Correspondence *Division of Rheumatology, The University of Texas Health Science Center at Houston, 6431, Fannin, Houston, TX 77030, USA

Email john.d.reveille@uth.tmc.edu

Introduction

In the 26 years since the first reported cases of HIV infection, the disease has attained pandemic status, especially in sub-Saharan Africa and Central Asia. Therapeutic developments and improved utilization of public resources, however, mean that treatments are available to most patients, at least in the developed world. By the end of 2006, the Joint WHO–United Nations Programme on HIV and AIDS estimated that the number of people who were living with the virus globally was 33.5 million, which represented a decrease from the estimates of previous years.¹ This reduction in estimated numbers is partly caused by genuine declines in HIV prevalence in several countries. In addition to the declining prevalence of HIV, the number of deaths from AIDS is also thought to have fallen from approximately 3.1 million in 2005 to 2.9 million in 2006.¹ As mortality from AIDS decreases, the morbidity associated with chronic conditions (and their treatment) in HIV-infected individuals becomes increasingly apparent, and rheumatic diseases, therefore, are encountered increasingly often in this population. Since the first reports of rheumatic disease in HIV-positive patients in the 1980s,² the spectrum of rheumatic conditions associated with HIV and AIDS has evolved, especially with the introduction of highly active antiretroviral therapy (HAART).

Pathogenesis of autoimmunity in patients with HIV and/or AIDS

The fact that autoimmune and inflammatory diseases can occur despite an apparent loss of immunocompetence caused by HIV infection is a true paradox.³ In general, one would expect that illnesses mediated by CD4⁺ T cells—such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE)—would occur less frequently in this setting, but this pattern is not seen in practice (Box 1). The worldwide distribution of rheumatic manifestations in patients with HIV is shown in Supplementary Table 1 online. Diseases in which CD8⁺ T cells are predominant, such as psoriasis, reactive arthritis and diffuse infiltrative lymphocytosis syndrome (DILS), also occur in HIV-infected patients, and can even be the initial manifestation of AIDS in such patients. The degree of immunosuppression, reflected by CD4⁺ T-cell counts, correlates with the diseases that are likely to be encountered.

T regulatory cells, a subset of CD4⁺ T cells whose main function is to maintain peripheral self-tolerance and avoid the development of autoimmunity, are specifically depleted in active HIV infection.⁴ Cytokine production is believed to be important in HIV pathogenesis, and possibly contributes to the development of autoimmune complications. During the primary phase of HIV infection, numerous inflammatory cytokines such as tumor necrosis factor (TNF), interleukin 6, interleukin 12 and interferon- can be detected in serum. In subsequent stages of the disease, increased concentrations of TNF have been correlated with increased levels of viral replication. As in other virus-mediated autoimmune diseases, the molecular mimicry that results from homology between HIV and host antigens might have a role in pathogenesis.

Arthralgias and arthritis

Unexplained arthralgias and myalgias occur in about 5% of patients with HIV, sometimes in association with HIV seroconversion. HIV-associated arthralgia rarely progresses to inflammatory joint disease and is treated symptomatically.

HIV-associated arthritis is usually an oligoarthritis that predominantly involves the lower extremities; it tends to be self-limited and to last less than 6 weeks (Figure 1).⁵ However, some patients with HIV-associated arthritis have been reported to have a disease course of more than 6 weeks with joint destruction. Synovial fluid cultures are typically sterile, and radiographs of the affected joints are usually normal, except in those rare patients with a prolonged duration of symptoms, in whom joint-space narrowing can occur.

Figure 1 MRI scans of a patient with HIV-associated arthritis.

(A) Erosive changes in the scaphoid, capitate, and ulnar styloid process of the right wrist appear as bright signals on a coronal T₂-weighted image with fat saturation (2,500/80). (B and C) Bulging of the flexor retinaculum on axial MRI scans of the right wrist, taken at the level of the scaphoid. The median nerve is bright on the T₂-weighted image (B) (4,917/88), and is enhanced with contrast on the T₁-weighted image (C) with fat saturation (630/9). These findings indicate carpal tunnel syndrome. Permission obtained from Springer © Tehranzadeh J et al. (2004) Skeletal Radiol 33: 311–320.

