Human Immunodeficiency Virus: Musculoskeletal ManifestationsDz

ICD-9 Code: HIV, 042.0.

Definition: A variety of rheumatic syndromes may be associated with HIV-1 infection.

Etiology: Some rheumatic syndromes (e.g., septic arthritis and pyomyositis) may result from immunodeficiency secondary to CD4 T cell depletion. Others such as the lymphocytic infiltrative syndromes are a consequence of the host response to chronic antigenic stimulation by HIV-1. The diffuse infiltrative lymphocytosis syndrome has been associated with certain human leukocyte antigens (HLA): HLA-B45, HLA-B49, HLA-B50, HLA-DR5, and HLA-DR6. Infection with HIV-1 causes immune dysregulation manifest as abnormal cytokine production, which may be responsible for inflammatory arthritis. CD8-dependent diseases such as Reiter ’s syndrome and psoriasis seem to have a more aggressive course in HIV-1 infection.

Demographics: Forty million people are infected with HIV worldwide. Rheumatic problems usually occur later in the disease or in those with evidence of recent progression to AIDS. Epidemiologic studies on those with Reiter syndrome and psoriasis have yielded conflicting data. In general, rheumatic syndromes in the HIV-positive population seem to occur with the same frequency as in immunocompetent populations, although they may be more aggressive or demonstrate atypical features.

Clinical Subsets: Several distinct syndromes have been reported in HIV-positive patients.
—Arthralgia/myalgia: This syndrome occurs in one-third of patients with HIV, usually later in the disease. These symptoms are thought to be reactive in nature rather than owing to direct infection with the virus.
—Inflammatory arthritis: An RF-positive, symmetric, erosive polyarthritis rarely occurs in HIV-1 infection, despite CD4 T cell depletion. There are anecdotal reports of patients with RA developing HIV infection with improvement of synovitis. However, this occurrence is rare, and the relationship between RA activity and HIV infection remains unresolved. There are more than 25 reports of HIV and SLE in the medical literature.
—Reiter’s syndrome and psoriatic arthritis: Onset is usually heralded by urethritis or enteritis and is later followed by skin and joint disease. Uveitis and sacroiliitis are rare. Cutaneous disease (psoriasis or keratoderma blenorrhagica) is very prominent. Keratoderma blenorrhagica, a papulosquamous eruption that occurs on the palms, soles, and penis, may be indistinguishable from pustular psoriasis. Oligoarticular arthritis (involving the knee or ankle), dactylitis, and enthesitis are common. Although features of SpA are often present, AS has not been associated with HIV or AIDS.
—Diffuse infiltrative lymphocytosis syndrome: This syndrome, a disorder resembling Sjögren’s syndrome, is caused by CD8 T cell infiltration with bilateral parotid gland enlargement (often massive), sicca symptoms (often minor), and prominent extraglandular sites of lymphocytic infiltration (lung, muscle, lymph nodes). CD8 T cell infiltration of the lung causes a lymphocytic interstitial pneumonitis presenting with dyspnea and can progress to fibrosis. Diffuse infiltrative lymphocytosis syndrome is associated with a very slow progression to AIDS.
—Myopathy: CD8 T cell infiltration may cause a myopathy indistinguishable from idiopathic PM, with elevated serum creatine kinase levels, proximal muscle weakness, and occasionally skin lesions characteristic of DM (heliotrope, Gottron papules, periungual erythema). HIV therapy with zidovudine (AZT) can cause a myopathy similar to PM but with less inflammatory infiltrate.
—Vasculitis: Sporadic reports in the literature describe HIV associated with hypersensitivity vasculitis (often a drug reaction), PAN, granulomatous angi-itis, or primary angiitis of the CNS.
—Musculoskeletal infections: As in normal individuals, S. aureus infection accounts for >70% of cases of nongonococcal septic arthritis. Such patients often present with an acute monarthritis with systemic symptoms. Pyogenic sacroiliitis, primarily occurring in intravenous drug users, is also usually caused by S. aureus. With advanced CD4 T cell depletion, fungal (e.g., cryptococcal) and mycobacterial septic arthritis have been reported. The arthritis is generally monarticular and more indolent, with subtle inflammation. Juxtaarticular osteomyelitis is not an uncommon complication. Pyomyositis, or deep muscle abscess, typically presents with acute muscle pain (often in the thigh), with woody induration, swelling, and erythema; it is usually caused by S. aureus.

