1. Home>
2. Specialties>
3. HIV/AIDS Clinical Care>
4. Feature

Musculoskeletal Manifestations of HIV Disease

Musculoskeletal disease in HIV patients can represent opportunistic infections, noninfectious HIV complications such as malignancy, toxicities of therapy, or an unrelated rheumatologic disorder whose course has been altered by the effects of HIV infection on the immune system. The relation between HIV and autoimmune rheumatologic conditions has proven complex and controversial, while musculoskeletal infections appear to be surprisingly uncommon.

The prevalence of musculoskeletal complaints in HIV patients is high and appears to increase with disease progression. Large cohort studies of HIV patients from Baltimore, Cincinnati, San Francisco, and Spain report a prevalence in the 5.5% to 11% range. In prospective studies at HIV specialty clinics in Tampa and Canada, 65% to 71% of patients, most of whom had advanced HIV disease, reported nonspecific arthralgias or other rheumatic complaints. Musculoskeletal symptoms have been reported in 66% of HIV patients in Buenos Aires, and a marked increase in rheumatologic conditions, particularly Reiter's syndrome, has been reported in HIV patients in sub-Saharan Africa. Although most published prevalence studies are plagued by selection bias, providers caring for HIV patients in diverse populations are still likely to encounter musculoskeletal conditions in their practices.

Arthritis

Arthralgias and frank arthritis are the most common forms of musculoskeletal disease in HIV patients. In general, nonspecific arthralgias typically affect the large joints, including the knees and ankles, and can range from mild, intermittent symptoms to chronic, severe disease. Classification of different types of arthritic disease can be difficult, as HIV patients often present with incomplete or unusual manifestation of specific rheumatologic conditions, and the pathogenesis of HIV-related arthritides is incompletely understood. A useful approach divides HIV-related arthritides into five types: spondylarthropathies, including Reiter's syndrome and psoriatic arthritis; acute symmetric polyarthritis, including rheumatoid arthritis; HIV-associated (nonspecific) arthritis; painful articular syndrome; and septic arthritis. Each of these will be discussed below. Keep in mind that individual HIV patients may present with features of more than one process, and that the stage of HIV disease, coexisting conditions, and treatment regimen will further modify clinical presentations.

An association between HIV infection and various immune-mediated rheumatologic conditions -- including Reiter's syndrome, psoriatic arthritis, and rheumatoid arthritis -- has been postulated since the earliest days of the epidemic. As described below, the data are inconsistent, and the relation between HIV and these conditions, as well as potential pathophysiologic mechanisms, remain controversial.

Spondylarthropathies

Among the spondylarthropathies, Reiter's syndrome (also called "reactive arthritis") has been most closely linked to HIV. Classic Reiter's syndrome presents as large-joint arthritis, conjunctivitis, and urethritis or cervicitis, often following enteric or urogenital infection. Oral ulcers, circinate balanitis (a vesicular rash of the glans penis), and keratoderma blennorrhagica (a psoriatic rash of the palms and soles) occur frequently. In HIV patients an "incomplete" form of Reiter's syndrome is more common than the classic form and may be difficult to distinguish from nonspecific arthritis. The manifestations of Reiter's syndrome are often self-limited; severe or persistent disease merits therapy. Use of methotrexate has been associated with worsening immunodeficiency in some HIV patients, so alternative drugs or extremely judicious use of methotrexate is warranted. Encouraging results from sulfasalazine treatment have been anecdotally reported.

The relation between HIV-related Reiter's syndrome and antecedent enteric infections and the HLA B27 class I antigen, well known in nonimmunocompromised hosts, remains unclear. A 1987 report on 13 HIV patients suggested that a predisposition to Reiter's syndrome may play a role. Subsequently, prevalence rates for Reiter's syndrome as high as 4% to 11% were reported in HIV referral populations. Moreover, a survey in Zimbabwe, where spondylarthropathies are unusual, found 14 of 20 consecutive patients who were diagnosed with Reiter's syndrome also to be HIV positive; none were HLA B27 positive. However, large surveys of HIV-positive cohorts in Spain and the United States have found a prevalence of only 0.3% to 0.5% for Reiter's syndrome, in line with expected prevalence in HIV patients.

