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Rheumatologic
Rheumatologic and Musculoskeletal Manifestations of HIV
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General Considerations
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Bones and Joints
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Muscle Pain or Myositis
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Psoriasis and Psoriatic-Like Arthritis
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transparent imageClinical Manifestations
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transparent imagePathogenesis
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Reiter's Syndrome
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transparent imageFrequency in HIV-Infected Persons
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transparent imageClinical Manifestations
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transparent imagePathogenesis
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HIV-Associated Salivary Gland Disease (Sjogren's Syndrome and Diffuse Infiltrative Lymphocytosis)
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transparent imageClinical Presentation
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transparent imagePathogenesis
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transparent imageDifferential Diagnosis of Sicca Syndrome in HIV-Infected Patients
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transparent imageTreatment
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Myositis in HIV-Infected Patients
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transparent imagePolymyositis
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transparent imageDermatomyositis
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transparent imageTherapy and Response to Therapy
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transparent imageZidovudine-Associated Myositis
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References
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Tables
Table 1.Musculoskeletal Syndromes in HIV-Infected Patients
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General Considerations
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Musculoskeletal syndromes that occur in HIV-infected patients include manifestations of drug toxicity, reactive arthritis, Reiter's syndrome, infectious arthritis, and myositis (Table 1).

Principles to keep in mind when evaluating an HIV-infected patient with a musculoskeletal syndrome include the following:

  1. Any musculoskeletal syndrome in non-HIV infected patients can occur in HIV-infected patients; such syndromes may not be related to the HIV infection.

  2. HIV infection can alter clinical presentation and course. Reactive arthritis, inflammatory arthritis, or musculoskeletal infections may be more severe in presentation and course in HIV-infected persons. In some cases, musculoskeletal infections may be more insidious and subtle in onset.

  3. Ruling out or correctly diagnosing infections is especially important to prevent the spread of infection in an immunocompromised patient.

  4. The probability of an opportunistic infection as a cause for a musculoskeletal complaint depends on the stage of the patient's HIV disease. At early stages (CD4 count above 300), opportunistic infections are unlikely, although resistance to common bacterial pathogens may be reduced.

  5. Generally, diagnostic tests and treatment regimens for musculoskeletal syndromes are the same as when the syndromes occur in non-HIV infected patients, except that the patient's HIV-related medications may cause side effects and interactions that impact differential diagnosis and limit therapeutic options, and there should be a very high threshold to using immunosuppressive drugs.

Some risk factors for HIV infection are also risk factors for other conditions that may present as musculoskeletal syndromes. Examples include injection drug use and arthritis associated with hepatitis B virus infection or endocarditis, sexual promiscuity and the arthritis syndromes associated with sexually transmitted infections such as gonorrhea and chlamydia, and hemophilia and hemarthrosis. Clinicians need to examine HIV-infected patients who present with acute or subacute musculoskeletal pains for evidence of infection in the joints and muscles. Careful examination of the skin may reveal a fungal infection that has spread to the joints. Septic arthritis may be difficult to differentiate from reactive arthritis, but cultures of the synovial fluid and blood will be sterile in cases of reactive arthritis. Septic arthritis in HIV-infected injection drug users (IDUs) is most commonly due to Staphylococcus aureus and usually responds well to treatment. In patients with advanced HIV disease who are not IDUs, clinicians must always consider opportunistic infections in joints, bones, and muscles. HIV-infected patients with muscle pain and weakness must be evaluated for idiopathic polymyositis, myositis secondary to zidovudine (AZT) toxicity, and infectious pyomyositis. Although many clinicians believe that HIV infection predisposes patients to musculoskeletal infections and has a negative impact on the outcome of the therapy, this hypothesis is not yet proved.

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Bones and Joints
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Both Reiter's syndrome and septic bursitis can cause a monarticular arthritis in an HIV-infected patient.(1) Evaluation of synovial fluid is necessary to rule out infection and make a diagnosis. Clues to help the clinician differentiate between infectious and reactive arthritis in patients with HIV disease include a history of urethritis, cervicitis, diarrhea, or conjunctivitis, and findings of psoriasiform lesions, nail changes, and enthesopathy (inflammation of tendinous insertions), as these may accompany a reactive arthritis.

