Clinical and Experimental Rheumatology 2005; 23: 247-250. CASE REPORT Drug-induced ABSTRACT penia related to treatment with tumor agranulocytosis during Agranulocytosis is a disorder charac- necrosis factor-α blockers have been terized by a severe decrease in the num- reported. treatment with ber of granulocytes in blood, that fre- We describe a case of a 20-year-old infliximab in enteropathic quently occurs as an adverse reaction Caucasian male affected by enteropath- spondyloarthropathy to some drugs. By now, there are no re- ic (Crohn’s disease) spondiloarthropa- ports in literature of agranulocytosis thy, who developed a severe transient E.G. Favalli, M. Varenna, caused by tumur necrosis factor-α agranulocytosis, possibly triggered by L. Sinigaglia blockers. i.v. infliximab treatment. We describe the case of a 20-year-old Department of Rheumatology, Gaetano Caucasian male affected by enteropa- Case report Pini Institute, Milan, Italy. thic (Crohn’s disease) spondyloarthro- A 20-year-old Caucasian male was Ennio Giulio Favalli, MD; Massimo pathy HLA B27 negative, successfully admitted with an 11-year history of Varenna, MD PhD; Luigi Sinigaglia, MD. treated with infliximab. After the sec- Crohn’s disease (diagnosis performed Please address correspondence to: ond infliximab infusion, he was found by ileocolonscopic gut biopsy) and Ennio Giulio Favalli, MD, to have a severe transient neutropenia enteropathic spondyloarthropathy HLA Via Lanfranco della Pila no. 14, (0.5 x 109/L). Routine serum chemistry B27 negative with significant axial in- 20162 Milan, Italy. and full blood cell count (apart from volvement. He had been treated for 7 E-mail: [email protected] neutrophil count) were normal. Serolo- years with sulfasalazine (2000 mg Received on June 28, 2004; accepted gy excluded an active infection. Bone daily) and nonsteroidal anti-inflamma- in revised form on November 17, 2004. marrow needle aspirate showed a nor- tory drugs (NSAIDs) and then with © Copyright CLINICAL AND EXPERIMEN- mal trilineage differentiation. Autoan- mesalazine (800 mg daily) and oral TAL RHEUMATOLOGY 2005. tibody assessment showed negative steroids for 4 years without significant ANA, anti-dsDNA, anti-ENA, and improvement. Key words: Infliximab, spondy- ANCA, but positive granulocyte-bound At the time of admission, the patient loarthropathy, neutropenia, agranulo- antibodies (GBA) and neutrophil-spe- presented with active disease and a ery- cytosis, autoimmunity. cific (CD 16+)-bound antibodies (anti- throcyte sedimentation rate (ESR) of NA). 90 mm/hour, C-reactive protein (CRP) Ten weeks after infliximab infusion, level of 9.3 mg/L (normal range < 1 neutrophil count and GBA and anti-NA mg/L), Bath Ankylosing Spondylitis assay returned spontaneously within Functional Index (BASFI) of 8, and normal range and we observed the same Bath Ankylosing Spondylitis Disease progress after every successive inflix- Activity Index (BASDAI) of 8.2. imab infusion we performed. Because of lack of efficacy, mesalazine These data indicated that infliximab and oral steroids were discontinued and possibly triggered production of granu- the patient was administered i.v. inflix- locyte and neutrophil autoantibodies imab (5 mg/Kg). At the beginning of with resultant autoimmune agranulocy- therapy, routine serum chemistry and tosis. full blood cell count were essentially normal (WBC: 6.00 109/L, with 61.8% Introduction neutrophils and 29.7% lymphocytes). Agranulocytosis is defined as a de- Based on previous experience with crease in the number of granulocytes in onset of drug-induced lupus syndrome circulating blood, resulting in a neu- in a patient treated with infliximab (2), trophil count of less or equal to 0.5 x we decided to perform routine detec- 109/L. Most instances of neutropenia tion of antinuclear antibodies (ANA) result from exposure to many drugs, and anti-double-stranded DNA (anti- and either the drug itself or a metabo- dsDNA). Both tests, as well as rheuma- lite may be causative. Some of these toid factor, gave negative results. drugs, such as chlortalidone, clozapine, Before performing the second infusion antithyroid drugs, sulfamethoxazole- (2 weeks after the first one), we regis- trimethoprim, penicillins, benzodiaze- tered a significant improvement in the pines, antidepressants, and phenotya- physical findings and axial involve- zines, are well-known causes of neu- ment, with an ESR of 20 mm/hour, trophil count decrease (1); for others CRP of 0.9 mg/L, BASFI of 20, and drugs, this is less certain. To date, in the BASDAI of 2.5. Full blood cell count medical literature, no cases of neutro- was normal (WBC 5.59 109/L, with 247 CASE REPORT Infliximab induced agranulocytosis/ E.G. Favalli et al. 51.8% neutrophils and 33.4% lympho- cytes). Therefore, the