Psoriatic arthritis, which can be difficult to distinguish from Reiter's syndrome and may have a similar immunopathogenesis, has been described at higher than expected frequencies in HIV patients. As with Reiter's syndrome, methotrexate is relatively contraindicated but has been used successfully in severe cases. Oral gold therapy is an alternative. In both psoriatic arthritis and Reiter's syndrome, treatment and control of the rheumatologic disease has been associated with a rise in CD4 cell counts, although the significance of this observation remains unclear.

Acute Symmetric Polyarthritis and Rheumatoid Arthritis

An uncommon inflammatory arthritis of the small joints, hands, and fingers has been described in several individual reports and case series. Distinguishing this condition from rheumatoid arthritis or from the HIV-associated arthritis described below may be difficult. Clinically, it behaves like rheumatoid arthritis, with acute onset of symptoms, morning stiffness, and an indolent course, but patients are negative for the rheumatoid factor.

The relation between HIV and rheumatoid arthritis (RA) has been even more controversial than that between HIV and the spondylarthropathies. Case reports from 1983 to 1985 described the hypothesis that RA results from processing of unknown antigen triggers by class II major histocompatibility complex molecules, leading to activation of autoreactive CD4 cells and CD4-mediated synovitis and joint inflammation. Subsequently, the notion that RA regresses when there is coexisting HIV disease was widely disseminated. Recently, though, several cases of severe RA in the setting of progressive HIV disease have called this into question. Clinicians should realize that the debate on the relation between HIV and RA rests on only a handful of case reports and theoretical models of RA pathogenesis. In the absence of case-control studies or a better understanding of the immune mechanisms underlying RA, the exact nature of the relationship remains speculative.

HIV-Associated Arthritis

Monoarthritis and oligoarthritis without a definable infectious or rheumatologic cause is well known in HIV patients. This "nonspecific" arthritis generally presents with moderate to severe effusions of the knees and occasionally other joints. HIV has been isolated from the synovial fluid of several patients in the absence of other opportunistic pathogens. There does not appear to be any HLA association. Most cases are self-limited or respond to nonsteroidal antiinflammatory medications. Severe cases will respond to intraarticular steroid injections.

Painful Articular Syndrome

A 1988 report described four HIV patients from Albany and Boston who presented with a subacute onset of severe pain in the knees, ankles, and shoulders, with symptoms lasting 2 to 24 hours. The syndrome has since been recognized in several case series, with a reported prevalence as high as 10% in selected populations with advanced HIV disease. The pathophysiology is unknown, but the syndrome appears to be distinct from nonspecific HIV-associated arthritis. Joint fluid analysis of these patients reveals a sterile inflammatory synovitis, and radiographic evaluation is normal. Treatment consists of pain control, which frequently requires narcotics.

Septic Arthritis

Septic arthritis is surprisingly uncommon in the HIV population. A recent observational study from Atlanta identified only 10 cases of septic arthritis in more than 3,000 HIV patients followed over a five-year period. Earlier cases series from Tampa and London support its relative rarity. The disease does not appear to be associated with advanced HIV infection, as most patients reported have had CD4 counts greater than 200 cells/mm³. Not surprisingly, Staphylococcus aureus and Neisseria gonorrhoeae are the most common pathogens isolated; other organisms include histoplasma, Mycobacterium tuberculosis, streptococcus species, and salmonella species, the latter especially in regions of high salmonella endemicity. A recent literature review on septic arthritis in HIV revealed only 99 case reports of either common or unusual pathogens, including candida and other fungi, gram-negative organisms, and the atypical mycobacteria, including M. haemophilus and M. terrae.

Myositis

Three distinct muscle diseases affect HIV patients. Myopathy is well recognized as a toxicity of AZT therapy. The etiology remains unproved but has been postulated to result from an interaction between AZT and mitochondrial DNA polymerase. Myopathy occurs in up to 6% of patients on AZT for more than 6 months and is independent of CD4 count and stage of HIV disease. Clinically it presents with proximal muscle weakness, myalgias, muscle wasting, and elevated creatine phosphokinase (CK) levels. Muscle biopsy reveals "ragged red fibers," a relative lack of inflammation, and characteristic mitochondrial distortion. Symptoms will usually reverse with cessation of AZT therapy; prednisone has been used as adjunctive therapy.

HIV-related polymyositis can be difficult to distinguish from AZT myopathy. Its clinical features -- progressive proximal muscle weakness and elevated CK -- are similar to those of AZT myopathy and polymyositis in the non-HIV patient. Muscle biopsy reveals a perivascular lymphocytic infiltrate that is easily distinguished from the histopathology of AZT myopathy. Although HIV can be detected in some infiltrating mononuclear cells in these patients, the pathophysiology of HIV-related polymyositis remains unknown.

