The Scourge of HIV Infection in Sub-Saharan Africa -A Rheumatological Perspective
Nowhere has the devastation from HIV/AIDS been more greatly felt than in sub-Saharan Africa. Of the estimated 33 million people globally who live with HIV/AIDS, 22.5 million or 5% of the adult population are from this region and 1.3 million people have succumbed to the infection in 2009 1 . Much of the clinical and research efforts have been directed, and rightly so, at preventing the spread of the disease and treatment with highly active antiretroviral therapy (HAART). But like syphilis in previous times, HIV/AIDS has become the great mimic of the 21st century, and the burden from noninfectious systemic complications is substantial.
The Scourge of HIV Infection in Sub-Saharan Africa -A Rheumatological Perspective
Since the first report of HIV-associated reactive arthritis almost a quarter of a century ago 2 , a wide spectrum of HIV-related rheumatic syndromes have been reported 3 . Many of the syndromes have clinical features that overlap with those of the more classical rheumatic disorders. A striking example is diffuse infiltrative lymphocytosis syndrome masquerading as primary Sjögren's syndrome. The spondyloarthropathies (SpA), previously very rare in Africa, have emerged in the wake of the HIV pandemic, adding significantly to the diagnostic and therapeutic rheumatic burden 4 . Seemingly benign isolated soft-tissue lesions, such as Achilles tendonitis and epicondylitis, not infrequently herald the onset of a SpA. A range of autoantibodies, including antinuclear antibodies, antiphospholipid antibodies, antineutrophil cytoplasmic antibodies, and rheumatoid factor (RF) can occur in HIV/AIDS 5, 6 . Interpreting autoantibody tests can thus be challenging in an HIV-positive patient, although the antibodies are present mostly in low titers and are not associated with any clinical rheumatic disease.
The Scourge of HIV Infection in Sub-Saharan Africa -A Rheumatological Perspective
Anti-citrullinated peptide antibodies (ACPA), especially antibodies to cyclic citrullinated peptide (anti-CCP), because of their presence in early disease and superior specificity to RF 7 , are an important component in the diagnosis of rheumatoid arthritis (RA). In this issue of The Journal, Du Toit, et al report on the prevalence of anti-CCP antibodies and RF in advanced HIV disease 8 . Nine of 60 (15%) asymptomatic patients were anti-CCP-positive, all in low titers. Following highly active antiretroviral therapy, there was a significant decline of anti-CCP antibody titers, and only 2 (4%) of 49 patients tested positive at 6-month followup. Almost half the patients were also RF-positive at baseline, declining to 7% following HAART. Importantly, after a year of followup, no patient who tested positive for anti-CCP antibodies developed joint symptoms and only 1 of the RF-positive patients developed a self-limiting oligoarthritis.
The Scourge of HIV Infection in Sub-Saharan Africa -A Rheumatological Perspective
The mechanism of autoantibody production in HIV/AIDS is poorly understood. Possible explanations are cross-reactivity between the virus and autoantigen 3 and nonspecific polyclonal hypergammaglobulinemia due to B cell activation 9 . The authors conclude that although the anti-CCP antibodies can occur with advanced HIV disease, it has a better specificity for RA than RF. In real life, however, coinfection with tuberculosis (TB), which is a major cause of morbidity and the commonest cause of death in HIV/AIDS 10 , is a potential confounder. Anti-CCP antibodies have been detected in up to 37% of patients with TB 11 .
The Scourge of HIV Infection in Sub-Saharan Africa -A Rheumatological Perspective
As a next step, it would be worth exploring the fine specificities of ACPA in HIV/AIDS. A recent study in North American Indians has shown that the anti-Sa (citrullinated vimentin) antibody assay has better specificity for RA than the anti-CCP test 12 . Another aspect that warrants further investigation is the clinical utility of the anti-CCP antibody test in HIV-associated inflammatory arthritis, particularly in reactive arthritis and psoriatic arthritis subtypes. There is mounting evidence of an increased prevalence of anti-CCP antibodies in idiopathic psoriatic arthritis and some early evidence that their presence is associated with more aggressive disease 13 .
The Scourge of HIV Infection in Sub-Saharan Africa -A Rheumatological Perspective
In the broader rheumatology context, to the clinician working in HIV-endemic areas, the challenges go beyond distinguishing HIV-related rheumatic syndromes from more classical rheumatic disorders. Assessing disease activity in a patient with preexisting rheumatic disease who contracts HIV infection can be difficult. In a patient with systemic lupus erythematosus, proteinuria, leukopenia, and thromboSee Lack of specificity of anti-CCP antibodies in advanced HIV infection, page 1055
Rheumatology
The Journal of on July 31, 2017 -Published by www.jrheum.org Downloaded from cytopenia can be explained equally on the basis of active lupus and HIV infection 14 . Moreover, HIV-associated immune complex glomerulonephritis can be indistinguishable histologically from lupus nephritis 15 . A nonspecific increase in erythrocyte sedimentation rate is common in advanced HIV infection and hence is a poor marker of active inflammation in a patient with RA who is HIV-positive 16 . The risk of severe infections with the use of immunosuppressive drugs, in an already immunocompromised host, is of serious concern. There is a pressing need for controlled trials to assess the safety of methotrexate in patients with HIV/AIDS, given the widespread use of the drug in the rheumatic diseases. As in HIV/AIDS, methotrexate use in RA is associated with increased risk of Pneumocystis pneumonia 17 and B cell lymphomas 18 .
Rheumatology
An emerging problem is that of HAART-related rheumatic complications, ranging from immune reactivation inflammatory syndromes, e.g., sarcoidoisis, to bone disorders like osteoporosis and osteonecrosis (ON) 3 . As more patients receive HAART, the burden of ON from pain and physical disability is likely to put further strain on limited health resources in most of sub-Saharan Africa and where there is very limited access to arthroplasty surgery. Retrospective studies suggest that dyslipidemia, intravenous drug abuse, and protease inhibitors are risk factors for ON 19 , but these findings are not sufficiently robust to develop guidelines for screening of early preclinical disease which, in the case of hip ON, may be amenable to less costly core decompression surgery.
Rheumatology
It is clear from this brief overview that many aspects of the interaction and potential impact of HIV/AIDS on diagnosis and management of rheumatic diseases require further research. While this may not appear to be one of the priorities for the industrialized world, it behooves the international rheumatology community to collaborate and support Africa in its efforts to find answers to these clinical conundrums 20 . The benefits will be for all! MOHAMMED TIKLY, FRCP, PhD, Division of Rheumatology, Chris Hani Baragwanath Hospital, University of the Witwatersrand, Johannesburg, South Africa

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