The onset of reactive arthritis in HIV-positive patients usually occurs in the foot and ankle, and the common types of inflammation are enthesopathy (involving the Achilles tendon, plantar fascia, or anterior and posterior tibial tendons) and multidigit dactylitis. Synovitis is rare but may occur in joints of the lower extremities. In the upper extremities, dactylitis and enthesopathy occur in the tendinous insertions in the lower part of the arms. Cutaneous symptoms include psoriasiform rashes, keratoderma blennorrhagicum, and onychodystrophy.

In reactive arthritis, the synovial fluid is usually inflammatory, with a few thousand white blood cells and a synovial glucose level that is at least two thirds the serum glucose level. Gram stain or culture of synovial fluid is the only reliable way to make the diagnosis of a septic arthritis or bursitis. If the diagnosis is entertained, aspiration and culture should be performed immediately. If the synovial fluid is purulent, it may be prudent to initiate broad antibiotic coverage while waiting for the results of definitive synovial fluid cultures. Also, if the synovial fluid is initially unobtainable (as in axial joint infection), it is prudent to initiate antibiotic coverage. Blood cultures should be obtained during the work-up of the arthritis, as they may become positive before the synovial fluid cultures. HIV-infected patients who are at high risk for septic arthritis include IDUs and hemophiliacs. Clinicians must always consider and rule out acute infectious synovitis in these patients.

Gram-positive bacteria, such as S. aureus and Streptococcus pneumoniae, commonly found in non-HIV infected patients with septic arthritis and bursitis, are causative factors in most reported cases of septic arthritis and bursitis in HIV-infected persons.(2,3) Infections with organisms not common to the skin have also been reported.(4) One report described osteomyelitis in HIV-infected patients, but usually it results from direct extension from a septic joint.(2) Clinicians must frequently re-examine HIV-infected patients treated for septic arthritis for evidence of worsening or unchanging symptoms and signs. If bone pain and fever continue despite antibiotic coverage, extension of the infection to the surrounding bone should be considered; surgical debridement may be necessary.

In most HIV-infected patients with acute joint or bursa infections, broad antibacterial coverage to cover common skin organisms (including staphylococcal and streptococcal infections) should be initiated. Patients with advanced HIV disease occasionally have opportunistic joint infections, such as sporotrichosis, cryptococcosis,(4) and Mycobacterium avium intracellulare.(5,6) Often these patients have extraarticular features suggestive of such infections, including typical skin lesions. These opportunistic infections often present with a more indolent course than that of a bacterial septic arthritis. If extraarticular features of fungal infection are present or hyphae or budding yeasts are seen on direct synovial fluid examination, the patient should receive standard doses of intravenous amphotericin B.

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Muscle Pain or Myositis
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HIV-infected patients may present with muscle pains. It is important to examine the patient to determine whether weakness accompanies the pain, and whether the pain is generalized or localized to one muscle group; localized pain may be a sign of polymyositis, whereas generalized pain suggests a systemic process. It is also important to determine whether the patient is taking zidovudine (AZT), and whether the muscle pain began soon after initiation of the drug therapy.

Muscle problems in HIV-infected persons include idiopathic polymyositis, polymyositis secondary to AZT toxicity, and pyomyositis. Weakness in the shoulder or hip girdle muscles, along with an elevated level of creatine phosphokinase (CPK) or aldolase, or both, suggests polymyositis. AZT-induced polymyositis is similar to the idiopathic form, with muscle weakness, elevated CPK levels, and on muscle biopsy, myofibril necrosis with scant inflammation. In most cases, the patient improves gradually when AZT is discontinued, and the CPK level returns to normal.

Pyomyositis refers to solitary or multiple muscle abscesses that are not formed by local extension from superficial subcutaneous tissue. Although originally reported only in tropical climates, a number of cases were more recently described recently in North America, usually in healthy subjects but also in immunocompromised hosts.(7) The quadriceps muscle is most commonly involved, and 75% of patients have a single abscess.

