*Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics, Massachusetts General Hospital, USA
†Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
Received 5 May, 2008
Accepted 16 June, 2008
Address correspondence and reprint requests to Garrett C. Zella, MD, Department of Pediatrics, Division of Pediatric Gastroenterology, Massachusetts General Hospital, 175 Cambridge St, 5th Floor, Boston, MA 02114, USA (e-mail: email@example.com).
Dr Zella reports no conflicts of interest; Dr Weinblatt receives grant support from Abbott and Amgen, and provides consultancy for Abbott, Amgen, Wyeth, Centocor, and UCB; and Dr Winter receives clinical research grant support from and provides consultancy for Centocor.
With the increasing use of infliximab in adults and children, untoward events such as acute infusion reactions, delayed serum sickness–type reactions, and infectious complications have become more apparent (1–3). However, autoimmune phenomena are being increasingly recognized as nonacute side effects of infliximab and other biologic therapies. Induction of autoantibodies has been described in patients receiving infliximab therapy for either inflammatory bowel disease (IBD) or rheumatoid arthritis (RA) (4–7). Although the occurrence of anti-nuclear antibodies and anti-double-stranded DNA (dsDNA) antibodies is relatively common in patients receiving infliximab infusions as therapy for Crohn disease, development of a systemic lupus erythematosus–like syndrome is rare (1,4). Among adult patients receiving infliximab for IBD or RA, there are few reports of drug-induced lupus (DIL) (4,5,8). Criteria for the diagnosis of DIL include continuous treatment with a suspected drug, common presenting symptoms including arthralgias and malaise, the presence of autoantibodies, and prompt symptom resolution after discontinuation of the drug (9). We report a case of an adolescent female presenting with presumed DIL associated with 2 anti-tumor necrosis factor-alpha agents, infliximab and adalimumab.
The patient presented at age 13 years with a perirectal abscess and a 1-year history of abdominal pain and intermittent bloody diarrhea. A colonoscopy identified edema and erythema extending from the splenic flexure to the rectum with multiple aphthous lesions in the left colon. Granulomas were noted and biopsies confirmed chronic Crohn pancolitis. Treatment was initiated with mesalamine and metronidazole, and corticosteroids and 6-mercaptopurine (MP) were added. Her symptoms gradually improved. One year later, remission was maintained on 6-MP, ciprofloxacin, and mesalamine.
Three years later, at age 17 years, she developed active steroid-refractory symptoms. After starting infliximab, symptoms resolved and remission continued on infliximab, 6-MP, and mesalamine for the next 2 years. At that time, she developed leukopenia and 6-MP was stopped. Three months later, she presented with swelling in her fingers, wrists, elbows, knees, and ankles. Her joints became stiff with inactivity and walking became difficult when symptomatic. She noted that the pain and swelling became worse about 2 weeks after each of the 3 most recent infliximab infusions and resolved completely during the following 2 weeks. She had no gastrointestinal manifestations of Crohn disease (CD). Her mother had Sjogren syndrome.
Physical examination revealed swollen and tender toes, ankles, and knees with no rash. Laboratory evaluation was significant for white blood cells (WBC) 4500/mm3 with a normal differential, hemoglobin 12.6 g/dL, platelets 289,000/mm3, albumin 3.7 g/dL, normal liver function tests, erythrocyte sedimentation rate (ESR) 50 mm/hour, anti-nuclear antibodies (ANA) positive at greater than 1:5120, dsDNA Ab positive at 1:40, a positive human anti-chimeric Ab (HACA), normal complement levels, negative rheumatoid factor, negative anti-histone Ab, and negative antibodies to Ro, La, Smith, ribonucleoprotein, mitochondria, and smooth muscle.
Infliximab was stopped and her symptoms resolved completely 2 weeks after the final infliximab infusion. Six weeks after her last infliximab infusion, a dose of adalimumab was given. One week later, she returned with recurrent joint symptoms. Adalimumab therapy was stopped and the joint symptoms resolved. Her gastrointestinal symptoms remained in remission for more than 1 year with mesalamine monotherapy.
Drug-induced lupus (DIL) is a rare adverse reaction to a wide variety of medications that occurs in 15,000 to 30,000 patients each year in the United States (10). Drug-induced lupus resembles native systemic lupus erythematosus (SLE) in its clinical presentation and laboratory findings and differs mainly by its resolution following cessation of the initiating medication. Although the presentation of DIL may be varied and subtle, the most frequent clinical signs and symptoms are arthralgias, myalgias, malaise, fever, anorexia, weight loss, and serositis (11). Arthralgias occur in up to 90% of patients with DIL and may be the only presenting symptom in many patients (9). The interval between medication exposure and symptom onset may range from 1 month to 12 years, but typically mild symptoms begin insidiously and become worse with time and increasing medication exposure (11). Symptoms of DIL are typically milder when compared with native SLE, and major organ involvement is rare. Symptoms that are common in native SLE such as a malar rash, photosensitivity, oral ulcers, and alopecia are rare in DIL. The most distinguishing feature of DIL is that the associated symptoms improve within days to weeks after discontinuation of the offending substance (9). DIL also should be differentiated from anti-tumor necrosis factor-alpha (TNF-α)-associated serum sickness, which presents almost invariably with fever and rash and without autoantibodies (12).
