Dr. Atkinson has received consultant fees (less than $10,000) from Idera Pharmaceuticals, owns stock and/or holds stock options in Taligen Therapeutics, and serves on the scientific advisory board for Genentech, Inc., and Compliment Corporation.
Rheumatologists are frequently called upon to diagnose and treat inflammatory polyarthritis, of which the majority fall into several well-defined categories (rheumatoid arthritis [RA], spondylarthropathy, gout). Presentations that are seronegative or have atypical features, however, may present diagnostic challenges. In such cases, extraarticular clues may be present that point toward a diagnosis.
We present a case in which the joint disease was highly suggestive of RA. Extraarticular signs, however, eventually led to the diagnosis of both human immunodeficiency virus (HIV) and syphilis infection, with an ultimate diagnosis of a syphilitic arthropathy. The case presents an opportunity to review the rheumatologic manifestations of these diseases. In particular, HIV infection may initially manifest with, or be complicated by, a variety of rheumatic syndromes. Given the increasing incidence of both HIV and syphilis, it is imperative that the rheumatologist be familiar with the diseases and their rheumatologic manifestations, so that they are in the differential diagnosis in the appropriate clinical setting.
A 38-year-old African American man presented to our emergency department with progressively increasing joint pain and swelling of a duration of 6 months. The arthritis was additive and symmetric, began in the knees and elbows, and then involved the ankles, wrists, shoulders, and metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints. He had a 20-pound weight loss over the preceding 3 months. Over the past month he had daily fevers, primarily in the evenings, up to 101°F. Naproxen sodium (250 mg twice daily) had provided initial benefit but its effect had waned. A review of systems was notable for patchy hair loss of the scalp and beard. He denied oral ulcers, sicca symptoms, ocular inflammation, or photosensitivity. He reported no pain or stiffness in the neck, low back, or heel. He had noted darkening of the palmar skin and peeling of the skin on his soles. There was no history of sexually transmitted diseases, and he denied dysuria, diarrhea, or other gastrointestinal or genitourinary symptoms.
The patient's medical history was unremarkable. There was no family history of autoimmune disease. He took no medications other than naproxen sodium, and he had an allergy to sulfa. He was a college professor, and denied alcohol, tobacco, or illicit drug use. He was divorced from his wife and lived with his fiancée. On physical examination he had a fever of 39.3°C. His blood pressure was 104/66 mm Hg and his heart rate was 92 beats/minute. Oxygen saturation was 100% on room air. Several 1–2-cm shallow painless ulcers were on the hard palate. Patchy alopecia was prominent in the scalp, beard, and eyebrows. Small, nontender, freely mobile cervical lymph nodes were palpable. A peeling, hyperkeratotic rash was on his soles. The skin on the distal palms appeared darker that that on the proximal palms, but no other rash was evident. There was a symmetric polyarthritis of the PIP joints, MCP joints, and wrists. The elbows were warm, each with 15° of flexion contracture. The knees and ankles had detectable effusions. There was no dactylitis, nail changes, or tenosynovitis. The remainder of the physical examination was unremarkable.
Laboratory results showed normal chemistries, including renal and hepatic function. Blood counts demonstrated a hemoglobin level of 10.1 gm/liter, a platelet count of 288,000/mm3, and a white blood cell count of 3,800/mm3 (78% neutrophils, 15% lymphocytes). The erythrocyte sedimentation rate was 51 mm/hour and the C-reactive protein level was 76 mg/liter. Urinalysis showed 1+ protein but no casts or cells. Blood and urine cultures were negative. Hand films demonstrated several small erosions (Figures 1 and 2). Rheumatoid factor (RF), antibody to cyclic citrullinated peptide, and antinuclear antibody tests were negative. Complement components C3 and C4 were normal. HIV antibody test returned positive, as did the Western blot. The viral load was 99,000 copies/ml and the CD4 count was 31, consistent with acquired immunodeficiency syndrome. The rapid plasma reagin (RPR) was positive at a titer of 1:64, with a positive fluorescent treponemal antibody absorption (FTA-ABS) test. Cerebrospinal fluid (CSF) examination demonstrated 28 nucleated cells with a lymphocyte predominance and normal protein. The CSF VDRL test was negative.
