Arthralgia

The results of multiple cohort studies across several continents suggest that pain and stiffness localised to joints (arthralgia) is also common in HIV. Patients define it as one of the most ‘bothersome’ symptoms of their infection . However, it is difficult to draw conclusions as to how common arthralgia is in HIV with prevalence estimates varying widely between 1% and 79% and no clear pattern comparing studies carried out pre-cART (1.6–45%) or post-cART . In their large case–control study in San Francisco, Hochberg and colleagues concluded that there was no increase among those with prevalent HIV infection as compared with those without . Notwithstanding the reported variation, the studies suggest that arthralgia is usually intermittent and that arthralgia is most common at the knees, elbows and shoulders . It is most commonly polyarticular , but it has been described in just one joint .

Painful articular syndrome

Berman et al. first described this condition in 1988 , estimating a prevalence of 10% among US patients in the late stages of the infection. Similar rates were reported subsequently in Argentina by the same author . It was described as being different from arthralgia, associated with exquisite pain that is short-lived (lasting between 2 and 24 h), in the absence of synovitis or other signs of inflammation. Large joints were more commonly involved, although smaller joints (metacarpophalangeal joints) could be affected . The severity of the pain was such that the patients often required admission to hospital for analgesia (commonly with anti-inflammatories or opiates). It is worth noting that this condition has not been reported in a number of other case series outside of the Americas . However, 10 cases of painful articular syndrome were described in an Indian cohort study (prevalence 3.3%), where it was associated with distress and sickness absence . Seven of these patients were receiving cART, and three were not. It is therefore unclear whether this manifestation is peculiar to some countries or populations of infected patients. It is possible that it is more common among patients infected with HIV by intravenous drug use, but further research is required.

Myalgia

The results of case–control studies suggest that myalgia is almost twice as common among HIV-infected cases than uninfected controls (OR 1.9) . In the pre-cART era, myalgia was reported in 1.7–11% of HIV patients . Since the advent of cART, prevalence estimates between 0% and 77% have been reported . On the face of it, these raw data might suggest an increase in myalgia since cART, but in a large cohort of female patients there were similar rates among cART-naïve patients as compared with those on stable therapy ; in a Thai study, the prevalence of myalgia was reduced after commencement of cART . However, in another study, discontinuation of cART improved the symptoms of myalgia . In some studies, zidovudine (azidothymidine (AZT)) use was implicated in causation or exacerbation of myalgia . Therefore, it is currently unclear whether treatment improves or exacerbates myalgia.

Although rates of myalgia have been widely reported in the literature, few studies have incorporated detailed investigation to separate out myopathy or myositis so that the estimated prevalence rates may be misleading.

Fibromyalgia syndrome

The prevalence of the chronic widespread pain syndrome fibromyalgia has been explored in several studies of HIV patients, particularly in the post-cART era. However, the methodology of these studies has varied widely, particularly in the case definitions utilised. Rates of prevalence between 1% and 17% have been reported . The highest prevalence estimates were in USA and the lower ones in India and China .

HIV-associated arthritis

There is currently dispute as to whether there is an ‘HIV-associated arthritis’. The first case reports of ‘AIDS-associated arthritis’ published in 1988 described arthritis developing in patients at an advanced stage of HIV . Hochberg and colleagues disputed its existence after their large San Francisco study . However, since then, other investigators have published data in keeping with this picture, with a prevalence rate ranging from 0.4% to 13.8% . Most of these studies were from North America, where the estimated prevalence ranged between 3.8% and 11% . However, the highest prevalence estimate came from a study in central Africa, where 32 of 39 patients (82%) had an asymmetrical acute non-deforming polyarthritis that was self-limiting , making ‘HIV arthritis’ the leading cause of inflammatory articular disease in their cohort. Clearly, it is difficult to differentiate this clinical picture from that of reactive arthritis or even sero-conversion with HIV. The African studies have not reported such high prevalence rates, although most have reported the diagnosis . Reveille and colleagues described ‘HIV arthritis’ as an acute arthritis of the large joints, lasting <6 weeks, in the absence of either human leucocyte antigen (HLA) B27 positivity or radiological changes, which was described as being distinct from any other recognised rheumatological entity, with no discernible infective triggers, or other classical features in keeping with another recognised inflammatory arthropathy .