Patients present initially with fever, and localized muscle pain. If the abscess is not deep in the muscle, redness, swelling, and a gradually developing woody induration may occur. If a painful area is found in a muscle during a physical examination, ultrasound, computed tomography, or magnetic resonance imaging is helpful in identifying and localizing the abscess or abscesses and in providing guidance during needle aspiration for identification of the pathogenic organism. S. aureus is responsible for the infection in the majority of cases, although a number of other bacteria have been recovered, including Escherichia coli and Salmonella enteritidis.(7) After the area of the infection is defined, a diagnostic aspiration of the mass can be done under ultrasonic guidance. Systemic antibiotics usually cure a single small abscess, but large or multiple loculated abscesses often require surgical incision and drainage.

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Psoriasis and Psoriatic-Like Arthritis
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Psoriatic arthritis with or without psoriasis occurs in HIV-infected persons.(8-12) The prevalence of psoriasiform skin changes and psoriatic arthritis in HIV-infected persons probably is the same as that in non-HIV infected persons (1 to 2%), but the severity of the HIV-associated psoriasis and psoriatic arthritis tends to be worse.(12-14)

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Clinical Manifestations
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The foot and ankle are the most common, as well as the most severe, sites of inflammation in HIV-infected patients with psoriatic-like arthritis. Intense enthesopathy and dactylitis, especially in the feet, usually accompany the arthritis. The enthesopathy can be a major cause of disability. Frank synovitis and synovial effusions are less common, but can occur at the ankle and subtalar, metatarsal phalangeal, and interphalangeal joints of the feet. Sacroiliac and spine involvement may also occur.(11) The radiologic appearance of these joints may mimic classic psoriatic arthritis, with "pencil and cup" deformities and osteolysis, even in the absence of frank psoriasis.

Nail involvement is a common presenting symptom of arthritis, especially in the distal interphalangeal joints of the hands and feet. Many patients with psoriatic skin manifestations or onycholysis have only these musculoskeletal findings and do not meet the criteria for a diagnosis of psoriatic arthritis. Nail involvement occurs in most patients who present with inflammatory articular symptoms. There is a high clinical correlation between skin and joint involvement, and joints may develop erosive changes and crippling deformities. Patients with HIV infection and psoriatic arthritis fall into one of two patterns of disease: either the articular disease is sustained and aggressive, progressing to joint erosions, or it is characterized by mild and intermittent joint involvement.

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Pathogenesis
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It is unknown whether HIV-associated psoriatic syndromes are strictly analogous to idiopathic psoriatic arthritis in non-HIV infected patients. Evidence against this possibility is that none of the human leukocyte antigen (HLA) alleles found in patients with idiopathic (non-HIV) psoriasis vulgaris or psoriatic arthritis (such as Cw6, B13, or B17) occur with greater frequency among HIV-infected patients with psoriatic-like arthritis.(10,15)

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Treatment
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The treatment of spondyloarthropathy in HIV-infected patients is similar to that for non-HIV infected patients. Nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin (75 to 150 mg per day), can be used initially for the joint symptoms, but results have been disappointing. There are few data on second-line agents such as gold, methotrexate, and azathioprine. There are reports that phenylbutazone (100 mg 3 times per day) is an effective drug for this arthritis, and neutropenia has not been a problem even in patients receiving AZT concurrently.

Patients in whom psoriatic skin or joint disease does not respond to NSAIDs may be treated with phenylbutazone (100 mg 3 times a day) or sulfasalazine (1 to 2 g per day). Etretinate may also be helpful. The use of psoralen and pulsed UV actinotherapy (PUVA) has helped the skin and joints of some HIV-infected individuals with psoriatic arthritis.

