis and two had recurrent arthritis despite treatment.
HIV-associated spondyloarthropathy-like disorder (Table 3)
Seven of the 12 children with SPA-like features (all males) had arthritis and enthesitis (ERA). The mean number of active joints was 7 (range 114). The joints most frequently involved were the knees (86%), ankles (71%), hips (57%), midtarsal (43%) and sacroiliac joints (29%). One child with recurrent arthritis and enthesitis had significant involvement of the small joints of the hand. Three of these seven children had anterior uveitis and one had chorioretinitis. The HLA B27 antigen was negative in four of five children tested and one child with sacroiliitis, anterior uveitis and enthesitis tested positive. Three (43%) had significant disability (Steinbrocker class 4). The median duration of arthritis in this group was 23 months (range 372 months). Five children (71%) were followed up for a mean period of 26 months (range 354 months). Arthritis resolved within 6 months in two (40%), two had recurrent episodes of arthritis and enthesitis and one had persistent arthritis despite treatment.
Five children had features suggestive of the incomplete form of ReA (three males and two females). The mean number of active joints was 3 (range 17). The joints most frequently involved were the ankles in five (100%), knees in two (40%), and the small joints of the hand in two (40%). The extra-articular features suggestive of ReA included one with bilateral conjunctivitis, two with acute diarrhoeal illness in the preceding month, another with urethritis and Salmonella species was isolated on blood culture in the fifth child. The joint fluid in this child was sterile, but the arthritis persisted for months after completion of antibiotics. One child had a synovial biopsy that showed non-specific chronic inflammation. The HLA B27 antigen was negative in all three children tested. Three children (60%) were in Steinbrocker class 1 and 2 and two (40%) were in Steinbrocker class 3. The median duration of arthritis was 4 months (range 254 months). Five children were followed up for a mean period of 16 months (range 348 months). Arthritis resolved within 6 months in four (80%) and one child had persistent arthritis despite treatment.
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Discussion |
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One of the important questions which arises from this report is whether there is a true association between arthritis and HIV infection in children or whether this is a coincidental finding due to the high background prevalence of HIV infection in our population. Fortunately, this study was able to compare patients with HIV infection and arthritis with other HIV-uninfected children with idiopathic arthritis from the same ethnic group at a single centre.
The evidence for the association of HIV infection with arthritis in adults has included electron microscopy findings of tubuloreticular structures within the endothelial cells in synovial tissue [30, 31], isolation of HIV from the synovial fluid [9], detection of P24 antigen in cells of the synovial lining layer and in mononuclear cells of subsynovial inflammatory infiltrates [10] and the detection of HIV DNA within dendritic cells isolated from the synovium and peripheral blood of HIV-infected individuals [11]. Clinical studies which support a direct role of HIV in producing rheumatic manifestations include two reports on HIV-positive and HIV-negative patients in Argentina [18] and Mexico [19] which showed a significant increase in the prevalence of rheumatic manifestations in HIV-positive patients. Further support was provided by a longitudinal study of 117 patients, followed up for a mean period of 24.6 months (range 0.585 months), which showed that the majority of symptoms developed during the longitudinal evaluation [32].
Some of the observations arising out of this report, which suggest that there is a true association, will be discussed. First, the prevalence of HIV infection in 27% of our children with arthritis is higher than would be expected in children in the 212 yr age group. A recent Human Science Research report recorded the prevalence of HIV infection in children, of all ethnic groups between the ages of 2 and 14 yr, in South Africa to be 5.6% [24]. The prevalence of HIV infection in children aged 512 yr in a rural community in Uganda was noted to be 0.4% [33]. Our finding of an incidence of 27% HIV infection, in a fairly low risk group of 212-yr-old children with arthritis, supports an association between HIV infection and the development of arthritis in children.
Secondly, there was a significantly higher proportion of males, with a male to female ratio of 2.5:1, in our HIV-infected children compared with a nearly equal ratio of 0.9:1.0 for HIV-uninfected children. The male:female ratio in 521 Caucasian children with JIA in the United Kingdom was reported as 0.5:1 [34]. The higher proportion of males among HIV-infected children may be a reflection of the increased incidence of SPA-like features in this group.
Thirdly, SOJIA accounts for about 1420% of JIA in most large studies of children with arthritis, and was recorded in 14% of 521 children in the UK study. We recorded SOJIA in 16% of our HIV-uninfected children. All HIV-infected children with systemic manifestations had concomitant infections to explain their systemic illness. The pattern of fever and types of skin rashes were different from those seen with SOJIA and therefore none of our HIV infected children were considered to have a systemic onset pattern of arthritis.