Assuming its existence as an entity, the literature suggests that the majority of cases have been reported in men, with an average age of 35 years, most commonly in the Centers for Disease Control and Prevention (CDC) stage IV of HIV infection (susceptible to ‘other’ diseases including AIDS-defining illnesses). The most common presentation was with a relatively mild arthritis, although severe and incapacitating manifestations have also been reported . Self-limitation seems to be universal and it has been reported to respond to symptomatic treatment with either anti-inflammatories or intra-articular corticosteroids . There is minimal evidence of any destructive sequelae or erosive pathology, although it has rarely been followed up in the long term. There are a few exceptional cases of synovitis that took a longer time to resolve (up to 3 months) .

Where laboratory tests were available, this diagnosis was made only in people who were seronegative for rheumatoid factor (RF), HLA B27 and anti-nuclear antibodies (ANAs). Synovial fluid was inflammatory in nature but with no other diagnostic features. Where data were available, the arthritis was not associated with mucocutaneous manifestations. Synovial biopsy has been rarely carried out, but one study found a mild chronic synovitis with mononuclear and plasma cells and no organisms were cultured . Occasional immune complexes were also demonstrated in the synovial fluid in one study . It has been hypothesised that ‘HIV arthritis’ is a type of reactive arthritis, perhaps triggered by the virus.

It is difficult to know what, if any, impact cART might have had on the occurrence of HIV arthritis, as there are few comparative studies.

Reactive arthritis

One problem with the literature is that there is apparent overlap of the features of reactive and psoriatic arthritis (PsA) in some studies . For example, some studies describe patients with PsA who presented with a pustular form of psoriasis as being indistinguishable from keratoderma blennorrhagica and with features common to reactive arthritis, psoriasis and PsA such as onychodystrophy, conjunctivitis, uveitis, enthesitis, balanitis and dactylitis. It is possible that HIV infection is associated with a new type of PsA that overlaps with reactive arthritis (termed ‘undifferentiated spondyloarthropathy’ by some authors). Of interest, when HLA B27 testing was available, HIV-infected patients with overlapping features of PsA and reactive arthritis were often positive for the HLA B27 allele , and most HIV-infected patients with PsA who tested negative for HLA B27 apparently did not have these overlapping features . Unfortunately, few of these available studies have analysed for the HLA allele subtypes typically associated with PsA (Cw6, B17).

Given the classification issues discussed above, it is not surprising that the estimated rate of occurrence of reactive arthritis in HIV pre-cART has varied widely between 0% and 11%. Interestingly, the higher estimates come from the smaller studies (3.8% to 11% ) and the more conservative estimates from larger studies (0.1% , 0.2% and 0.5% ). Importantly, the largest studies, the San Francisco Men’s Health Study (SFMHS) and the Johns Hopkins Multicenter AIDS Cohort Study, recruited >2000 men who completed a questionnaire, were examined and underwent HIV antibody testing ; these studies found no differences in the occurrence of reactive arthritis in HIV-infected versus uninfected patients. Similarly, in a study of 1100 unselected HIV patients over 7 years, all examined by one physician, only one case of reactive arthritis was diagnosed, as compared with an expected number of 1.4 cases in the local uninfected population and the case occurred prior to HIV acquisition .

It is not immediately obvious why the studies in Mexico and Argentina found much higher prevalence rates. It is possible that there is a true difference between North American and Central and South American populations in their susceptibility to reactive arthritis in the context of HIV infection. However, it may reflect the behaviour underlying the mode of acquisition of HIV infection and a tendancy towards risk taking. Reactive arthritis is triggered by a range of organisms but a common group of responsible organisms are those causing sexually transmitted infections (STIs). It seems obvious therefore that people undertaking high-risk behaviours putting them at a risk of sexually acquired HIV are also those at a risk of STIs that might trigger reactive arthritis. Certainly, in Spain, where much of the prevalent HIV infection has been acquired though intravenous drug use rather than sexual contact, there appear to be fewer cases . In intravenous drug users, the more common musculoskeletal manifestations have been pain and musculoskeletal infections .