second infliximab infu- sion was performed at the same dose. Two weeks later, clinical improvement was confirmed (ESR 12 mm/hour, CRP 0.8 mg/L. BASFI 22, and BASDAI 2.4). Complete blood cell count dis- closed a WBC count of 5.82 109/L (with 9% neutrophils [0.5 x 109/L] and 82.5% lymphocytes), and a normal hae- moglobin, red blood cell, and platelet count. Physical findings were grossly negative. There were no symptoms or signs that suggested any infective com- Fig. 1. Neutrophil count time-course and antineutrophil antibodies detection after the second inflix- plication and serology excluded active imab infusion. infection with Epstein-Barr virus, Par- vovirus B19, TORCH, Brucella, Sal- monella, HIV, HBV and HCV; Man- toux test was negative. Chest X-ray, ab- dominal ultrasonic tomography, and routine serum chemistry were essenti- ally normal, as well as serum comple- ment, vitamin B12, folate and lympho- cyte subpopulations. ANA, anti-ds- DNA, anti-estractable-nuclear antibod- ies (anti-ENA), rheumatoid factor, and ANCA were negative. Bone marrow needle aspirate showed a myeloid/erythroid ratio of 1.4, and nor- mal trilineage differentiation. No matu- ration arrest of granulocytes in bone marrow testing was observed. Colony- forming units of the bone marrow cells were within normal limits. Fig. 2. Neutrophil count time-course during the first 5 infliximab infusions. Detection by granulocyte immunofluo- rescence test (GIFT) of granulocyte- showed a significant progressive re- human recombinant granulocyte- bound antibodies (GBA), serum granu- duction of GBA and anti-NA levels, colony-stimulating factor (G-CSF, Fil- locyte antibodies (SGA), neutrophil- which were completely negative at the grastim: 0.5 megaunits/Kg sc daily for specific (CD 16+)-bound antibodies 12th week determination. 5 consecutive days), producing a short- (anti-NA), and serum neutrophil-spe- Based on the time-progress of neutro- er duration of neutropenia with faster cific (CD 16+) antibodies was also per- phil count and anti-granulocyte and haematological recovery of neutrophil formed on peripheral blood. anti-neutrophil antibodies demonstra- count (Fig. 2). As shown in Figure 1, both GBA and tion, we conclude that neutropenia in anti-NA IgG and IgM antibodies were this patient was probably autoimmune Discussion strongly positive, whereas SGA and in nature and possibly triggered by in- Agranulocytosis is a life-threatening serum neutrophil-specific IgG and IgM fliximab. disorder characterized by a profound antibodies were negative. Considering the significant improve- and transient decrease in the number of The WBC count was repeated and the ment of the patient spondiloarthropathy granulocytes in circulating blood, with general condition of the patient was and his good general conditions in spite a neutrophil count equal to or less then monitored weekly for 2 months; the of neutropenia, in this case we decided 0.5 x 109/L (3). neutrophil count remained significantly to continue with the infliximab therapy, Most cases of agranulocytosis result low till the 8th week and then started to periodically monitoring neutrophil count from exposure to drugs, but other caus- increase progressively, till normaliza- (Fig. 2). es include infectious diseases (expeci- tion within the 12th week (neutrophils After the 5th infusion, neutrophil count ally viral), immune disorders as auto- 2.8 x 109/L). Autoantibodies detection, (0.4 x 109/L) decreased so significantly immune neutropenia, systemic lupus repeated at the 8th and 12th week, that the patient was administered with erythematosus, or Felty’s syndrome, 248 Infliximab induced agranulocytosis/ E.G. Favalli et al. CASE REPORT nutritional deficiencies (vitamin B12 prevailing hypotheses to explain DIA after the infusion (21)]. and folate), haematological diseases and are supported by clinical and ex- The management of DIA begins with (such as myelodisplastic syndrome), perimental data (12). In the first case, it the immediate withdrawal of any po- and congenital or chronic neutropenia is suggested that implicated drugs, or tentially causative drug. Measures to be (cyclic neutropenia, Kostmann’s syn- more likely their reactive metabolites, undertaken concomitantly include the drome) (4). may interact with specific components aggressive treatment of any diagnosed Drug-induced agranulocytosis (DIA) is of the bone marrow extracellular ma- sepsis, as well as the prevention of sec- an uncommon event; the overall inci- trix (such as fibronectin, hemonectin, ondary infections (5). In our case, the dence ranges from 2.6 to 10 cases per and other adhesion molecules) and may patient remained always asymptomatic million patients exposed to drugs per interfere with the normal regulation of and did not