The fourth important observation is the significant increase in the prevalence of SPA-like features, which was noted in 34% of HIV-infected children compared with only 5% of HIV-uninfected children (P<0.001). Seventy-one per cent of all children with SPA-like features were HIV infected. The male:female ratio in this group was 5.5:1. Burgos-Vargus et al. [35] describe classical SPA as a group of HLA B27-associated disorders that are characterized by enthesitis and arthritis affecting the lower extremities. Additional features include a variety of extra-articular manifestations with bacterial infections as triggers in some cases. ReA is defined as a form of arthritis that appears following an infection [35]. This term is usually restricted to HLA B27-associated ReA triggered by arthritogenic bacteria such as Salmonella, Yersinia, Campylobacter, Shigella and Chlamydia [35, 36]. The link between the SPA and ReA is the HLA B27 antigen.
The pattern of SPA in HIV-infected children differed from the classical SPA in that the HLA B27 was negative in seven of the eight children tested, four (33%) had involvement of the upper limbs and the arthritis resolved within 6 months in six (50%) of these children. Therefore we describe them as a SPA-like disorder. Features that were suggestive of SPA in this group included arthritis and enthesitis (compatible with the ESSG criteria for SPA) and extra-articular manifestations of ReA like acute gastroenteritis, urethritis, conjunctivitis and ReA-triggering infections like Salmonella enteritides. HLA B27-negative ReA triggered by Yersinia and Campylobacteria infection is reported to follow a rather short, benign course of disease [35], similar to our cohort. This suggests that HIV virus or an unidentified co-infection may trigger a form of ReA in HIV-infected children. Upper limb involvement, although unusual, has been reported in patients with Salmonella and Yersinia ReA arthritis [35].
Our observation of an increase in the incidence of SPA-like features in HIV-infected children is consistent with the findings of HIV arthritis reported in adult Black Africans [15]. SPA was considered a rare disease in Africa prior to the HIV epidemic. A previous report by Lutalo [37] identified only three adults with SPA in a series of 52 patients with rheumatic disease in Zimbabwe. The low prevalence of SPA in Africa was attributed to the low prevalence of HLA B27 (0.68% in Zimbabwe). With the HIV epidemic, large cohorts of adults from Zimbabwe, Rwanda and Zambia [1317] were reported with HIV infection and arthritis and specifically a significant increase in HIV-associated SPA was noted. The largest series came from Zambia where Njobvu et al. [15] reported on 344 adults with arthritis who were tested for HIV infection; 289 were HIV infected. Of these 289 adults, 223 were considered to have HIV-associated SPA and 66 were classified as having arthritis alone.
The pattern of arthritis in 521 UK children with JIA [34], was reported as SOJIA (14%), oligoarthritis (45%), polyarthritis (27%), ERA (7%) and psoriatic arthritis (7%). In our cohort of JIA we recorded SOJIA (16%), polyarthritis (38%), oligoarthritis (38%) and ERA (5%). Juvenile chronic arthritis in Black South African children was described in 1984 by Haffejee et al. [38]. A detailed description of the pattern of joint involvement, the severity of arthritis and the associated features is contained in that paper. The clinical findings are similar to our series of JIA, except that more children had polyarthritis (50 vs 38%). RF-positive polyarthritis was present in 9% of our JIA cohort compared with 7% in the UK cohort [34]. There was no significant relationship between ANA, oligoarthritis and uveitis in our series of JIA. A retrospective review of 35 African American and 137 Caucasian children with pauciarticular and polyarticular JIA reported racial differences in disease expression [39]. African American children were less likely to be ANA positive (33 vs 70.7%) and more likely to be RF positive (20 vs 3.8%). Uveitis was less common in African American children and was associated with a negative ANA. Haffejee et al. [38] did not find any relationship between ANA and oligoarthritis with uveitis among Black South African children.
Polyarthritis (40%) was commoner than oligoarthritis (26%) in HIV-infected children. Arthritis was the presenting feature of HIV infection in 78% of the children and it occurred at any stage of the HIV disease. HIV-associated arthritis may present as oligoarthritis, polyarthritis, with SPA-like features or with systemic features. This study emphasizes the difficulty in distinguishing between HIV-associated arthritis and JIA at presentation and that HIV arthritis may mimic JIA.
Conclusion
The 27% HIV prevalence in a relatively low risk group of 212-yr-old Black African children with arthritis, together with the predominance of males and an increased prevalence of SPA-like features, suggests that HIV infection may be causally associated with arthritis in children. HIV-associated arthritis can mimic JIA and must be considered in the differential diagnosis of arthritis in children in an HIV endemic area. Arthritis may be the presenting feature of HIV infection or may occur at any stage of the HIV disease.
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Acknowledgments |
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The authors have declared no conflicts of interest.
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References |
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