In Black African populations, the HLA B27 allele is virtually unknown and, therefore, there was a low prevalence of reactive arthritis prior to the HIV epidemic, despite the high rate of prevalence of the enteric and urogenital infections that are associated with reactive arthritis. Since 1989, the results of some African studies suggested that the occurrence of reactive arthritis had increased, and where diagnosed, it was highly significantly associated with coexistent HIV. For example, out of 65 Zambian patients diagnosed with reactive arthritis, 61 (95%) were HIV infected and 37.5% of a series of patients in Zimbabwe had reactive arthritis . In other African studies, however, there have been lower rates of reactive arthritis; for example, in Congo, seven patients were classified with reactive arthritis over 1 year amongst whom two (29%) were HIV infected. These discordant data may be explained by case attribution in that, over the same period that the Congo study was carried out, 32 cases of ‘HIV arthritis’ were diagnosed .

The results of Asian studies have also shown no clear picture, as studies from China and Thailand found no cases amongst 98 inpatients and 178 outpatients, respectively. In Asia, the principal mode of HIV transmission is thought to be heterosexual, often involving commercial sex workers but, probably because of social stigma, the mode of transmission is frequently undisclosed. The apparent differences in prevalence of reactive arthritis in Asia and Africa may be worthy of further investigation as both continents have a high prevalence of arthritogenic pathogens and, at least as far as is known, HIV infection is transmitted predominantly heterosexually.

Conceivably, reactive arthritis might be associated with only the late stages of immunosuppression in HIV. This would explain the apparently low prevalence of reactive arthritis in the US studies where most patients were in the early asymptomatic phase . Moreover, since cART, there has been less published about reactive arthritis in HIV in the developed world, suggesting perhaps that HIV infection per se does not affect the risk. On the other hand, high-risk sexual practices could possibly have become more restricted since the HIV epidemic, resulting in reduced transmission of arthritogenic urogenital and enteric infections . It is also conceivable that an effective cART regimen could affect the development and course of reactive arthritis. However, a comparison of rates of reactive arthritis among 80 HIV patients – 38 on unspecified single and dual therapy and 42 ARV naïve – appeared to make no impact on the frequency . To confuse the picture further, new reactive arthritis has been reported to emerge on commencement of cART, as a manifestation of IRIS . At present, the epidemiological data pre- and post-cART are confusing, and it is impossible to draw clear conclusions about the relationship between HIV infection and reactive arthritis.

Psoriatic arthritis

Skin psoriasis has been reported in association with HIV since the 1980s, with initial reports of psoriasis as a manifestation of end-stage AIDS. In parallel, psoriasiform rash and arthritis has also been described in several cohorts pre- and post-cART . The estimated prevalence rates of PsA have ranged between 0.02% and 5.7% , but they were most commonly found to be between 0.02% and 2%. The estimated population prevalence of PsA is 0.25% in the US, which might imply that HIV increases the risk of PsA. However, the results of the two large US case–control studies found no cases of PsA amongst >2000 HIV-infected men but it may be relevant that most of those found infected were in the asymptomatic (early) stage. From a longitudinal study , there were three incident cases of PsA amongst 395 HIV-infected individuals over 11 years of follow-up (estimated incidence rate 0.07% per annum), which approximates to the 0.05% incidence rate reported in the general population.

In addition to suggesting a possible increase in occurrence rates, the pre-cART studies also reported that HIV-infected patients with psoriasis had more severe and persistent lesions and that the PsA was severe, deforming, erosive and refractory to conventional treatment. However, this again may be influenced by the fact that most cases were in the late stages of HIV (World Health Organization (WHO) stages 3 and 4) . The importance of late-stage disease might be best illustrated by a description of three HIV patients with ‘mild’ PsA, amongst whom one patient was in the asymptomatic stage, one had lymphadenopathy only and only one had AIDS .

The available evidence from Africa suggested that PsA was uncommon pre-HIV. However, subsequently, a Zimbabwean study involving 64 HIV-infected people with rheumatological symptoms found three patients with severe, persistent PsA, all positive for HLA B17, and one for HLA Cw6 . A Zambian study over 44 months identified 28 patients with PsA amongst 702 (4%) patients with inflammatory arthritis: 27/28 (92%) were HIV infected, over half of whom were in the asymptomatic stage . In each case, PsA was the first presenting feature of HIV. The skin lesions were extensive and symmetrical occurring simultaneously with a seronegative asymmetrical erosive polyarthritis, typically affecting the lower limbs. Seven of the PsA patients who developed AIDS continued to have active psoriatic skin lesions but their arthritis was in remission in the pre-terminal stages. In Burkina Faso, another study in the post-cART era described only one patient with PsA amongst a population of 4084 . Similar rates of prevalence have been found in Asian studies pre- and post-cART .