The patient was treated initially with prednisone 20 mg/day. He felt much better as the synovitis improved. Prednisone was discontinued after 3 days, when HIV was diagnosed. He was then treated with hydroxychloroquine (200 mg twice daily) and naproxen sodium (500 mg twice daily). The working diagnosis was HIV arthropathy. Because of the CSF pleocytosis and because the CSF VDRL has only a 70% sensitivity for the detection of neurosyphilis in HIV patients, he received a 2-week course of intravenous penicillin for presumed neurosyphilis (1). He was seen in the clinic 1 month later and the joint symptoms had nearly resolved. Joint examination revealed only mild synovitis at several MCP joints. The rash on the hands and feet had resolved. The timing of his response to penicillin led to revision of the diagnosis to syphilitic arthropathy. He had been receiving antiretroviral therapy for only 2 weeks and hydroxychloroquine for 4 weeks at that time. Repeat testing revealed an RPR titer of 1:16 and a persistently positive FTA-ABS.
We describe a patient whose presenting manifestations of HIV infection were diffuse symmetric peripheral joint pain and swelling, alopecia, oral ulcers, and rash. The symmetric nature of the arthritis, especially with small joint involvement and erosions on radiographs, suggested RA. Atypical features included patchy alopecia, painless oral ulcers, rash, and leukopenia, prompting consideration of systemic lupus erythematosus (SLE). The rash on the feet suggested keratoderma blennorrhagicum, but the distribution of the joints involved was not that of reactive arthritis or another spondylarthropathy. The leukopenia led to an evaluation for HIV infection, subsequently an evaluation for syphilis, and eventually to a diagnosis of syphilitic arthropathy.
Multiple rheumatic syndromes have been described in association with HIV infection (Table 1). Several, including HIV-associated arthritis and the diffuse infiltrative lymphocytosis syndrome, are unique to HIV. Others, such as arthralgias, psoriatic arthritis, reactive arthritis, and gout, are more common in HIV patients (2).
Table 1. Rheumatic manifestations of human immunodeficiency virus (HIV) infection
Increased in HIV
Disorders of joints
Disorders of bone
Disorders of muscle
Serologic abnormalities (antineutrophil cytoplasmic and antiphospholipid antibodies)
Unique to HIV
Diffuse infiltrative lymphocytosis syndrome
Spondylarthropathies, among which reactive arthritis and psoriatic arthritis are variants, are the most common form of arthritis seen in HIV patients. These arthritides are observed at increased rates in HIV patients compared to the general population. Spinal involvement and uveitis are less common in HIV-associated spondylarthropathies than in non-HIV–associated disease. These spondylarthropathies often precede the immunodeficiency. Interestingly, although spondylarthropathies were rare in Africa due to the low frequency of the HLA–B27 allele, they are now commonly reported in HIV-positive patients, especially those carrying the HLA–B5703 allele. Currently, nearly all African patients developing spondylarthropathy have undiagnosed HIV infection (2).
HIV-associated arthritis is a joint disease unique to HIV patients. Typically, it is a lower extremity oligoarthritis of a duration of less than 6 weeks. In the largest reported series, 270 consecutive HIV patients were examined, among whom 21 (7.8%) exhibited this form of arthritis. The majority of patients presented with either monarticular or oligoarticular arthritis, and were distinguished from the more common spondylarthropathies based on a lack of mucocutaneous lesions or other extraarticular manifestations as well as a self-limited course that averaged 2 weeks. Unlike the spondylarthropathies, enthesopathy was not observed and the synovial fluid was noninflammatory. Most patients were HLA–B27 negative, and RF was uniformly negative. HIV-associated arthritis was more common in patients with advanced HIV infection (3). Other reports have described similar features of HIV-associated arthritis with frequent involvement of the knees and ankles (4).
Reactive arthritis occurs frequently in the HIV population, with an incidence between 0.4% and 10%. Whether this is due to the HIV virus itself or to concomitant infections is not clear. As in the non-HIV population, it is characterized by a lower extremity seronegative oligoarthritis, frequently accompanied by enthesitis, urethritis, circinate balanitis, or keratoderma blennorrhagicum. The HLA–B27 allele is present in 80–90% of patients with reactive arthritis in North America, but is rarely seen in African cases. Unlike other spondylarthropathies that may occur at any point during HIV infection, psoriatic arthritis is more common in advanced HIV infection, with an incidence of 1.5–2%. Its onset frequently heralds the development of opportunistic infections, and it may be most effectively treated by antiretroviral therapy.
Diffuse infiltrative lymphocytic syndrome is an increasingly rare Sjögren's syndrome–like illness characterized by an oligoclonal expansion of CD8+ T cells manifesting as painless parotid enlargement and sicca symptoms, but also occasionally with lymphocytic pneumonitis or hepatitis. Its incidence has decreased in the antiretroviral era (2).
The incidence of diffuse arthralgias in patients with HIV infection has ranged from 5% in a retrospective study to as high as 45% in prospective studies (5, 6). The arthralgias most commonly involve the knees and shoulders and may result from immune complex deposition. Arthralgias are also seen as part of the HIV seroconversion syndrome in 30–50% of patients, although they usually do not progress to an inflammatory arthritis (7).
