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Treatment effectiveness of levamisole plus prednisolone on oral lichen planus patients with emphasis on levamisole-induced agranulocytosis or pancytopenia
Journal of the Formosan Medical Association (2019) 118, 1193e1201
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.jfma-online.com
Original Article
Treatment effectiveness of levamisole plus prednisolone on oral lichen planus patients with emphasis on levamisole-induced agranulocytosis or pancytopenia Shin-Yu Lu*, Tzu-Fan Chang, Chih-Jen Lin Oral Pathology and Family Dentistry Section, Department of Dentistry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan Received 9 February 2019; received in revised form 2 March 2019; accepted 6 March 2019
KEYWORDS Levamisole; Agranulocytosis; Pancytopenia; Oral lichen planus
Background/Purpose: Physicians’ and dentists’ knowledge of levamisole-induced agranulocytosis or pancytopenia remains incomplete. This study aimed to evaluate the treatment effectiveness of levamisole plus prednisolone on oral lichen planus (OLP) patients with emphasis on levamisole-induced hematological changes. Methods: Ninety patients with erosive OLP were given 120 mg/day new levamisole (Levazol) and 15 mg/day prednisolone for three consecutive days each week. Three cases with levamisole-induced blood-cytopenias were assessed and treated within one year. Results: Most patients reported significant pain relief and showed no evidence of erosive OLP after 4e8 weeks of treatment with few side effects; nevertheless, three female patients developed agranulocytosis or granulocytopenia with concomitant thrombocytopenia or pancytopenia within 2e6 weeks after levamisole (Levazol) treatment. One case with previously unknown double episodes of agranulocytosis revealed her first episode following interruption of levamisole (Decaris) treatment for 4 months. High fever and sore throat were the most common symptoms, but two agranulocytosis cases remained asymptomatic one week before diagnosis, and were treated with levamisole withdrawal and empiric antimicrobial initiation as well as utilization of granulocyte colony-stimulating factors. Neutrophil recovery took about 1 week, but over 4 weeks in one of the cases (an elderly patient) with septic shock. Conclusion: Agranulocytosis or pancytopenia usually developed within 2 months after levamisole treatment, but it might be delayed. Agranulocytosis was more likely to occur in females and onset was acute. Levamisole is an effective immunomodulator for OLP patients; however, it should be used with caution and administered with regular blood monitoring.
* Corresponding author. Kaohsiung Chang Gung Memorial Hospital, 123 Dapi Road, Niaosong District, Kaohsiung, 833, Taiwan (R.O.C).Fax: þ886 7317123x8288. E-mail address: [email protected] (S.-Y. Lu). https://doi.org/10.1016/j.jfma.2019.03.007 0929-6646/Copyright ª 2019, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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S.-Y. Lu et al. Copyright ª 2019, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).
Introduction Agranulocytosis or pancytopenia is a rare but lifethreatening complication of levamisole, and an up-to-date understanding of the subject is important. Agranulocytosis is characterized by a marked reduction of circulating granulocytes with an absolute neutrophil count (ANC) less than 500/ml (normal reference>1500/ml). Pancytopenia is defined when in addition to agranulocytosis, patients show total leukocyte count <4000/ml, hemoglobin <11 gm/dl and a platelet count <100,000/ml.1e6 The lower the neutrophil count and the longer it remains low, the greater risk of serious infections or sepsis. Agranulocytosis patients often experience ANC under 100/ml at greatest risk.6e8 Agranulocytosis usually occurs within the first two months following levamisole treatment; however, certain cases have demonstrated that agranulocytosis might occur after interruption or long-term treatment.1e9 Levamisole (Decaris) has been used as an anthelmintic in both human and veterinary since 1966. It attracted interest as an effective immunomodulator for diseases in which cellular immune deficiency was suspected, such as chronic and recurrent oral ulcers, primary and secondary immune deficiencies, rheumatoid arthritis, and in stabilization of tumor remission in cancer.10e21 When used with