Infliximab is a chimeric, murine-human, monoclonal antibody against tumor necrosis alpha which has shown great efficacy in the treatment of psoriasis. Serum sickness, which is an immune complex mediated syndrome consisting of a cutaneous eruption, fever, arthritis, edema, and lymphadenopathy, has been described in several patients receiving infliximab for the treatment of Crohn's disease. However, to our knowledge, this type of reaction has not been well described in a patient treated with infliximab for psoriasis. We describe a patient who developed serum sickness while receiving infliximab for psoriasis and discuss the pathogenesis, diagnosis, and treatment of serum sickness. We believe that with the increasing use of infliximab for psoriasis, more cases of serum sickness will occur. Therefore, awareness of this adverse effect is essential.
Infliximab is a chimeric monoclonal antibody directed against tumor necrosis factor alpha which was initially developed for use in patients with rheumatoid arthritis and Crohn's disease, but which has recently shown promise in the treatment of patients with refractory psoriasis (1-4). Infliximab has been observed to cause a variety of cutaneous reactions, including leucocytoclastic vasculitis (5), lichenoid eruptions (5), perniosis (5), drug induced lupus (6,7), bullous eruptions (8), pruritus (9), and infections (5,10). Serum sickness and serum sickness-like reactions have been reported infrequently in patients who are undergoing treatment for Crohn's disease. We describe a 44-year-old woman who was receiving infliximab for severe psoriasis and subsequently developed serum sickness.
Our patient is a 44-year-old Caucasian woman with no significant medical problems other than diet-controlled hypercholesteremia and a 20-year history of plaque psoriasis. For years she had tried various therapies including topical steroids, PUVA, and methotrexate. She did not respond well to any of the therapies, as they only effected sporadic, short, and incomplete remissions of her psoriasis. In September 2002, therapy with infliximab was begun. The patient received infusions of 5 mg/kg at 0, 2, and 6 weeks, and then every 8 weeks thereafter. Concurrently, the patient was receiving methotrexate 5 mg PO weekly. The patient responded extremely well to this therapy, and after only 2 infusions, she had no evidence of psoriasis other than a few small areas of mild dyspigmentation. However, 4 days after her eighth infusion (almost 1 year after treatment was initiated), the patient complained of fatigue, fevers, urticaria, arthritis (involving the hips, knees, and ankles), and edema of the hands and feet. The patient was treated with cetirizine and acetaminophen, and all of her symptoms resolved completely within 5 days.
At this time, the patient revealed that she had been developing urticaria ever since her first infusion. She stated that initially, she developed mild urticaria one week after the first infusion and that it resolved, without therapy, within 3 to 4 hours. With each subsequent infusion, the patient developed urticaria (Figures 1 and 2) more rapidly and for a longer period of time. Since it never bothered her very much, she never brought it to our attention. She indicated that she never associated the symptoms with the infliximab infusions until the seventh infusion, after which her routine urticaria was accompanied by mild fatigue and arthritis. Human anti-chimeric antibodies were positive at 11.64 mcg/ml (normal < 1.69 mcg/ml). ANA and dsDNA were negative.
Serum sickness is a syndrome that is caused by the injection of a heterologous serum protein and results in an immune response which is mediated by immune complex deposition (11). Serum sickness was first described by Von Pirquet and Schick in 1905, when they reported a characteristic symptom complex in patients who received horse serum diphtheria antitoxin (12).
Since the initial description of serum sickness, many other drugs and proteins have been shown to cause either serum sickness or a serum sickness-like reaction. Indeed, the distinction between the two entities (serum sickness and serum sickness-like reactions) is somewhat blurred in the literature, with different authors defining the 2 terms slightly differently (11-16).
However, most of the literature on the subject of serum sickness and serum sickness-like reactions appears to conform to the designations given by Buhner and Grant, who define serum sickness as the classic syndrome which occurs in response to an antigen that is derived from heterologous serum. In contrast, serum sickness-like reactions are defined as those reactions which have clinical features that may differ slightly from the classic syndrome and occur in response to an antigen which is not derived from heterologous serum (16). Using this terminology, our patient's reaction would be classified as serum sickness, as infliximab has a murine component. However, we acknowledge that there are those who may believe that our patient's reaction is more correctly described as serum sickness-like. In our view, the precise nomenclature is of little importance, since the pathophysiology, clinical presentation, and treatment of the two entities is almost identical.
Interestingly, the confusion related to nomenclature is compounded when discussing serum sickness due to infliximab. As Cheifitz et al. point out, different authors have used various terms to describe serum sickness due to infliximab (15) including "delayed hypersensitivity reactions," "delayed hypersensitivity-like reactions," and "delayed severe systemic reactions." (17) However, they note that these different names are all likely referring to the same immune complex mediated syndrome (15).
The pathogenesis of serum sickness has been elucidated by studies involving animal models (18,19). Exposure to excess quantities of the inciting antigen results in the generation of antibodies which will interact with the antigen, forming soluble circulating immune complexes. If the immune complexes cannot be removed by the mononuclear phagocyte system, then they may be deposited in the vessels of organs, including (but not limited to) the skin, joints, and kidneys. These deposits are capable of activating complement and producing an inflammatory response that is manifested as the classic symptoms. Many of these pathogenetic features have been well demonstrated in serum sickness associated with rituximab which, like infliximab, is a murine-human chimeric monoclonal antibody (20,21).