Gout is also common in HIV patients, with an incidence of 0.5%. Hyperuricemia is described in up to 42% of patients, and may relate to uncontrolled viral replication and cell turnover. In addition, antiretroviral therapies such as didanosine and ritonavir cause hyperuricemia (8).
None of the aforementioned HIV-associated joint diseases typically manifest in an RA-like distribution. One series of 64 patients with HIV reported 8 to have an “RA-like polyarthritis” (9). However, no mention was made of possible syphilitic coinfection, which is common in HIV patients. In another series of 75 patients with HIV and various “musculoskeletal complaints,” 4 had a symmetric seronegative arthritis, one of which was erosive (10).
There is a single report of syphilitic arthropathy mimicking RA in a patient who was concomitantly diagnosed with HIV (11). This 18-year-old man presented with a 1-month history of arthritis of the hands, wrists, and knees, as well as weight loss and fatigue. There was synovitis of the MCP and PIP joints and a knee effusion. An eczematous rash and alopecia were also present. Subchondral bone resorption was observed at the wrists, but there were no true erosions. He had positive antinuclear antibodies, antibodies to double-stranded DNA, and RF, but initially a negative RPR. When his synovitis worsened on naproxen, RPR was repeated and was positive, as was the confirmatory FTA-ABS. He was found to be HIV positive. His arthritis remitted completely after the third dose of intramuscular penicillin, although the rash and alopecia persisted.
Classic tabetic arthropathy, a neuropathic arthropathy in the setting of tertiary syphilis, favors weight-bearing joints and would not explain our patient's symptoms (12). Given the rapid improvement in our patient's alopecia (the well-described “moth-eaten” alopecia of syphilis), oral ulcers, and arthritis after a course of penicillin, our patient likely had a syphilitic arthropathy. The HIV viral load remained detectable for more than 2 months after his joint symptoms had resolved, making the role of antiretroviral therapy in his improvement highly improbable. Therefore, we believe our patient is the second case reported in the literature of HIV infection presenting with a syphilitic arthropathy with RA-like features.
There is an increased rate of false-positive RPR in HIV patients, especially in intravenous drug users (13). The specificity of a positive FTA-ABS test is reported to be 96%. While it may be lower in patients with SLE or other autoimmune diseases, it does not appear that HIV infection lowers the specificity (14). As such, our patient's positive RPR and confirmatory FTA-ABS, in a compatible clinical setting, reliably confirmed a diagnosis of syphilis.
The treatment of the joint disease associated with HIV infection is problematic due to concerns about drug-induced immunosuppression compounding those caused by the disease itself. Both nonsteroidal antiinflammatory drugs and hydroxychloroquine appear to be safe in HIV patients. In fact, inhibition of HIV viral replication by both indomethacin and hydroxychloroquine has been demonstrated in vitro, and hydroxychloroquine has beneficial effects on viral load in vivo as well (15, 16). Some authors suggest that sulfasalazine may also be beneficial for HIV patients. In one series, the CD4 counts of all 4 patients given the drug increased (17). Successful use of methotrexate has been reported in a few small case series, although opportunistic infections have also been described in some patients receiving the drug. Several authors have concluded that its cautious use in conjunction with antiretroviral therapy may be successful in carefully selected patients (18, 19). Case reports exist regarding the successful use of tumor necrosis factor (TNF) antagonists. In the largest series, 8 patients were successfully treated, all of whom had CD4 counts >200 (20). Infectious complications arose in another patient with a CD4 count <50 treated with etanercept (21). Therefore, TNF antagonism should be very cautiously considered in HIV-associated arthritis, but only in patients without advanced immune deficiency. No specific treatment is indicated for syphilitic arthritis beyond treatment of the infection itself. It is prudent to screen for and treat other sexually transmitted diseases, such as chlamydia and gonorrhea, given their frequent cotransmission with HIV infection.
In conclusion, we describe a patient whose presenting manifestation of HIV infection was a syphilitic arthropathy in an RA-like pattern. To date, there is only one other report of an arthropathy mimicking RA as the presenting manifestation of syphilis in a patient who was concomitantly diagnosed with HIV. These cases illustrate that syphilitic arthropathy may mimic RA in patients with HIV, and an RA-like arthritis in patients with HIV should prompt a diagnostic evaluation for syphilis.
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Ranganathan had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study conception and design. Phillips, Atkinson, Ranganathan.
Acquisition of data. Phillips, Reno, Atkinson, Ranganathan.
Analysis and interpretation of data. Phillips, Atkinson, Ranganathan.