At our institution, treatment of patients with severe arthritis with low doses of methotrexate (5 to 10 mg per week) has led to rapid (< 4 weeks) improvement in inflammatory joint symptoms as well as improvement in skin lesions.(16) Methotrexate can be given until the skin and joint disease is under control, then slowly tapered by 2.5 mg per month, aiming for a maintenance dose of 5 mg per week. Patients must be monitored closely, because there are anecdotal reports of progressive immunodeficiency and opportunistic infections in HIV-infected individuals with Reiter's syndrome who are treated with methotrexate. Systemic glucocorticoid use is generally discouraged because of increased risk of infection, but intra-articular steroid injection (every 4 to 6 months) may provide substantial relief to individual arthritic joints.

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Reiter's Syndrome
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Reiter's syndrome, the first rheumatic syndrome reported in patients with HIV infection,(17) can be a severe illness in HIV-infected patients, but whether it occurs more frequently in HIV-infected patients than in the general population is controversial. One report(1) described nine patients with Reiter's syndrome and AIDS-related complex, and subsequent reports described additional patients.(18-26) The syndrome occurs in asymptomatic HIV-infected persons and in those with mild to severe immunodeficient states. Generally, the arthritis remains active and may increase in severity as HIV disease progresses.

The clinical manifestations of Reiter's syndrome either occur along with or, most commonly, follow the onset of clinically apparent immunodeficiency. In those patients in whom Reiter's syndrome precedes clinical evidence of immunodeficiency, a period of up to 2 years may elapse before HIV infection becomes clinically apparent.(24,27)

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Frequency in HIV-Infected Persons
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Controversy exists about the prevalence of Reiter's syndrome among HIV-infected persons. Two small retrospective studies in which rheumatologists examined cohorts of HIV-infected patients showed the prevalence of Reiter's syndrome to be between 5 and 10%, 100 to 200 times higher than the expected prevalence in the general population.(26,28) Other researchers who studied more than 1,000 homosexual men retrospectively, however, found the frequency of Reiter's syndrome to be only 0.3 to 0.5%, and there was no difference in frequency between HIV-positive and HIV-negative subjects.(27) Unfortunately, all these studies were retrospective and information was obtained by questionnaire. A large-scale prospective study is needed to resolve the differences between the two sets of studies.

Between 63 and 75% of HIV-infected patients with Reiter's syndrome have HLA-B27 cell-surface antigen, a percentage that does not differ significantly from the 70 to 80% usually reported for white persons without HIV infection.(17,22)

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Clinical Manifestations
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The classic triad of arthritis, urethritis, and conjunctivitis occurs in some HIV-infected patients with Reiter's syndrome; more often, however, an incomplete form of Reiter's occurs.(22,26,29) A common symptom is oligoarthritis of the large weight-bearing joints (usually the ankles or knees). Other common extraarticular manifestations include balanitis circinata, keratoderma blennorrhagicum, stomatitis, and uveitis. Enthesopathy, a disorder of the muscular or tendinous attachment to the bone, is a relatively common cause of disability and may involve the Achilles tendon, plantar fascia, anterior and posterior tibial tendons, and tendons of the feet.

Multidigit dactylitis, especially in the upper extremities, is common and may be relatively painless. Frank synovitis is less common but may occur at the ankle and the subtalar, metatarsal phalangeal, and interphalangeal joints of the feet. Knee involvement is common, often asymmetric, and without radiologic changes. Hip involvement is uncommon.

Synovitis of the wrist, elbow, and shoulder is uncommon but may lead to contractures and joint fusion. Enthesopathy may occur at the medial and lateral epicondyles, rotator cuff, or flexor tendons of the digits. The axial skeleton is usually not involved, and although radiographs may reveal sacroiliitis, clinical sacroiliitis is uncommon. Patients with HIV-associated arthritis have significant periarticular muscle atrophy, the etiology of which is unknown.(26,29)

Constitutional features of Reiter's syndrome, including weight loss, malaise, lymphadenopathy, and diarrhea, are difficult to distinguish from features of adrenal HIV disease.

Clinicians should recommend HIV testing for patients with Reiter's syndrome whose behaviors put them at an increased risk for HIV infection. Symptoms such as weight loss and malaise suggest early manifestations of HIV infection. In some centers and practices, HIV testing is routinely performed on patients with Reiter's syndrome.