In patients with serum sickness, the deposition of immune complexes is classically associated with 5 symptoms: cutaneous eruption, arthritis, fever, edema, and lymphadenopathy (16). More serious symptoms, such as glomerulonephritis, serositis, generalized vasculitis, and peripheral neuropathy, can also occur in more severe cases (11). The symptoms of serum sickness usually occur 8 to 14 days after the administration of the offending drug (22). However, in some cases, the symptoms may take up to 3 weeks to develop (23). Furthermore, repeated exposures can result in a more severe, accelerated reaction which develops within 2 to 4 days (11).
Of the 5 symptoms which characterize classic serum sickness, cutaneous manifestations are the most common. The skin disorders that may be observed in patients with serum sickness include urticaria, purpura, maculopapular eruptions, and erythema multiforme. Of these dermatoses, urticaria is the most common (11). It is also not uncommon for a patient to develop a non-urticarial eruption several days after the development of urticaria (16). Arthritis and arthralgias are also quite common, occurring in 10-50% of patients. Usually, multiple large joints are affected (11). Lymphadenopathy, when present, is most commonly seen in nodes regional to the site of injection (16).
Serum sickness is largely a clinical diagnosis. There is no definitive diagnostic test that will allow a diagnosis of serum sickness to be made (16). There are various assays, which are generally only routinely available in research settings, which may demonstrate elevated levels of circulating immune complexes. In addition, levels of C3 and C4 are usually depressed, while erythrocyte sedimentation rate and C-reactive protein are often elevated (20). Moreover, direct immunofluorescence of skin biopsy specimens may demonstrate immune complex deposition. However, these findings would not be diagnostic of serum sickness and may be absent in patients with serum sickness (11,12). It has been also been observed that patients receiving infliximab who develop serum sickness will have absent HACA (human anti-chimeric antibodies) titers prior to the inciting dose, but will develop high HACA titers with the onset of the reaction (24). Unfortunately, these titers have not been reported in many of the previously reported cases of infliximab-associated serum sickness or serum-sickness like reactions, so it is difficult to gauge the usefulness of HACA titers as a diagnostic tool.
Since the cardinal features of serum sickness are quite non-specific, the differential diagnosis of serum sickness includes a variety of infectious or inflammatory diseases. The key to distinguishing serum sickness from other diseases that may mimic it is that serum sickness resolves quite rapidly once the inciting agent is eliminated--usually within a few days to weeks. If symptoms of serum sickness persist for longer than 1 month, then other diagnoses should be strongly considered (11). Drug-induced lupus may be difficult to distinguish from serum sickness, since many patients receiving infliximab will develop new positive ANA and dsDNA titers (25). The presence of skin lesions with classic lupus morphology (e.g., butterfly rash) and characteristic skin biopsy findings would suggest a diagnosis of drug-induced lupus.
The incidence of serum sickness or serum sickness-like reactions due to infliximab, based on large series by Cheifitz et al. and Hanauer et al., is approximately 2-3% (15,26). Patients who develop serum sickness have an excellent prognosis with a lack of any serious long-term sequelae. Some patients treated with infliximab who developed serum sickness experienced spontaneous resolution of their symptoms, whereas others were successfully treated with short courses of antihistamines or systemic steroids (15,17,25).
There is no consensus about the ability of patients who develop serum sickness from infliximab to safely receive further therapy. Sandborn and Hanauer suggest that patients with a history of serum sickness due to infliximab can reduce the chance of future reactions by receiving concomitant immunosuppressive therapy (such as methotrexate, azathioprine, or 6-mercaptopurine) and premedication with diphenhydramine, acetaminophen, and steroids (25). Kugathasan et al. treated 8 patients with Crohn's disease and prior infliximab-associated serum sickness with a rapid, high-dose steroid taper prior to retreatment with infliximab. None of the patients developed serum sickness in response to the retreatment (17). Unfortunately, this steroid protocol may not be practical in psoriatic patients, since it may precipitate flares.
Despite these techniques, it is imperative to realize that potentially life-threatening serum sickness reactions should be a contraindication to further infliximab therapy (even with premedication and immunosuppression). Moreover, because of the high HACA titers seen in patients with severe serum sickness due to infliximab, the therapeutic benefits of the infliximab are likely to be diminished in these patients (25).
The same medications that are used to prevent future reactions in patients with infliximab-induced serum sickness may be used to avoid them completely. Concomitant immunosuppressive therapy and premedication with corticosteroids have each been shown to reduce HACA formation by 30% to 50% (9,25,27), so these measures, at least theoretically, should reduce the incidence of serum sickness. Furthermore, it is important to realize that the effects of corticosteroids are reduced in patients who are on immunosuppressive therapy (25). Therefore, the inability of psoriatic patients to take high doses of steroids only places them at a minor disadvantage. Additionally, it has been suggested that a dosage schedule involving multiple early infusions (0, 2, and 6 weeks) may help prevent against serum sickness. Kagathasan et al. observed a statistically significant difference in the incidence of serum sickness between patients who had multiple early infusions and those who did not. Serum sickness was observed only in patients who had an interval of greater than or equal to 20 weeks between their first 2 infliximab infusions. None of the patients who had multiple early infusions had serum sickness (17). In contrast, our patient developed serum sickness despite multiple early infusions and concomitant immunosuppressive therapy with methotrexate.
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RAVI S. KRISHNAN MD, SYLVIA HSU MD
DEPARTMENT OF DERMATOLOGY, BAYLOR COLLEGE OF MEDICINE HOUSTON, TEXAS
ADDRESS FOR CORRESPONDENCE:
Sylvia Hsu MD
Department of Dermatology
Baylor College of Medicine
One Baylor Plaza, FB800
Houston, Texas 77030
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