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A dramatic increase in the prevalence of spondyloarthritis—primarily reactive arthritis and undifferentiated spondyloarthritis, and to a lesser extent psoriatic arthritis—was noted with the spread of the HIV pandemic in Africa. This suggests a pathogenic role for HIV infection in these diseases.⁶ Spondyloarthritis is associated with HLA-B27 positivity in white individuals, but not in black Africans. The most typical presentation is a seronegative peripheral arthritis that predominantly involves the lower extremities and is usually accompanied by enthesitis (sausage-like swelling of toes or fingers, Achilles tendonitis, and plantar fasciitis). Mucocutaneous disease features are common, especially keratoderma blennorrhagicum (Figure 2) and circinate balanitis; psoriasiform skin rashes are also common and can be extensive. The clinical overlap between the symptoms of HIV-associated reactive arthritis and those of psoriatic arthritis can make their differential diagnosis difficult, which has led to speculation that these entities represent points along a disease continuum.⁷ Axial involvement and uveitis seem to be uncommon in HIV-associated spondyloarthritis, but do occur. The clinical, diagnostic, and radiographic features of HIV-associated spondyloarthritis are indistinguishable from those of the conventional HLA-B27-related disease, although HIV-positive patients have a higher overall frequency of uveitis, keratoderma, and onycholysis, and often a worse outcome, than HIV-negative patients.⁸ Most HIV-positive patients with arthritis do well with conventional drugs but respond best to initiation of antiretroviral treatment. The differences between HIV-associated arthritis and reactive arthritis are shown in Table 1.

Figure 2 Keratoderma blenorrhagicum in a patient who has HIV with reactive arthritis.

 

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Table 1 Contrasting features of HIV-associated arthritis and reactive arthritis.

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HIV-associated polymyositis

A spectrum of muscle involvement is associated with HIV-1 infection (Box 2).

Box 2 Myopathies that occur in HIV-infected patients.

 

HIV-associated myopathies

HIV polymyositis

Inclusion-body myositis

Nemaline myopathy

Diffuse infiltrative lymphocytosis syndrome

HIV wasting syndrome

Vasculitic processes

Myasthenia gravis and other myasthenic syndromes

Chronic fatigue and fibromyalgia

 

Myopathies secondary to antiretroviral therapy

Zidovudine myopathy

Toxic mitochondrial myopathies related to other nucleoside analog reverse transcriptase inhibitors

HIV-associated lipodystrophy syndrome

Immune-restoration syndrome related to highly active antiretroviral therapy

 

Other myopathies

Opportunistic infections that involve muscle

Tumor infiltrations of skeletal muscle

Rhabdomyolysis

A subacute, progressive, proximal muscle weakness with raised creatine kinase levels can be the initial presentation of HIV infection. Skin involvement is unusual, as is involvement of extraocular and facial muscles. The clinical and histopathological features of HIV-associated polymyositis are basically similar to those of polymyositis in patients who are not infected with HIV (Figure 3). Electromyography typically shows short-duration, polyphasic, motor-unit potentials and abnormal spontaneous activity, but a number of patients have normal electromyography findings. Serum creatine kinase levels are often increased, but this characteristic does not correlate with disease severity. Muscle biopsy is the definitive test for establishing a diagnosis of polymyositis and excluding other conditions, especially infectious etiologies such as toxoplasmosis or human T-cell lymphotropic virus type I in conjunction with specific serologic findings. Biopsy may show the characteristic triad of scattered necrotic and basophilic fibers, multiple foci of mononuclear inflammatory cells within fascicles, and focal invasion of non-necrotic muscle fibers by inflammatory cells. Most often, however, the lesions are less well-defined, and may include rare necrotic fibers and inflammatory infiltrates without a clear focal attack on muscle fibers (Figure 4).⁹ In one HIV outpatient clinic in Texas, HIV-associated myositis occurred in 0.22% of 4,998 HIV-infected patients.¹⁰ Overall, the prognosis of patients with HIV-associated polymyositis is fairly good, and treatment is the same as for polymyositis in the non-HIV setting, albeit with careful attention to the degree of immunosuppression.