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Pathogenesis
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Approximately one third of patients reported to have HIV-associated Reiter's syndrome also have documented infection with an enteric organism preceding by several weeks the emergence of clinical reactive arthritis, including Shigella flexneri, Salmonella, Campylobacter jejuni, and Yersinia enterocolitica. In another third of the patients, the appearance of Reiter's syndrome coincides with infection with organisms not usually linked to reactive arthritis, including Mycobacterium avium-intracellulare, Chlamydia, Giardia lamblia, and Borrelia burgdorferi. In the final third of HIV-infected patients who develop Reiter's syndrome, there is no detectable infection coinciding with HIV.

The pathogenesis of HIV-related Reiter's syndrome is complex and includes the following factors: decreased CD4+ lymphocytes, increased CD8+ cytotoxic lymphocytes, induction by infectious agents, association with the class I allele HLA-B27, and direct and indirect consequences of HIV infection. There is no consensus on the role of HIV infection and Reiter's syndrome at this time. Further research on the interrelationship of the two diseases may elucidate the immunologic triggers that manifest Reiter's syndrome in an HIV-infected host.

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Treatment
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The initial approach to treating Reiter's syndrome in persons with HIV infection is similar to that in the non-HIV infected population. Therapy should begin with nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin (50 mg 2 to 3 times per day). Unfortunately, standard NSAIDs give limited relief for enthesopathy and there are few data on the use of second-line agents, such as gold, for this disease. Phenylbutazone (100 mg 2 to 3 times per day) is quite useful for HIV-associated Reiter's syndrome and should be used early in the course of the disease.(26,28,29) No report has described adverse effects on the leukocyte count, even in patients concurrently taking zidovudine (AZT) and/or sulfasalazine. Patients usually obtain relief after 5 to 7 days of therapy. A decrease in joint and tendon swelling and decreased pain while walking are considered a good response. Usually, this therapy must continue indefinitely, so white blood cell count and differential should be monitored every 4 weeks. Sulfasalazine (Azulfidine) has been effective as a second-line therapy in a number of patients with Reiter's syndrome. Usually a dose of 1 to 3 g per day is necessary to obtain a response, and often patients develop gastrointestinal discomfort and require dose reduction. Patients who respond to sulfasalazine should receive it indefinitely. Sulfa allergy is common in HIV-infected patients, and may limit the use of sulfa drugs unless allergic patients are properly desensitized under the care of an allergist. A combination of phenylbutazone and sulfasalazine is somewhat effective in some patients.(28-30) There are anecdotal reports of patients benefiting from treatment with injectable gold (Myochrysine, 50 mg intramuscularly once per week for a total dose of 1 g), antimalarial agents (hydroxychloroquine sulfate [Plaquenil], 200 mg twice per day), and etretinate (0.75 mg/kg/day),(29,31,32) but there have been no controlled studies, and the dosage for maintenance therapy is unknown.

In general, low-dose corticosteroids have not been found to be beneficial in HIV-infected individuals with Reiter's syndrome. Occasionally, symptomatic relief is achieved with 40 mg or more a day of oral prednisone used for up to 10 days then rapidly tapered over another 7 days. Some patients with spondyloarthropathy syndromes tolerate oral steroids quite well, whereas others develop severe invasive candidiasis. Intraarticular corticosteroid injections usually provide effective symptomatic control, and can be a practical treatment when one or two joints or tendons are involved. The benefits of corticosteroid injections can be augmented by immobilizing the affected joint in a splint for 5 to 7 days after the injection. Although secondary septic arthritis from intraarticular steroid injections does not seem to be a significant problem in HIV-infected individuals, the patient should be instructed to watch carefully for signs of infection.

