Therapy Insight: The Changing Spectrum of Rheumatic Disease in HIV Infection

Rashmi M. Maganti; John D. Reveille; Frances M. Williams

Disclosures

Nat Clin Pract Rheumatol. 2008;4(8):428-438. 

In This Article

Altered Patterns of Disease After the Introduction of HAART

The introduction of HAART in 1995 led to HIV infection becoming associated with a new spectrum of disorders, including osteonecrosis, rhabdomyolysis and IRIS.[33] Before the use of HAART, reactive arthritis, painful articular syndrome and psoriatic arthritis dominated epidemiological studies of HIV-associated conditions. The frequency of reactive arthritis and psoriatic arthritis is now decreasing dramatically in some, but not all, sites in the US.[33]

High-dose zidovudine monotherapy (up to 1.2 g per day) was commonly used to treat HIV infection before the HAART era. This treatment was associated with a reversible toxic mitochondrial myopathy that resembled polymyositis.[34] Affected patients presented with myalgia, muscle tenderness and proximal muscle weakness. Histologically, this myopathy is characterized by presence of 'ragged red fibers', loss of thick myofilaments, and cytoplasmic-body formation. Symptoms tend to improve after high-dose zidovidine is discontinued, and creatine kinase levels return to normal within 4 weeks of discontinuing the drug. Myalgia associated with zidovudine therapy responds to NSAIDs or sometimes to low-dose prednisone. With the introduction of combination therapy, however, this myopathy has been seen less frequently.

Rhabdomyolysis, which can lead to acute renal failure, has been reported with the use of protease inhibitors, particularly when these drugs are administered in combination with statins. Since statins are often used to treat dyslipidemia, a recognized complication of protease-inhibitor treatment, combinations of protease inhibitors and statins should be used with extreme care. In addition, cases of adhesive capsulitis, Dupuytren contractures, tenosynovitis and temporomandibular joint dysfunction have been reported as a consequence of indinavir treatment.[35] Parotid lipomatosis has also been associated with the use of protease inhibitors.

Osteopenia and osteoporosis occur more commonly in patients who are taking HAART than in HIV-infected individuals who are not receiving these medications.[36] Bisphosphonates can be used in the prophylaxis of HAART-associated bone loss.

An increased prevalence of avascular necrosis of the bone has been reported in HIV-positive individuals, even before they have started to take antiretroviral agents,[37] and although the increased prevalence of bone necrosis has been attributed to HAART, there have been no controlled studies that prove this association. The most common presenting symptom in patients with avascular necrosis is pain on weight bearing, although pain can also occur at rest. Avascular necrosis can be asymptomatic in some patients, and might be an incidental finding in radiological studies. Surgical stabilization of the affected bone might be required.

Numerous serological abnormalities were described in HIV-positive individuals in the pre-HAART era, including hypergammaglobinemia, cryoglobulinemia, positivity for rheumatoid factor and antinuclear antibodies (usually in low titers), and anticardiolipin IgG antibodies (which are present in up to 95% of untreated HIV-infected patients, particularly those with advanced disease,[38] although they are rarely associated with thrombotic complications). These abnormalities have decreased in frequency since the introduction of HAART. The presence of circulating cryoglobulins is rarely of clinical consequence; this finding usually indicates the presence of hepatitis C coinfection, and has also decreased in frequency after the introduction of HAART.[39] Both cytoplasmic and perinuclear types of antinuclear neutrophilic cytoplasmic antibodies have been described, which occasionally have reactivity against myeloperoxidase and neutrophil elastase, although without any stigmata of vasculitis.[40]

With the restoration of immune competence that follows successful HAART, a resurgence of autoimmune diseases occurs that is now termed IRIS ( Table 2 ).[41] HAART results in a biphasic repopulation of T cells: the first phase is characterized by release of predominantly memory CD4+ cells and lasts a few weeks to months; the second phase, from approximately 6 months onwards, constitutes the main phase of naive T-cell release and is accompanied by changes in the cytokine-production profiles of T-helper (TH) lymphocytes. IRIS has been linked to increases in CD4+ cells, CD8+ cells, the CD4+ T cell:CD8+ T cell ratio, and cytokine levels (e.g. of interleukin 6 and interferon γ), as well as to imbalances in TH1 and TH2 profiles and expression of chemokine receptors (e.g. CC-chemokine receptors 3 and 5) on monocytes and granulocytes.[42] IRIS typically occurs in the early stages of immune reconstitution, during the rapid increase in numbers of CD4+ cells that takes place via a thymus-independent, homeostatic, peripheral expansion of lymphocytes.

Shelburne suggested four diagnostic criteria for IRIS: a pre-existing diagnosis of AIDS; a response to anti-HIV therapy with increased CD4+ counts and decreased HIV-1 viral load; infectious or inflammatory symptoms that appear during anti-HIV therapy and cannot be explained by another etiology.[43] Unexpected exacerbation of inflammatory disease and atypical clinical features that resemble the symptoms of autoimmune disease might arise during IRIS. Organ-specific autoimmune phenomena such as Graves autoimmune thyroiditis and pulmonary sarcoidosis are increasingly being described and occur during immune reconstitution.[44] Generalized autoimmune diseases such as SLE, RA and polymyositis also occur. Most reported cases of IRIS seem to represent de novo autoimmunity, although approximately 20% are flares of a (previously mild) pre-existing disease that was in apparent remission because of the immunosuppressive effects of advanced HIV infection. The mean onset of IRIS symptoms is about 9 months from initiation of HAART.[33]

If a diagnosis of IRIS is made, HAART is continued and most symptoms resolve with little or no therapy. However, if the inflammatory symptoms involve areas where damage due to uncontrolled inflammation is likely to occur, such as the central nervous system or eye, HAART should be stopped and careful use of corticosteroids considered. Of note, IRIS is less likely to occur if the CD4+ T-cell count is below 200 when HAART is initiated. Most individuals with IRIS have a favorable prognosis, because the presence of a robust inflammatory response suggests that the patient will have an excellent response to HAART in terms of immune reconstitution and also, perhaps, improved survival.

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