Figure 3 Polymyositis associated with HIV infection.

Axial T₂-weighted MRI scans (A) without (10,850/90.0) and (B) with fat saturation (6,536/90.0) show a slightly increased signal in the quadriceps muscles of both legs, to a greater extent on the left than the right. Permission obtained from Springer © Tehranzadeh J et al. (2004) Skeletal Radiol 33: 311–320.

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Figure 4 Skeletal muscle biopsy specimen from a patient with HIV-associated polymyositis.

Hematoxylin and eosin staining shows multiple foci of mononuclear cell infiltrates within fascicles.

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Diffuse infiltrative lymphocytosis syndrome

DILS is characterized by parotid-gland enlargement and peripheral CD8⁺ lymphocytosis, which is often accompanied by sicca symptoms and extraglandular features. DILS is found in about 3–4% of HIV-positive individuals.^{11, 12} Submandibular and lacrimal gland enlargement often occurs (Figure 5). A subset of extraglandular features are prominent in patients who are not on antiretroviral therapy, including lymphocytic interstitial pneumonitis, irreversible palsy of cranial nerve VII (caused by mechanical compression of the nerve by inflamed parotid tissue), peripheral neuropathy¹³ (characterized by marked CD8⁺ T-cell infiltration and abundant HIV particles in nerves), and, less commonly, renal tubular acidosis, polymyositis, lymphocytic hepatitis, and lymphoma. In DILS, lymphocytic infiltration of muscles is usually found in the setting of peripheral neuropathy,¹⁴ but we have reported a high prevalence of DILS in HIV-infected patients with inflammatory myopathy.

Figure 5 Parotid salivary gland enlargement in a patient with diffuse infiltrative lymphocytosis syndrome.

 

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Studies published more than 15 years ago suggested that HIV patients with DILS had a better prognosis than other HIV patients.¹⁵ The incidence of DILS has decreased since the introduction of HAART. This suggests that DILS is caused by a viral-driven response, and its primary treatment should be antiretroviral therapy.¹⁶ Studies of circulating and tissue-infiltrating lymphocytes and analysis of salivary-gland T-cell receptor sequences suggested that DILS results from MHC-restricted, antigen-driven, oligoclonal selection of CD8⁺, CD29^- lymphocytes that express selective homing receptors. These lymphocytes infiltrate the salivary glands (Figure 6), lungs, and other organs, where they are postulated to suppress HIV-1 replication.¹⁷ Biopsies of minor salivary glands show focal sialadenitis, similar to that observed in Sjögren's syndrome, although there tends to be less destruction of the salivary glands in DILS than in Sjögren's syndrome. CD8⁺ lymphocytes constitute most of the inflammatory infiltrate, in contrast to that seen in primary (non-HIV-associated) Sjögren's syndrome.

Figure 6 Minor salivary gland biopsy specimen from a patient with diffuse infiltrative lymphocytosis syndrome.

Hematoxylin and eosin staining shows focal lymphocytic infiltration.

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Diagnostic criteria for DILS have been proposed: HIV seropositivity, confirmed by enzyme-linked immunoassay and western blot analysis; bilateral salivary gland enlargement or xerostomia that has persisted for more than 6 months; and finally, either histologically confirmed lymphocytic infiltration of the salivary or lacrimal glands in the absence of granulomatous or neoplastic enlargement, or comparable findings on ⁶⁷Ga scintigraphy of the salivary glands.¹⁸ Biopsies of minor salivary glands usually gave definitive results in the pre-HAART era (Figure 6), but biopsies from patients with DILS who are taking HAART can appear normal. Confirmatory ⁶⁷Ga scintigraphy should be performed instead. Antiretroviral therapy is an effective treatment for the complications of DILS. Low-to-moderate doses of corticosteroids are an effective treatment for both the glandular swelling and sicca symptoms, although this effect is transient. Lymphocytic interstitial pneumonitis might require up to 60 mg per day of prednisone, sometimes for extended periods.