low-dose prednisolone therapy for patients with oral lichen planus (OLP), erythema multiforme, pemphigus vulgaris or pemphigoid, levamisole has been shown to be effective and relatively safe in comparison with high-dose prednisolone.14e21 Significant side effects from levamisole are skin rash, headache, palpitation and insomnia that were typically mild, whereas agranulocytosis was serious.1e6,13e21 Studies have reported that the hematologic toxicity is a significant and disturbing consequence of long-term levamisole administration, approaching in frequency and severity as agranulocytosis induced by antithyroid drugs, in particular for methimazole.1e6,22e28 In causality assessments of 980 reported cases with agranulocytosis induced by non-chemotherapy drugs in MEDLINE (1966e2006), 10 cases (1.0%) were associated with levamisole; however, case reports cannot provide rates of drug-induced complications.6 Sun et al. reported that the incidence of agranulocytosis was about 0.2% in OLP patients on Decaris therapy.20 In over 30 years of managing almost three thousands of OLP patients in a medical center, the present researchers have experienced three patients with agranulocytosis following Decaris plus prednisolone treatment in 1986e2017 and three patients with agranulocytosis or neutropenia and concomitant thrombocytopenia or pancytopenia after the addition of new levamisole (Levazol) to prednisolone during 2018, with an incidence near 0.2%. However, widespread clinical trials of levamisole as an immunopotentiating agent in rheumatoid arthritis,
metastatic carcinoma, and immunodeficiency states have been complicated by agranulocytosis in 2.5%e13% of patients.2,10e13 Symoens et al. reported that 88 of 3900 patients on levamisole therapy had agranulocytosis, an incidence of 2.3% with 8 recorded deaths exhibited most frequently in rheumatoid arthritis patients.1,2 A much higher incidence of 13% was found in a small series of women receiving combined chemotherapy and levamisole for breast cancer.2 Agranulocytosis often occurs abruptly and patients present with signs of infection together with high fever. Clinical suspicion is therefore important and immediate blood sampling is needed. In a case series study of 754 Graves’ patients with antithyroid drug-induced hematologic complications, agranulocytosis was diagnosed in 670 (88.9%) patients, whereas 84 (11.1%) were reported with pancytopenia or aplastic anemia.22 Tajiri et al. reported that 12 Graves’ patients with antithyroid drug-induced agranulocytosis revealed normal white blood counts (WBC).25 We witnessed six OLP patients with agranulocytosis or granulocytopenia and concomitant thrombocytopenia or pancytopenia after levamisole therapy. Thus, monitoring of complete blood counts (CBC) and not only granulocyte counts or WBC is necessary. The aim of this report is to evaluate the treatment effectiveness of Levazol pus prednisolone on OLP patients with emphasis on characteristics of levamisole-induced blood-cytopenias.
Patients and methods The study was approved by the Institutional Review Board. A total of 90 consecutive patients (79 women and 11 men, mean age 58.1 years, range 30e87 years) with sore mouth visiting the Oral Medicine Clinic of the study hospital between November 2017 and October 2018 and finally diagnosed as having OLP were included in this study. Upon the terminated supply of Decaris since November 2017, Levazol (40 mg) and prednisolone (5 mg) administered three times a day for 3 consecutive days each week were used as long as evidence of symptomatic OLP was seen. Patients were monitored once every two weeks for the first 3 months and once a month thereafter for recording of clinical responses and side effects. Data were retrieved from the chart notes made at each visit. The clinical effectiveness across treatment periods was analyzed by using JMP statistical package, version 14.0.0 (SAS Institute Inc., Cary, NC, USA). A p-value <0.05 was considered statistically significant.
Results As shown in Table 1, 84 patients reported significant pain relief and showed no evidence of erosive OLP after 4e8 weeks of treatment. They also remained free from
Levamisole-induced agranulocytosis or pancytopenia Table 1
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Disease activity during the treatment of levamisole (Levazol) plus prednisolone on 90 patients with oral lichen planus.