Infectious myositis, also called pyomyositis or tropical myositis, was a rare diagnosis in temperate climates prior to the HIV era. Infectious myositis presents subacutely over two to three weeks; three phases have been described. The initial invasive phase is marked by local tenderness and mild swelling of the involved muscle, and occasionally with low-grade fevers. After one to three weeks, a purulent phase develops, with painful induration, edema, local heat without erythema, and systemic fevers. Most patients present during this phase and may have leukocytosis and an elevated sedimentation rate, but CK levels are usually surprisingly low. Blood cultures are rarely positive at this stage. MRI is the most sensitive diagnostic tool, but ultrasound and CT scanning will also reveal a purulent abscess in the involved muscle; occasionally more than one muscle is involved. Left untreated, a third disseminated phase ensues, with septic shock and associated morbidity.

The incidence of infectious myositis has increased in North America and temperate climates since 1980, and HIV has been identified as a risk factor. In the tropics the overwhelming majority of cases are due to S. aureus; no single phage type has been identified, and the pathophysiology is poorly understood. Most nontropical cases are also due to S. aureus, and a small percentage to streptococcus species. There are several case reports of unusual causative organisms in HIV patients, including salmonella, cryptococcus, microsporidia, nocardia, toxoplasma, and gram-negative organisms. Accurate diagnosis and treatment relies on a high clinical index of suspicion, as patients often present with nonspecific findings and infectious etiologies may be overlooked.

Osteomyelitis

Osteomyelitis in the HIV patient population is also uncommon. Most reported cases derive from small case series and individual reports; larger prospective studies from Atlanta, San Francisco, and Spain revealed few cases, with prevalence rates ranging from 0.5% to 2%. Although the distinction between contiguous and disseminated infections applies to HIV patients, opportunistic pathogens such as atypical mycobacteria can reach bone through any of several mechanisms, including direct inoculation, reactivation, contiguous spread, and hematogenous dissemination. Thus the presentation of osteomyelitis in HIV patients, particularly in advanced HIV disease, may not resemble the local, indolent process commonly seen in immunocompetent patients. Reported mortality rates for HIV-related osteomyelitis have been extremely high, upwards of 20%, likely reflecting concomitant infection of other organs and advanced AIDS.

The microbiology of osteomyelitis in HIV varies widely depending on geography, CD4 count, and stage of HIV disease. Early in the course of HIV disease, S. aureus is the most common pathogen, especially in the United States and among intravenous drug users. In endemic areas, skeletal tuberculosis is not uncommon, although large case series are lacking. In advanced HIV disease, atypical mycobacteria, especially M. haemophilum and M. kansasii, have been identified as causes. Osteomyelitis in the setting of disseminated Mycobacterium avium complex (MAC) disease has also been reported, although focal MAC osteomyelitis is exceedingly rare. Interestingly, in prospective case series in the United States, M. tuberculosis has been underrepresented as a cause of osteomyelitis. Bartonella osteomyelitis has been increasingly identified in a San Francisco cohort of HIV patients. Other reported pathogens include nocardia, salmonella, cytomegalovirus, and fungi. In addition to infection, other important diagnostic considerations in the evaluation of bony lesions in HIV patients include Kaposi's Sarcoma (KS), avascular necrosis, and lymphoma. Radiographic imaging studies are entirely nonspecific. In particular, although bony KS usually presents as an erosive lesion in the setting of known KS in other organs, differentiating KS from bacillary angiomatosis due to bartonella in a patient with nodular skin lesions and bone disease can be difficult, and biopsy is necessary.

Summary

HIV can have myriad effects on joint, muscle, and bone. Clinicians should remain aware of the variety of presentations of HIV-related joint disease, the potential interactions between HIV immunodeficiency and autoimmune arthropathies, and the need for a high level of clinical suspicion when diagnosing a musculoskeletal infectious presentation.

— William Rodriguez, MD

Dr. Rodriguez is currently Chief Medical Resident at the Brigham and Women's Hospital and recently completed a clinical infectious diseases fellowship at Massachusetts General Hospital and Brigham and Women's Hospital.

Published in AIDS Clinical Care July 1, 1998