Methotrexate, other immunosuppressive agents, and phototherapy should be used only with extreme caution, because their administration has been associated with sudden fulminant immunodeficiency characterized by the appearance of Kaposi's sarcoma and severe and sometimes fatal opportunistic infections in patients who are HIV infected and have Reiter's syndrome.(25)

Zidovudine (AZT) does not seem to affect the natural history of Reiter's syndrome, but due to the emergence of severe immunodeficiency following the development of the arthritis in some patients, we recommend that all HIV-positive patients who present with arthritis begin two to three antiviral medications. We recommend that patients receive early physical therapy and splinting of affected joints as needed to prevent atrophy and contractures. Splinting and steroid injections every 3 to 4 months for individual joints or tendons may assist in maintaining function.(28,29)

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HIV-Associated Salivary Gland Disease (Sjogren's Syndrome and Diffuse Infiltrative Lymphocytosis)
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A syndrome superficially resembling Sjogren's syndrome has been found in adult and pediatric patients infected with HIV or human T-cell leukemia virus type I (HTLV-I). It is characterized by massive parotid enlargement and xerostomia and is referred to as diffuse idiopathic lymphocytic syndrome (DILS).(33-42) DILS can appear at any stage of HIV disease (at any CD4 level). The actual incidence of DILS in children or adults is unknown; over 50 cases have been reported in the literature.

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Clinical Presentation
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Exocrine gland manifestations of DILS include xerophthalmia (dry eyes), xerostomia (dry mouth), salivary gland enlargement, and arthralgias.

The extraglandular involvement in DILS may include lymphocytic hepatitis due to CD8 lymphocytic infiltration of the liver. Infiltration of the lung causing lymphocytic interstitial pneumonitis (LIP) is the most serious manifestation of this disorder; it can progress to pulmonary insufficiency. Other organs and systems affected include the gastrointestinal tract, kidney (most commonly as type IV renal tubular acidosis), thymus, and nervous system.(41) Gastric infiltration may result in a syndrome resembling linitis plastica. Lymphadenopathy is a frequent finding.

Sjögren's syndrome or DILS in HIV-infected patients differs from idiopathic Sjögren's syndrome in the following ways:

  • Most reported cases are in males (which reflects the predominance in the United States of HIV infection in males)

  • There can be massive parotid swelling and large neck masses

  • Arthritis is absent

  • There is somewhat less xerophthalmia and more frequent extrasalivary lymphoid infiltration, including lymphocytic interstitial pneumonitis, and lymphocytic infiltration of the gastrointestinal, neurologic, and reticuloendothelial systems

  • Results of serologic studies are negative (including tests for cytoplasmic RNA antibodies and Ro and La antibodies)

  • There are increased numbers of CD8+ (suppressor-cytotoxic) T cells in the blood and tissue

  • There is no associated increase in HLA-DR2 or DR3 cell-surface antigens

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Pathogenesis
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DILS seems to reflect a distinct host immune response occurring in persons with the cell-surface antigen type HLA-DR5.(43) Although clinically it resembles classic Sjogren's syndrome, DILS is distinguished by a CD8+ and CD29+ lymphocyte infiltrate, extraglandular visceral involvement, a paucity of autoantibodies, and a strong association with HLA-DR5 in African American patients with DILS, and with HLA-DR6 and HLA-DR7 in Caucasian patients. The extent of CD8 lymphocyte infiltration in the lungs and parotid glands correlates with the numbers of peripheral circulating CD8 cells.

CD8 lymphocytes that bear CD29 suppress replication of HIV in simian immunodeficiency virus (SIV) in vitro(44,45); therefore circulating CD8 cells in patients with DILS may suppress HIV replication.(26)

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Differential Diagnosis of Sicca Syndrome in HIV-Infected Patients
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The differential diagnosis of chronic salivary gland enlargement in HIV-infected patients includes bacterial sialoadenitis, viral infections (such as mumps, Epstein-Barr virus, and possibly HIV), tumors, and DILS. The clinician should recommend HIV testing in a patient with a chronic Sjogren-like syndrome.

All evaluations of patients complaining of dry eyes or dry mouth should include a careful drug history to rule out iatrogenic illness, such as from drugs like tricyclic antidepressants and antihistamines.