Response within 2 weeks Response within 4 weeks Response within 6 weeks Response within 8 weeks Remission period (months)
Remarkable response
Partial response
No response
P
46 66 81 84 4.3 1.8
44 (2 þ Case 2) 21 (Case 3)c 5 (Case 1)c 1 3.3 1.4
0 0 0 0 0
0.054 0.045a 0.023 0.012
b
Remarkable response (80%e100% remission of symptoms and signs). Partial response (50%e75% remission of symptoms and signs). No response (unchanged or worsening of symptoms and signs). a The treatment effectiveness was statistically significant after 4 weeks (P < 0.05). b Levamisole was discontinued after 2 weeks due to skin rash in two patients and granulocytopenia combined with thrombocytopenia in Case 2 (Table 2). c Upon the onset of agranulocytosis and pancytopenia, levamisole was discontinued after 3 weeks in Case 3 and after 6 weeks in Case 1 (Table 2).
symptoms months after the treatment ended. Levazol was discontinued in five patients with adverse reactions, although there were otherwise improved OLP symptoms. Significant side effects were minor skin rash and headache in two cases, but three female patients subsequently developed agranulocytosis or granulocytopenia with concomitant thrombocytopenia or pancytopenia within 2 months following medications during January to May 2018. Raising patient education at time of prescription was carried out and prompt blood sampling was taken just the day before and 2e4 weeks after Levazol therapy; no new agranulocytosis case was found until the end of 2018. The results of blood-cytopenias in three patients are summarized in Tables 2 and 3 and Fig. 1. The first case of a 46-year-old female presented to the Emergency Department (ED) complaining of high fever up to 40 C, sore throat and general weakness for two days in February, 2018. Her past medical history was unremarkable except for hyperthyroidism with subtotal thyroidectomy and she had received thyroxin therapy for nine years. She reported no
drug allergy history. Six weeks previously, she had begun to take 120 mg/day Levazol plus 15 mg/day prednisolone 3 days a week for erosive OLP and desquamative gingivitis. Her physician obtained a CBC as part of a new patient visit, and the WBC of 300/ml and calculated ANC of 12/ml demonstrated severe leukopenia with agranulocytosis. The metabolic profile revealed elevated inflammatory marker C-reactive protein (CRP), 101.78 mg/L (reference range <5 mg/L) and mild abnormal liver function. No deficiency of iron, B12 or folate was found. Blood cultures and chest xray showed no abnormalities, but abdominal ultrasonography revealed fatty liver. Medications were carefully reviewed and levamisole as the culprit drug was favored. Accordingly, in stopping levamisole, empirical antibiotic initiation and supportive care were undertaken immediately. The granulocyte-colony stimulating factor (G-CSF) was also given at the first admission date. Her ANC remained low, 8/ml in the sixth hospital day, but dramatically rose to 3762/ml in the eighth day. She was discharged without any complications.
Table 2 Analysis of agranulocytosis or granulocytopenia with concomitant thrombocytopenia or pancytopenia in three oral lichen planus patients receiving levamisole plus prednisolone therapy. No.
1 2 3 3aa 3ba
Age /Sex
46/F 57/F 87/F 83/F 83/F
Lev mg per day /wks
AG or GP onset wks
120/6 120/2 120/3 150/6 150/4
6 2 3 22b 4
Hematological changes Before therapy WBC 1000 /ul 3.5e11
Neu ratio % 42e47
ANC /ul
_ 4.9 4.6 4.8 4.7
_ 47.6 50.7 50.0 62.7
AG/GP at diagnosis WBC 1000 /ul 3.5e11
Neu ratio % 42e47
ANC /ul
>1500
Plt 1000 /ul 150-400
_ 2332 2332 2400 2947
_ 252 159 127 148
0.3 3.6 <0.2 0.5 0.7
4.0 40.1 25.0 0.0 0.0
Neu Recover within days
>1500
Plt 1000 /ul 150e400
12 1443 <50 0 0
152 98 11 76 48
8 <7 33 16 14
Abbreviation: AG, agranulocytosis; ANC, absolute neutrophil count; GP, granulocytopenia; Lev, Levamisole; Neu, Neutrophil; Plt, Platelets; WBC, White blood count; wks, weeks. AG is defined by ANC below 500/ul. GP is defined by ANC<1500/ul. Thrombocytopenia is defined by platelets<150 1000/ul. a Case 3 had the previous double episodes (3a and 3b) of agranulocytosis with pancytopenia within 2014. In other words, she had three recurrent episodes of AG within a four-year period. b 22 weeks in Case 3a indicated her first agranulocytosis following Decaris and prednisolone treatment 3 days each week for 6 weeks and the discontinuation of the same drug for 16 weeks.
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Table 3 The selective indices of hematological changes in three oral lichen planus patients with agranulocytosis or neutropenia combined thrombocytopenia or pancytopenia before treatment (day-), on the day of diagnosis (day 0) and after levamisole withdrawal. No.