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

Immune reconstitution inflammatory syndrome

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 (T_H) 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 ), as well as to imbalances in T_H1 and T_H2 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.

Table 2 Case reports of non-organ-specific autoimmune disease that occurred after initiation of HAART.

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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.

Treatment of rheumatic disease coexistent with HIV infection

The treatment of rheumatic diseases is broadly similar in HIV-positive and HIV-negative individuals. Most HIV-positive patients with rheumatic diseases do well with conventional anti-inflammatory therapy, but some might require cytotoxic therapy. The major caveats are potential drug interactions (e.g. between statins and protease inhibitors) and advanced immunosuppression (CD4⁺ T-cell count of less than 200/mm³).

Indomethacin directly inhibits HIV-1 replication.⁴⁵ Sulfasalazine is an effective treatment for HIV-associated arthritis and has been shown to improve CD4⁺ T-cell counts.⁴⁶ Hydroxychloroquine inhibits replication of HIV-1 in vitro.⁴⁷ Short-term prednisone use is safe even in advanced HIV infection.^{48, 49}

The experience with biologic agents, especially anti-TNF drugs, is growing. A study that investigated the effects of etanercept treatment in HIV-infected patients without rheumatic diseases also suggested that anti-TNF therapy is safe in such patients.⁵⁰ Several case reports that described the successful use of etanercept to treat RA⁵¹ and reactive or psoriatic arthritis,⁵² and of infliximab to treat reactive arthritis,⁵³ psoriasis⁵⁴ and Crohn's disease⁵⁵ in the setting of HIV infection attest to the safety and efficacy of these agents. In addition, rituximab has been used to treat patients with HIV-associated lymphomas, and one case report has described the use of rituximab to treat refractory immune thrombocytopenia in a HIV-infected patient.⁵⁶ Currently, however, there are no reports of rituximab therapy in HIV-associated rheumatic disease.

Whether or not TNF blockade is beneficial, detrimental or has any effect on the course and outcome of HIV and/or AIDS remains to be elucidated. However, the available literature indicates that anti-TNF agents do not worsen the morbidity or mortality of HIV-infected people. Ultimately, physicians must remain vigilant for the appearance of infections known to be associated with anti-TNF therapy (tuberculosis, histoplasmosis, coccidiomycosis, etc.).

Conclusions

The impact of the global HIV pandemic continues to grow, and consequently rheumatologists need to be aware of the wide spectrum of rheumatic diseases that occur in HIV-positive individuals. HAART has changed the natural history of HIV infection: this therapy has modified the frequency and presentation of some HIV-related clinical syndromes and has been associated directly (via toxic effects) and indirectly (via immune reconstitution) with the development of new ones. Prudent use of immunosuppressive therapy and constant vigilance for unusual and opportunistic infections are necessary. Rheumatologists need to be aware of these changes to ensure they can provide accurate diagnosis and optimum treatment for this group of patients.

Acknowledgments

The authors would like to acknowledge the support of the Thomas Street Directors—including TR Cate, MD (1989–1991), SM Miller (1991–1998), C Lehard, MD (1998–2005), and T Giordano, MD (2005–present)—throughout the period that their research was being carried out. The authors' work was supported by a grant from the University of Texas Health Science Center at Houston Clinical Research Center, and the Center for AIDS Research, Baylor College of Medicine.

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Supplementary information

Supplementary Table 1 (doc 79K)

Worldwide distribution of rheumatic manifestations in HIV patients

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Subject areas under which this article appears: Comorbidities | Miscellaneous rheumatic diseases