The laboratory findings in DIL most commonly include an elevated ESR in 80% of patients and a positive ANA (10). However, a positive ANA may not be necessary to establish the diagnosis of DIL. Patients with negative ANA and typical manifestations of DIL after therapy with lisinopril, procainamide, and hydralazine have been reported (10,13). Most frequently, the ANA fluorescence-staining pattern is homogeneous and is caused by antibodies to histones (14). The anti-histone antibodies, in particular, target the histone-DNA macromolecular complex in the cell nucleus and are present in approximately 50% to 90% of patients with DIL (9,10). Anti-histone antibodies are not specific to DIL, however, and are found in approximately equal numbers of patients with native SLE (15). Complement levels are typically normal in DIL, although hypocomplementemia occurs frequently in native SLE (10). Although ANA positivity is extremely common in DIL, antibodies to dsDNA occur in less than 5% of patients with DIL (9). Interestingly, most cases of anti-TNF-α-induced DIL described in patients with rheumatoid arthritis (RA) or CD have been positive for antibodies to dsDNA (10,16). Our patient's elevated ESR, positive ANA, normal complement levels, and positive dsDNA antibody reflect previously published cases of anti-TNF-α-induced DIL.
Drug-induced lupus is rarely seen in children and adolescents because many of the drugs associated with DIL, such as procainamide and hydralazine are rarely used in this population (17). Most reports of DIL in pediatrics involve the use of minocycline in adolescents (18). To our knowledge, there have been no published cases of DIL associated with infliximab use in the pediatric population, on the basis of English and nonEnglish literature obtained from Medline searches through April 2008 using the key words infliximab, Remicade, lupus, SLE, DIL, autoimmune, drug-induced, child, pediatric, and adolescent.
Evidence for the risk for developing DIL during infliximab therapy has become more prominent since its approval in 1998 for use in CD (see Table 1 (19–26)). Large trials using various doses of infliximab in adults with CD reveal rates of ANA seroconversion up to 56.8% and dsDNA seroconversion up to 35%. Ten cases of DIL have been reported among 1480 adult patients with IBD receiving various doses of the drug in these reported studies. Of 200 children with CD and 12 with UC receiving various doses of infliximab, none were reported to have developed DIL. Sarzi-Puttini et al (27) describe an 18-year-old male who developed signs of SLE after initiation of infliximab therapy. Unlike typical DIL, however, this patient's symptoms persisted for 3 months after cessation of infliximab therapy and required treatment for an additional 3 months before remitting.
The pathophysiology of the development of autoimmune disease in the setting of anti-TNF-α therapy is incompletely understood. Given the incidence of cases of DIL associated with other anti-TNF-α agents, namely etanercept (1,28,29) and adalimumab (1,30), a class effect may exist. It appears that neutralization of TNF-α may stimulate humoral immunity to DNA and other nuclear antigens, leading to the production of autoantibodies (7). Murine studies suggest that TNF blockade may induce humoral autoimmunity by selectively inhibiting the induction of cytotoxic T lymphocytes that would typically suppress autoreactive B cells (31). Additionally, TNF-α blockade may alter serum amyloid P or complement factors C1q or C4b, all of which are mediated by TNF-α and allow clearance of DNA through apoptotic bodies (7,32,33). Mice without these factors manifest antinuclear autoimmunity and lupus-like disease (7,32,33). A possible class effect of anti-TNF-α agents is supported in our case by the patient's recurrence of DIL symptoms with the initiation of adalimumab therapy.
In summary, although the development of ANA and anti-dsDNA antibodies during infliximab therapy is common, infliximab associated DIL is rare—especially in the pediatric population. We present a patient with DIL symptoms temporally related to infliximab infusions, positive autoantibodies, normal complement levels, complete symptom resolution with discontinuation of infliximab, and recurrence with adalimumab. The recurrence of DIL symptoms with additional anti-TNF-α therapy underscores the possibility of a class effect among these agents. The mechanism of a possible class effect of anti-TNF-α may involve an unchecked activity of humoral immunity. As children continue to be treated earlier and for longer periods of time with anti-TNF-α agents, awareness of DIL and appropriate diagnostic evaluation may uncover additional patients with this disorder.
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