The identification of a Sjogren-like illness in a young patient with atypical or uncommon clinical features should suggest HIV-associated salivary gland disease. Clinical and laboratory features suggesting this condition include young age (under 40 years of age), high-risk group (homosexual, bisexual, injection drug user, transfusion recipient, hemophiliac), male gender (79% of non-HIV-related Sjogren's syndrome occurs in females), generalized lymphadenopathy, and negative autoimmune serologic results.

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Treatment
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Treatment of HIV-associated Sjogren's syndrome is mostly symptomatic. Artificial saliva, used 2 to 3 times per day, reduces symptoms of dry mouth. Patients should avoid sugar because of the high incidence of cavities and periodontal disease associated with inadequate salivary flow. Artificial tears applied 2 to 3 times per day can help prevent corneal ulcerations. Also, due to salivary gland enlargement, recurrent sinus, middle ear, and oral cavity infections can occur. Treatment with antibiotics appropriate to the culture and infection site is usually effective for these problems.

Immunosuppressive therapy should be used only when patients are in life-threatening situations such as pulmonary insufficiency or renal disease. One report described DILS patients with pulmonary involvement and respiratory insufficiency who responded to treatment with prednisone (1 mg/kg/day) and chlorambucil.(41) Three patients showed clinical improvement and resolution of pulmonary infiltrates; none developed opportunistic infections. A number of HIV-infected patients with salivary gland enlargement showed striking decreases in parotid enlargement when treated with zidovudine (AZT),(41) and there are anecdotal reports that patients with lymphocytic interstitial pneumoniae respond to AZT. We suggest that HIV-infected patients with DILS receive anti-HIV drugs.

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Myositis in HIV-Infected Patients
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Inflammatory muscle disease occurs more often in patients with HIV disease than in the general population.(46) One report described interviews and examinations of 101 HIV-infected patients. Muscle involvement occurred in 18, myalgias in 10 (generalized in 7 and localized in 3), muscle atrophy in 6, and polymyositis in 2.(46) Myositis syndromes documented in patients with HIV disease include polymyositis,(47-49) dermatomyositis,(50,51) and zidovudine (AZT)-associated myositis.(52-55)

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Polymyositis
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The association between HIV infection and inflammatory muscle disease was recognized first in 19831,(1,49)and a report in 1986 described two patients with polymyositis as the initial manifestation of HIV infection.(48) Both patients were subsequently diagnosed with Centers for Disease Control (CDC)-defined AIDS after 2 and 6 months, respectively.

Generally, the presenting complaint is progressive proximal muscle weakness involving upper and lower extremities, with increasing difficulty rising from a chair, walking up stairs, and using arms for any length of time. In most patients, the lower extremities are affected more than the upper extremities. Dysphagia, shortness of breath, and skin rash of the face and hands generally do not occur. Most patients have myalgias, which is a prevalent and nonspecific complaint in HIV-infected patients.

Laboratory data show elevated levels of muscle enzymes, including creatine kinase with a mean elevation to 1,800 units per liter (range, 300 to 18,000 units per liter), aldolase, and serum aspartate transaminase (AST). Electromyographic studies show abnormal findings typical of polymyositis, including activity characterized by short-duration, low-amplitude, polyphasic potentials, and fibrillation potentials at rest.

Muscle biopsy specimens are abnormal in the majority of patients. Histologic examination of the muscle tissue shows extensive perivascular and interstitial inflammatory infiltrates, necrosis, and phagocytosis of degenerated muscle tissue, as well as myofiber regeneration. Electron microscopic studies confirm the light microscopy changes. Immunohistochemical staining using purified monoclonal antibody against HIV p24 antigen shows positive reaction of mononuclear cells and the cytoplasm of a few degenerating muscle fibers.(56)Both CD4 and CD8 T lymphocytes have been identified in the inflammatory infiltrate.(55,56) CD8 cells were predominant, and B lymphocytes and HLA-DR-positive cells also occurred. The myositis of HIV disease does not appear to result from direct HIV infection of muscle. One study used in situ RNA hybridization and the polymerase chain reaction to examine muscle biopsy specimens from 10 patients with HIV-associated polymyositis, and found evidence of HIV nucleic acid in sparse lymphoid cells surrounding the muscle fibers, but not in the muscle fibers or cultured myotubes.(57)