Diagnostic Tests: Abnormalities vary with the clinical picture. HIV-positive patients may have a low incidence of low-titer ANA and RF. Others have been described with cryoglobulins, APL antibodies, and false-positive VDRL results.
—Arthritis: Monarthritis or oligoarthritis with systemic features (e.g., fever) should prompt consideration of diagnostic arthrocentesis, synovial fluid analysis with cell count, and cultures for bacteria, fungi, and mycobacteria. Serologic tests (ANA, RF) and HLA-B27 testing are occasionally needed to diagnose inflammatory arthritis or reactive arthritis.
—Myopathy: Serum creatine kinase, urine toxicology screen (i.e., cocaine), and withdrawal of zidovudine (if applicable) with repeat serum creatine kinase assay in 4 to 6 weeks should be considered. Persistent unexplained serum creatine kinase elevation should be investigated with EMG or muscle biopsy for evidence of inflammatory myositis. In pyomyositis, imaging studies (ultrasonography, CT, or MRI) are necessary for diagnosis and can be used for diagnostic aspiration, Gram stain, and culture.
—Suspected vasculitis: Biopsy of the most accessible or involved tissue (e.g., skin, nerve, liver, kidney) or angiography may be required to document vasculitis.
—Diffuse infiltrative lymphocytosis syndrome: Exocrine involvement can be documented by minor salivary gland biopsy or noninvasively with gallium-67 scans.

Therapy: Many patients with HIV infection can be safely treated with corticosteroids and a few selected agents detailed below. However, some immuno-suppressive medications (e.g., MTX, azathioprine, cyclosporine, cyclophosphamide) should be avoided because they may further immunosuppress the patient and predispose to disease progression or infections.
—Infectious musculoskeletal disease: Antimicrobial therapy should be tailored to the causative organism. Septic joints should be serially aspirated. Inaccessible joints such as the sacroiliac require imaging-guided aspiration.
—Reiter’s syndrome or psoriatic arthritis: Initially, optimize antiretroviral therapy. Consider using sulfasalazine (2–3 g/day in divided doses). Both indomethacin (75–150 mg/day) and hydroxychloroquine (400 mg/day) have proven beneficial and have anti-HIV effects as well. Effective treatment with thalidomide or TNF inhibitors (e.g., etanercept) has been described, although there is a concern about secondary infections.
—Polymyositis (PM): Can be safely treated with prednisone (0.5–1.0 mg/kg/day for 3 months and quickly tapered to minimum effective dose). Refractory patients may respond to intravenous gamma-globulin therapy.
—Diffuse infiltrative lymphocytosis syndrome: Frequently, this syndrome responds to antiretroviral therapy alone. Prednisone (20–40 mg/day) will rapidly decrease salivary gland size and improve lymphocytic interstitial pneumonitis. Taper to minimum effective dose. Patients seem to tolerate low-dose prednisone well.
—Vasculitis: High-dose corticosteroids may be necessary for those with systemic necrotizing vasculitis. Advanced HIV infection often precludes immunosuppressive therapy, but it has been used in some patients with life-threatening vasculitis.

Prognosis: The HIV stage often determines the prognosis. Patients with advanced HIV infection generally have a poorer response to therapy. Patients with diffuse infiltrative lymphocytosis syndrome generally respond well and are typically long-term nonprogressors. Vasculitis in HIV-1 has a poor prognosis. The protease inhibitors (relatively new, powerful antiretroviral drugs) can, in some instances, dramatically reverse clinical disease.

BIBLIOGRAPHY

Medina Rodríguez F. Rheumatic manifestations of human immunodeficiency virus infection. Rheum Dis Clin North Am 2003;29:145–161.