The cytokines that modulate immune-mediated rheumatic diseases are rapidly
being
elucidated1,2.
In rheumatoid arthritis, persistent inhibition of tumor necrosis factor-alpha
(TNF-a) induces an appreciable reduction of disease activity.
TNF-a antagonists abrogate the inflammatory reaction by several
mechanisms3-5:
they reduce the expression of cytokines (TNF-a, interleukin-1a,
and interleukin-1ß), adhesion molecules, and chemokines (interleukin-8
and monocyte chemotactic protein-1) in the inflamed synovial tissue; they
diminish leukocyte chemotaxis through the endothelium; and they suppress the
activation and differentiation of osteoclasts that enhance bone
resorption.
Several studies have demonstrated that both etanercept and infliximab are
highly effective in the treatment of patients who have inadequate responses to
conventional disease-modifying antirheumatic drugs such as
methotrexate3-7.
To date, short-term clinical trials with anti-TNF-a agents have not been
associated with a higher prevalence of serious bacterial infections.
In this report, we present the case of a young woman with seropositive
rheumatoid arthritis in whom bilateral septic arthritis of the hip developed
after four months of therapy with etanercept alone. Staphylococcus
aureus infection was found unexpectedly during exposure of the hips at
the beginning of an elective total hip arthroplasty. This report highlights a
possible association between TNF-a blockade therapy and multifocal
septic arthritis. Our patient was informed that data concerning her case would
be submitted for publication.
Atwenty-seven-year-old woman with an eleven-year history of
adolescent-onset seropositive rheumatoid arthritis presented with sudden
agonizing pain on the right side of the groin a few days before a scheduled
total hip replacement on the right. The rheumatoid arthritis had been treated
initially with prednisone and methotrexate for four years and subsequently
with a combination of hydroxychloroquine and sulfasalazine for six years.
Radiographs demonstrated that, despite this therapeutic regimen, both hips had
extensive articular erosions with almost total obliteration of the joint
spaces.
Most recently, monotherapy with subcutaneous injection of etanercept (25
mg, twice weekly) was begun. However, despite four months of etanercept
treatment, the patient continued to have multiple joint involvement and was
scheduled to undergo elective total hip replacement of the right hip, which
was the most symptomatic joint. A week before surgery, the groin pain suddenly
became unbearable and she was unable to bear weight on the right lower
limb.
The patient was afebrile at the time of admission, was guarding the right
hip, and had active synovitis of the elbows, knees, ankles, and wrists as well
as of multiple metacarpophalangeal joints. She walked with an awkward right
antalgic gait. The physical examination otherwise revealed normal
findings.
Laboratory tests showed a white blood-cell count of 20 ×
109/L with predominantly polymorphonuclear cells. Over the next
twenty-four hours, the patient's temperature rose to 38.1°C, and she was
taken to the operating room, where aspiration of fluid from the right hip
joint revealed frank pus. A Gram stain and culture confirmed the diagnosis of
septic arthritis caused by Staphylococcus aureus. This finding
prompted aspiration of fluid from the left hip joint, and the same organism
was identified. Intravenously administered antibiotic treatment with cefazolin
and gentamicin was initiated, and the patient underwent bilateral resectional
arthroplasty. Within a day, the fever had abated and the patient's general
condition had improved greatly. After the course of antibiotics was completed
and repeated aspiration of fluid from the hip joints revealed no latent
staphylococcal infection, the patient underwent bilateral total hip
arthroplasty. Several months after surgery, the patient was convalescing well
and her gait had improved appreciably.
The data available from clinical studies and postmarketing surveillance
have indicated that TNF-a inhibitors have a relatively safe therapeutic
profile8,9.
However, the rate of upper respiratory tract infection in clinical studies has
been noted to be higher in patients who receive the drug than in patients who
receive a
placebo7,10,11.
Keane et al.12
recently reported that tuberculosis developed in seventy patients after
several months of therapy with infliximab. Moreover, the course of the disease
in these patients was aggressive; forty of them had extrapulmonary
involvement, and seventeen had disseminated disease. Warris et
al.13 described a
patient with Crohn disease who died from invasive pulmonary aspergillosis
three weeks after receiving a single infusion of infliximab. Phillips et
al.14 recently
reported their experience with 180 patients in whom treatment with etanercept
did not result in a higher rate of infection. However, septic arthritis
developed in two of the four patients in whom serious infection developed in
that series: it developed in the wrist in one and around a prosthetic hip
joint in another. Both patients had additional predisposing factors,
consisting of concomitant immunosuppressive therapy (prednisolone and
methotrexate) and insulin-dependent diabetes mellitus. Two episodes of
infectious arthritis have been reported in postmarketing surveillance
releases: one occurred following an arthroscopy, and the other occurred at the
site of a prosthetic
joint15. Baghai et
al.16 described a
thirty-seven-year-old woman with long-standing rheumatoid arthritis in whom a
fatal disseminated infection with Staphylococcus pneumoniae developed
several years after a total knee replacement. Septic arthritis developed
around the prosthetic knee replacement as well as in the native hip joints and
was associated with extensive necrotizing fasciitis.
These reports imply that patients with chronic inflammatory destructive
rheumatoid or juvenile arthritis, who because of these conditions are already
predisposed to the development of septic arthritis, may face an additional
risk when treated with TNF-a inhibitors and thus should be monitored
closely for evidence of infection. Even with heightened monitoring, however,
the signs and symptoms of infection can be subtle or absent. We recommend that
health-care providers maintain a high index of suspicion for infectious
disease in patients who are receiving biologic immune-modulating therapies and
that the patients themselves be cautioned to be vigilant for any signs of
infection.