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. 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. 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-γ 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.
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). 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.
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.
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. 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. 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. 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 .
A spectrum of muscle involvement is associated with HIV-1 infection ( Box 2 ).
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). In one HIV outpatient clinic in Texas, HIV-associated myositis occurred in 0.22% of 4,998 HIV-infected patients. 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.
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.
Skeletal Muscle Biopsy Specimen From a Patient With HIV-associated Polymyositis. Hematoxylin and eosin staining shows multiple foci of mononuclear cell infiltrates within fascicles.
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 neuropathy (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, but we have reported a high prevalence of DILS in HIV-infected patients with inflammatory myopathy.
Studies published more than 15 years ago suggested that HIV patients with DILS had a better prognosis than other HIV patients. 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. 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. 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.
Minor Salivary Gland Biopsy Specimen From a Patient With Diffuse Infiltrative Lymphocytosis Syndrome. Hematoxylin and eosin staining shows focal lymphocytic infiltration.
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. 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.
The spectrum of vasculitis reported in HIV-infected patients ranges from involvement of the small vessels, in hypersensitivity vasculitis secondary to drug treatment, to involvement of the aorta and its branches. A polyarteritis-nodosa-like vasculitis has been described, which comprises necrotizing, vasculitic lesions in medium-sized vessels within muscle or epineurium resulting in symmetric sensorimotor neuropathies, mononeuritis multiplex, muscle pain, and digital ischemia. A rapidly progressive focal necrotizing vasculitis of the aorta and large arteries, with aneurysm formation and rupture or spontaneous fistulization, has been described among African patients with HIV infection. Kawasaki disease has been reported in both children and adults who are HIV-positive, including in association with the immune-reconstitution phenomenon. Primary angiitis and angiopathy of the central nervous system can present either as a progressive loss of neurological function or as a rapidly fulminant encephalitic illness, especially in children; diagnosis of these conditions is made by brain biopsy. Churg-Strauss vasculitis, Henoch-Schönlein purpura and Wegener's granulomatosis have all been described in HIV-positive patients. An improvement in Behçet's disease with the initiation of effective antiretroviral therapy has been reported; however, reappearance of this disease with HAART has also been described. Determination of the patient's antineutrophil antibody status can aid the diagnosis of HIV-associated vasculitis; however, biopsies and bacterial cultures are important to rule out infections that can mimic these conditions. Corticosteroids or other immunosuppressive therapies such as intravenous immunoglobulin and cyclophosphamide are used to treat life-threatening vasculitic complications that involve the lungs, kidneys, or central nervous system, in conjunction with effective antiretroviral therapy.
Concomitant HIV infection and RA or SLE have been rarely described. SLE can be difficult to distinguish from HIV infection because of the high frequency of rheumatic complaints and autoantibodies in untreated HIV-positive patients and the protean multisystem manifestations of these conditions. Immunologically, T-cell abnormalities, including a decrease in CD4+ T cells, dysfunction of CD4+ and CD8+ T cells, polyclonal B-cell activation and similar changes of cytokines and chemokines, occur in the course of both diseases. When HIV and SLE coexist, active SLE can be difficult to distinguish from the primary or secondary manifestations of HIV infection. Findings of antibodies to double-stranded DNA and hypocomplementemia, neither of which is typically seen with HIV infection, might be helpful to ascertain the presence of active SLE. Pre-existing SLE can go into remission with HIV infection, especially in patients with low CD4+ T-cell counts, and can re-emerge or manifest de novo during immune reconstitution. Use of immunosuppressive agents to treat active SLE can also lead to dramatic increases in HIV viral loads.
The observation that patients with RA entered remission when they became infected with HIV initially suggested that these diseases were mutually exclusive. Subsequent case reports of the progression of destructive RA in HIV-infected patients, even those with depleted CD4+ T-cell counts, seemed to imply that the disease activity of RA might be independent of CD4+ lymphocyte numbers and function. In all such patients who have been described in the published literature, RA responded to standard DMARDs.
The emergence of immune-reconstitution inflammatory syndrome (IRIS) has, however, shown that new-onset RA and SLE can occur in the face of increasing CD4+ T-cell counts.
There are no data to suggest that bacterial infections of bones or joints with the usual infectious agents -- such as Staphylococcus aureus -- occur more frequently in patients infected with HIV than in the general population. One study of 482 HIV-infected patients admitted to a large, Italian university hospital between 1985 and 1996 found that S. aureus was the most common infectious agent encountered, but that parenteral drug use and not HIV infection per se accounted for these infections. Atypical mycobacterial septic arthritis or osteomyelitis is a late complication of HIV infection, which usually occurs when the CD4+ T-lymphocyte count is below 100/µl. Etiologic agents include the Mycobacterium avium complex, M. kansasii, M. haemophilum, M. terrae, and M. fortuitum. M. haemophilum is most frequently implicated in skeletal infections accounts for more than 50%; M. kansasii is the second most frequent skeletal infection, and accounts for an additional 25% of cases. Cutaneous lesions such as nodules, ulcers, and draining sinus tracts occur in approximately 50% of patients.M. tuberculosis arthritis seems to be no more frequent in HIV-positive than in HIV-negative individuals, but skeletal tuberculosis might emerge during immune reconstitution following effective HAART, in association with the expected virologic response. Fungal infections of the muscle and bone, such as disseminated histoplasmosis, cryptococcosis, sporotrichosis and blastomycosis, occur in patients with HIV and often cause osteomyelitis or septic arthritis and/or bursitis. Aggressive antimycobacterial or antifungal treatment, and possibly surgical drainage, is necessary. Toxoplasmosis can cause muscle weakness and elevations in levels of muscle enzymes, which mimics the effects of other types of myositis that can occur in the setting of HIV infection.
Nat Clin Pract Rheumatol. 2008;4(8):428-438. © 2008
Nature Publishing Group
Cite this: Therapy Insight: The Changing Spectrum of Rheumatic Disease in HIV Infection - Medscape - Aug 01, 2008.