Soon after the introduction of AZT as the first ART, it was reported that AZT therapy improved skin psoriasis . However, it is less clear what impact cART has had on PsA since then. In one Spanish study post cART, three patients developed psoriatic arthropathy over 7 years of follow-up, none of whom were taking cART . Overall, the epidemiological evidence may suggest that PsA is a feature of end-stage HIV typically in the pre-cART, era but the evidence is inconclusive at present.

Ankylosing spondylitis

It is interesting that although AS is the most common form of seronegative spondyloarthropathy in the Western world, there were very few reports of AS coexisting with HIV infection in the pre-cART era. It has been reported that HIV diagnosed 10–15 years after the onset of AS did not alter its course. More recently, however, a small number of cases have been described in France and Burkina Faso . In Africa, as expected, given the low prevalence of the HLA B27 allele, cases of AS are rare in the general population and seem to be similarly unusual in HIV . Some authors have suggested that the immunological mechanisms driving AS are independent of CD4+ T cells and therefore are not affected by the infection . However, the diagnosis of AS relies upon features of inflammatory back pain, HLA B27 positivity and radiographic sacroiliitis. In a study from Zambia, 14 patients presented with spontaneous sacroiliitis and had positive sacroiliac stress tests and raised erythrocyte sedimentation rate (ESR), with normal radiographs . Four of these 14 patients went on to develop polyarthritis and enthesitis at follow-up, and therefore they could have been classified with undifferentiated spondyloarthropathies. Longer-term follow-up would be needed to determine whether these patients developed diagnostic features of AS. In most cohort studies referenced in this review, undifferentiated spondyloarthropathy appears to be common and a proportion of AS may have been classified as undifferentiated spondyloarthropathy in the absence of radiographic studies or HLA B27 testing or long enough duration of follow-up.

Rheumatoid arthritis

The earliest mention of RA and HIV came from case reports pre-cART describing patients with established RA who experienced clinical improvement or remission after the development of HIV . This clinical phenomenon can be explained if the HIV-associated depletion of CD4+ helper/induced lymphocytes reduces the immunogenic autoimmune activity, which maintains the activity of RA; therefore, this led to an early view that HIV and RA were mutually exclusive diagnoses.

However, around the same time, Berman and colleagues described an HIV-infected patient with an RA-like symmetrical polyarthritis who was RF negative . The patient had radiographic erosive changes and the symptoms lasted longer than 6 months, clearly differentiating it from other types of presentation such as painful articular syndrome and reactive arthritis. Given the conviction that arose of RA and HIV being mutually exclusive, the cases subsequently described took different approaches in defining inflammatory arthritis in HIV. Some researchers described patients with a symmetrical erosive arthropathy as having RA, whilst others have described it as one end of a spectrum of inflammatory arthritis seen in HIV, with this pattern being generally more destructive and symmetrical than the others. In 1989, Rosenberg et al. discussed the radiological features of four patients as being ‘rheumatoid-like’ , but they labelled the condition ‘acute symmetrical polyarthritis’, likely because it was believed that the two conditions were mutually exclusive .

Whatever the nomenclature, there is a steadily growing body of global evidence that HIV-infected patients in the post-cART era can develop a new symmetric polyarthritis involving the small joints of the hands and feet, clinically suggestive of RA . For example, one Zimbabwean study described eight of 64 patients with arthritis and prevalent HIV infection who had a symmetrical polyarthritis affecting the hand and wrist joints, three of whom were positive for RF and one of whom developed radiographic erosions . The authors postulated that some of these eight patients had true RA and that others had a ‘symmetrical rheumatoid-like arthritis occurring with HIV’. Across the range of studies, the estimated rates of prevalence varied between 0.1% and 5% . It seems that most cases developed at a minimally advanced stage of HIV disease, that is, with CD4+ counts > 200 cells/mm ³ , and/or when there was an undetectable viral load . RA arising as an immune reconstitution syndrome has also been described .