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Dermatomyositis
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One report described coexistent dermatomyositis and HIV infection in a 22-year-old homosexual man who had tested positive for antibodies to HIV 1 year earlier.(51) The patient presented with characteristic rash on the face and hands and severe proximal muscle weakness. The histologic appearance of skin and muscle biopsy specimens was consistent with dermatomyositis. HIV p24 antigen was present in mononuclear cells and the cytoplasm of degenerating muscle cells. The report did not note CD4 count at the time of diagnosis. Clinicians treated the patient initially with prednisone and later added azathioprine to control disease activity. During the azathioprine treatment, there was a fall in lymphocyte count, but at the time of the report, the patient had not developed any opportunistic infection qualifying for the CDC-defined diagnosis of AIDS.(51)

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Therapy and Response to Therapy
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In general, most patients presenting with myalgias without associated weakness respond to nonsteroidal anti-inflammatory drugs and analgesic agents. A more aggressive therapeutic approach is required in patients with muscle weakness, to restore muscle strength and function. Due to the rapid deterioration of muscle function and strength in these patients, patients with the polymyositis-like syndrome are treated with moderate doses of steroids (prednisone for 4 to 6 weeks at 40 to 60 mg per day tapered gradually when muscle enzyme levels become normal). Our experience is that HIV-infected patients with polymyositis experience a fair to good clinical response, but one report described clinical and biochemical improvement, with HIV-associated polymyositis taking a longer time than the idiopathic form.(56) Patients appear to tolerate prednisone well and, to date, Kaposi's sarcoma has not been reported. A small number of patients receiving prednisone developed oral candidiasis,(56) which was controlled with oral anti-Candida medication (clotrimazole, nystatin) and lowering of their prednisone dose. In most patients, maintenance doses of prednisone (5 to 10 mg per day) were required to prevent further worsening of muscle weakness and elevation of muscle enzymes.

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Zidovudine-Associated Myositis
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AZT is a 2',3'-dideoxynucleoside analogue that inhibits a mitochondrial DNA polymerase (an enzyme found solely in the mitochondrial matrix) and interferes with the replication of mitochondrial DNA.(58) Idiosyncratic reactions to AZT, including muscle weakness and abnormalities of muscle enzymes, are common in HIV-infected persons and can occur at all CD4 levels.(52,53,59) Usually, patients with muscular symptoms have a subacute onset of myalgia, muscle tenderness, and proximal weakness. Creatine kinase elevation is common, and electromyograms show myopathic changes. Muscle biopsy specimens show a mitochondrial myopathy associated with endomysial inflammatory cell infiltrates consisting of CD8+ cells and macrophages surrounding or invading muscle fibers expressing major histocompatibility complex class I antigens. The abnormal mitochondria are found only in muscle specimens from AZT-treated patients, so it is likely that AZT is responsible for these changes.(54)

Patients with weakness or muscle pain who are receiving AZT should be evaluated for signs of myopathy. If creatine phosphokinase (CPK) levels are elevated, AZT should be discontinued. In most patients, muscle strength improves gradually when AZT is discontinued, and CPK levels return to normal. Some patients tolerate AZT at a lower dosage and recover muscle strength, but in a smaller number, progressive weakness requires discontinuation of AZT. Prednisone therapy should be reserved for patients whose muscle strength decreases or does not change after discontinuation of AZT. Prednisone (1 mg/kg/day for 10 to 14 days) can be given for muscle pain, weakness, and elevated CPK levels. As CPK levels normalize and symptoms resolve, the prednisone can be tapered off gradually. Another antiretroviral agent can be instituted if clinically indicated for HIV disease while the myositis is under treatment with prednisone. If CPK levels are mildly elevated on a routine laboratory test but there are no clinical symptoms, the patient can choose to continue with AZT therapy or to switch to another antiretroviral agent.

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References

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1.   Calabrese LH. Human immunodeficiency virus (HIV) and arthritis. Rheum Dis Clin North Am 1993;19(2):477-485.
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