Time course
WBC /ml (4000e11000)
Neutrophil % (42e74)
ANC /ml (>1500)
Lymphocyte % (20e56)
Hb g/dl (12.5e17)
Platelet 1000/ml (150e400)
1
Day 0 Day 3 Day 6 Day 8 Day 10 Day 16 Day-14a Day 0 Day 30 Day-180c Day -21b Day 0 Day 10 Day 14 Day 21 Day 33 Day 63 Day-135c Day 0 Day 3 Day 16 Day 23 Day-80b Day 0 Day 4 Day 14 Day 20
300 500 800 5700 14400 10300 4900 3600 9400 4600 3900 <200 300 700 2000 7200 5600 4800 500 800 4900 5300 4700 700 300 3300 6500
4.0 0.0 1.0 66.0 29.0 60.0 47.6 40.1 53.3 50.7 79.8 25.0 72.0 78.0 73.0 71.4 73.0 74.0 0.0 1.0 67.0 77.0 62.7 0.0 0.0 53.0 67.7
12 0 8 3762 4147 6180 2332 1443 5010 2332 3112 <50 216 546 1460 5140 4088 3552 0 8 3283 4081 2947 0 0 1749 4401
78.0 84.0 88.0 6.0 8.0 28.0 43.0 42.8 39.4 41.5 11.4 75.0 28.0 18.0 23.0 20.1 19.0 20.0 98.0 94.0 22.0 17.0 27.1 98.6 93.3 28.0 23.1
12.7 10.4 11.1 11.0 11.6 13.4 12.4 11.6 12.6 12.2 12.7 9.6 8.2 8.4 7.8 8.9 9.5 13.4 11.3 11.7 11.2 11.5 11.7 11.7 11.4 9.8 10.3
152 194 459 405 394 299 252 98 231 159 142 11 22 73 42 40 93 127 76 130 445 387 148 48 63 84 233
2
3
3a
3b
Abbreviation: ANC, absolute neutrophil count; WBC, white blood count; Hb, hemoglobin. a In Case 2, the day-14 indicated blood test just in the day (2 weeks) before levamisole treatment. b In Case 3, the day-21 indicated blood test just in the day (3 weeks) before levamisole treatment. c In Case 3 of day-180, case 3a of day-135 and case 3b of day-80 indicated the available blood indices 180 days, 135 days and 80 days before the start of levamisole treatment respectively.
The second case of a fifty-seven-year-old female had a past medical history of rheumatic heart disease and denied any drug allergy. Her erosive OLP was diagnosed and treated with Levazol plus prednisolone during April, 2018. Patient’s CBC with differential and serum iron, B12 and folate were taken just the day before medication and all showed normal reference ranges. Two weeks later, OLP response demonstrated much improvement, but she complained about occasional mild fever and discomfort after medications. Prompt CBC test was taken and the hematological changes within 2 weeks demonstrated mild neutropenia with severe thrombocytopenia. Immediate decisions of stopping levamisole and starting oral amoxicillin were taken to prevent infection. Without hospitalization, the patient was reviewed by telephone call 48 h later. No fever or any complaint was reported. Her available time for further CBC test was taken one month later. Her blood counts have recovered. She requested continuous levamisole therapy under mild neutropenia if there were otherwise improved OLP symptoms. However, while on a drug known to cause agranulocytosis, any patient with early
neutropenia should have such drug be immediately discontinued without rechallenge. The third case of an eighty-seven-year-old female patient had many medical diseases including hypertension, diabetes, gouty arthritis and pulmonary tuberculosis that were under control for many years. In April 2018, she asked for management of recurrent OLP which had been previously treated with Decaris plus prednisolone for 6 weeks during December 2013 to January 2014 and 4 weeks during September 2014. She denied any drug allergy history and began to take Levazol plus prednisolone 3 days a week in April 2018. Patient’s CBC with differential was taken just the day before medication and the results showed a mild leukopenia and thrombocytopenia. There was no deficiency of iron, B12 or folate. Three weeks later, she presented to ED with high fever and malaise for 3 days in May, 2018. Four days prior to ED, associated symptoms including sore throat, left neck pain and leg bruise occurred. Further CBC test was taken and the changes within 3 weeks demonstrated a severe agranulocytosis (ANC of <50/ml) with pancytopenia. Medications were reviewed carefully and
Levamisole-induced agranulocytosis or pancytopenia Figure 1 Case 3 with three recurrent episodes of levamisole-induced agranulocytosis with pancytopenia within a four-year period. The profile of hematological changes include absolute neutrophil count (ANC), platelet and hemoglobin (Hb). (3a) Left, the first episode in May 2014 developed following the discontinuation of levamisole treatment for 4 months. (3b) Middle, the second episode in October 2014 developed following 4 weeks of levamisole treatment. (3) Right, the third episode in May 2018 developed following 3 weeks of levamisole treatment.
