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Home , Agranulocytosis, Cyclic neutropenia

Clinical and Experimental Rheumatology 2005; 23: 247-250. CASE REPORT Drug-induced ABSTRACT penia related to treatment with tumor 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 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 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] count) were normal. Serolo- years with sulfasalazine (2000 mg Received on June 28, 2004; accepted gy excluded an active . 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- (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 -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 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, , 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. 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 (, 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- , as well as the prevention of sec- an uncommon event; the overall inci- trix (such as fibronectin, hemonectin, ondary (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 present any sign of any year (5). Diagnosis of DIA is based on (13). In the second case, infective complication. Because of this both exclusion of an underlying disease several immunological mechanisms, fact and the significant improvement of and identification of temporal corre- such as opsonizing neutrophils, neutro- the axial involvement, in this particular spondence between onset and recovery phil or early neutrophil precursors di- case we decided to go on with adminis- of agranulocytosis and drug somminis- rect cytotoxicity, and neutrophil agglu- tration of infliximab, strictly monitor- tration (6). Despite the existence of tination by antineutrophil antibodies, ing neutrophil count and clinical find- these consensual criteria of DIA, it is have been documented (14). Other ings. often difficult to establish a precise as- mechanisms, involving cytotoxic T cells, The usefulness of human recombinant sociation and to evaluate the risk con- haptens, autoimmunity and oxidative haematopoietic growth factors in nected with a particular drug. Even if modification of drugs, have been evok- agranulocytosis is described in drug- several drugs, such as chlortalidone, ed (15, 16). induced cases as well as in autoim- clozapine, antithyroid drugs, sulfa- Unfortunately, there is no way to deter- mune neutropenia (22). As in our expe- methoxazole-trimethoprim, penicillins, mine for certain whether toxic or im- rience, is generally well tol- benzodiazepines, antidepressants, and mune reactions (or both) cause DIA in erated, produces a shortening of the phenotyazines, have been reported to a given individual. duration to blood count recovery and be well-known causes of transient neu- In the case reported here, several fac- may prevent infective complications. tropenia (1), there have been to date no tors may have led to an immunological Therefore, the use of G-CSF can be reports in the literature of infliximab- reaction. First, the time-course of the considered a safe and effective proce- related DIA (7, 8) appearance and re-occurrence of agra- dure in all those infliximab-related In the case reported here, neutropenia nolocytosis upon every re-exposure to DIA cases, in which treatment with was disclosed one week after the sec- infliximab. The neutrophil count de- infliximab is absolutely necessary. ond infliximab infusion in a patient creased rapidly after every drug infu- who did not present any other specific sion, getting to the lower level within References risk factor for agranulocytosis. He was one week, excluding the possibility of 1. VAN DER KLAUW MM, GAUDSMIT R, HALIE and remained totally asymptomatic, as bone marrow direct toxicity, which is MR et al.: A population-based case-cohort study of drug-associated agranulocytosis. do a minority of DIA cases (9), despite instead typically characterized by a de- Arch Intern Med 1999; 159: 369-74. the fact that most patients develop iso- lay of 6-12 weeks between drug ad- 2. FAVALLI EG, SINIGAGLIA L, VARENNA M, lated , documented infections, ministration and occurrence of agranu- ARNOLDI C: Drug-induced lupus following septicaemia and or present locytosis (17) treatment with infliximab in rheumatoid arthritis. Lupus 2002; 11: 753-5. general , headache, , my- Second, the detection of GBA and anti- 3. PATTON WN, DUFFULL SB: Idiosyncratic algia, and arthralgia (1). NA by GIFT, present in a high titre in drug-induced haematological abnormalities: Before making the diagnosis of DIA, the first 8 weeks after infliximab ad- incidence, pathogenesis, management, and we excluded every other causes of ministration, progressively and sponta- avoidance. Drug Safety 1994; 11: 445-62. 4. BÉNICHOU C, SOLAL-CELIGNY P: Stan- agranulocytosis by performing further neously decreasing till normalization dardization of definitions and criteria for cau- tests. Bone marrow aspirate showed a within 12th week, when clearance of sality assessment of adverse drug reaction. normal total cellularity, as widely des- infliximab was complete. Drug-induced blood cytopenias: report of an international consensus meeting. Nouvelle cribed in the literature (10); serology Finally, it has been demonstrated that Revue Francaise d’Hematologie 1993; 33: excluded active infection with any of infliximab can induce the production of 257-62. the pathogen agents typically linked to a series of autoantibodies such as ANA, 5. ANDRÈS E, KURTZ JE, MALOISEL F: Non- DIA (11); no nutritional deficiency (vi- anti-dsDNA, by means of immunologi- drug-induced agranulocytosis: experience of the Strasbourgh teaching hos- tamin B12 or folate) was found; auto- cal mechanisms, which have not been pital (1985-2000) and review of the litera- antibody assays for ANA, anti-dsDNA, yet completely clarified (2,18,19,20). ture. Clin Lab Haematol 2002; 24: 99-106. anti-ENA, rheumatoid factor, and In the same way, it may be thought that 6. ANDRÈS E, KURTZ JE, PERRIN AE: The use ANCA excluded an underlying colla- the production of anti-granulocyte anti- of haematopoietic growth factors in antithy- roid-related drug-induced agranulocytosis: a gen autoimmune disease. bodies is triggered by infliximab and report of 20 patients. Q J Med 2001; 94: 423- Direct toxicity and antineutrophil anti- stopped exactly at the end of the period 8. body mechanisms represent the two of infliximab clearance [8-10 weeks 7. KAVENAUGH A, KEYSTONE EC: The safety

249 CASE REPORT Infliximab induced agranulocytosis/ E.G. Favalli et al.

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