A predominance of the cases of RA has been reported among men, but this almost certainly reflects the much larger numbers of HIV-infected men available for epidemiological studies. Certainly, Stein et al. found an equal gender distribution amongst their population, despite their relatively male population . The reported average age at diagnosis ranged between 27 and 58 years with the duration of cART ranging between 8 months and 9 years . In one study, smoking was a common risk factor with 50% of those developing RA being cigarette smokers.

As RF is not a specific autoantibody, it is unsurprising that very high rates of seropositivity to RF (35–47%) were reported in early HIV studies pre-cART . Since ART, it appears that the background prevalence of RF has dropped with rates comparable to those found in general population studies after treatment with cART . Anti-cyclic citrullinated peptide antibodies (ACPA) have rarely been assayed in HIV studies. There is evidence of increased rates of ACPA as high as 15% in HIV patients not taking cART but that these rates drop to <6% after 6 months of treatment with cART .

As far as clinical features are concerned, rheumatoid nodules have been described in HIV patients although not necessarily associated with seropositivity for RF. Radiographic erosions have been observed in these patients , as has periarticular osteopenia.

Systemic lupus erythematosus

The first available case report describing coexistent HIV and SLE was published in 1988 . Our review found >100 cases in the literature since this case report; however, considering the publication bias, it seems likely that this coexistence is uncommon. The association between HIV infection and this and other autoimmune diseases is becoming increasingly recognised; in particular, the immunological environment seen in HIV could provide an important insight into the intriguing pathogenesis of the two diseases.

When the two conditions coexist, interesting diagnostic as well as therapeutic dilemmas are raised. The two conditions have many similarities; firstly, both are systemic diseases that can present with vague, non-specific symptoms in a wide range of different ways. Secondly, HIV infection disrupts the immunological milieu, giving rise to autoantibodies, which may play an aetiological role in autoimmune disease. In addition, the pathogenesis of both conditions relies upon a crucial role of CD4+ lymphocytes.

Pathogenesis of SLE in HIV

The presence of autoantibodies is a common finding in patients with HIV, with reported prevalence rates of ANAs being up to 17–23% of patients, but most of whom were on early HIV therapy in the form of monotherapy with AZT (with the average CD4+ count < 400 cells/mm ³ ) . These rates are slightly higher than those found in the general population. In these HIV studies, the ANAs were usually of low titre and of a non-specific speckled pattern, and dsDNA antibodies were rarely associated. It is unclear if such rates of ANAs are seen among HIV patients treated with cART according to modern best practice guidance. Either way, ANAs of low titre are rarely pathogenic and their presence does not signify a raised risk of development of SLE. dsDNA antibodies are usually not found in isolated HIV infection and, where present, they are of low avidity. In some cases of people with prevalent SLE with dsDNA antibodies, these antibodies became undetectable after acquisition of HIV infection .

In conclusion, the coexistence of HIV and SLE is rare, but noteworthy, and it is likely to reflect an almost mutually exclusive relationship. Whilst advancing HIV disease can lead to suppression of autoimmunity, the reverse can also be true. Clinicians need to remember the importance of testing for HIV, especially in atypical cases or those resistant to treatment.

Anti-phospholipid syndrome

As with other autoantibodies, anti-cardiolipin (aCL) antibodies were shown to be common in patients infected with uncontrolled HIV. In a pre-cART study, aCL IgG was found in 94% of HIV patients ( n = 74) compared with none in controls . This is similar to findings from other studies , but higher than other cohorts where the prevalence was 13–64% . The prevalence was highest among those with advanced HIV disease . Similarly, lupus anticoagulant was found in 3–46% of patients in advanced stages of HIV not receiving cART , and it has been associated with the AIDS-defining illness Pneumocystis jirovecii . Much lower rates of prevalence have been shown in patients taking cART, including a Nigerian study, which found a prevalence of LA antibodies of 5%.

The risk of venous thromboembolism (VTE) has been shown to be elevated in individuals infected with HIV, although there is little evidence that the presence of anti-phospholipid syndrome (APS) autoantibodies are contributory . HIV patients are at a risk of many complications associated with increased VTE, including obesity, immobility, cardiovascular disease and cigarette smoking. Intravenous drug use is another independent risk factor. There have been a few isolated reports of VTE in individuals with HIV and anti-phospholipid antibodies , although given the many other potentially contributory factors in these individuals, and the rarity of this finding, it is difficult to postulate a major risk of clinical anti-phospholipid antibody syndrome in HIV at this time.