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1198 levamisole as the culprit drug was favored. A further test of HLA-B27 was taken but the result was negative. Unexpectedly, this was her third episode of agranulocytosis, but her memory and knowledge about the causes of the previous double episodes of agranulocytosis within 2014 was poor. In May 2014, she presented to ED complaining of dizziness and fever for 3 days, as well as intermittent night sweating and weight loss of 10 kg within one year, but with no cough, shortness of breath or diarrhea. The first agranulocytosis (ANC of 0/ml) combined with severe thrombocytopenia was diagnosed that had developed following the discontinuation of Decaris treatment for 4 months. Her ANC showed progressive improvement after antibiotic initiation, and then the addition of anti-tuberculosis therapy 10 days later, because the chest x-ray showed pulmonary infiltrates and abdominal computed tomography revealed multiple nodular patches in bilateral lower lungs as pulmonary tuberculosis. Tuberculosis-related agranulocytosis was favored. Bone marrow biopsy revealed marked myeloid hypoplasia. Sixteen days later, her ANC had risen to 3283/ml (Case 3a in Table 3). She was discharged without complications but continued anti-tuberculosis therapy. Her second agranulocytosis (ANC of 0/ml) with concomitant severe thrombocytopenia was diagnosed in October 2014 that had developed following 4 weeks of Decaris treatment (Case 3b in Table 3). The primary care physician did not consider levamisole as the culprit drug, but suspected associated autoimmune disease. Supportive care and empirical antibiotic treatment were undertaken immediately, but no immunosuppressive drugs were prescribed. Two weeks later, her ANC had risen to 1749/ml. She was discharged without complications. Her third episode of agranulocytosis (ANC< 50/ml) with pancytopenia developed following 3 weeks of Levazol treatment favored as the main cause in May 2018. The bacterial culture from blood revealed polymicrobial septicemia that rapidly resulted in septic shock with acute respiratory failure, kidney injury, myocardial infarction, and hypoxic encephalopathy. She was sent to the intensive care unit (ICU) for supportive care, parenteral broad-spectrum antibiotic initiation and G-CSF treatment. However, the utilization of G-CSF did not provide improvement in the recovery time, because recurrent sepsis and pancytopenia resulted in more prolonged neutropenia from exhaustion of marrow granulocyte. Her ANC slowly rose to 546/ml two weeks later, then to 1460/ml three weeks later, and to normal ranges after almost four weeks (Case 3 in Table 2). After two months of struggle with serious infections, she was discharged with complications of neurological dysfunction from hypoxic encephalopathy. The severity of three patients ranked from modest (Case 2), severe (Case 1) to very complicated (Case 3, multiple episodes with diverse complications).
Discussion During the last two decades, we have demonstrated successful results of levamisole (Decaris) used with low-dose prednisolone on OLP patients with few side effects.17,18 In the study, treatment with Levazol and low-dose
S.-Y. Lu et al. prednisolone may produce similar improved results as before in most treated OLP patients. However, the extraordinary emergence of these new agranulocytosis cases alerted us to the potential danger of levamisole therapy. The active ingredient dosage of levamisole in a Levazol tablet (40 mg) was less than that in a Decaris tablet (50 mg), but the inactive ingredients between them were almost different. Various drug manufacturers generally do not suddenly change the active ingredient in a medication, while they may change the inactive ingredients like pill color or excipients, which can cause side effects or spur an allergic reaction.29e31 The effects and side effects of generic drugs vs. brand-name drugs as well as strategies to increase drug safety were discussed in the Pharmacy & Therapeutics Committee of the study hospital. As the cause of unexpected Levazol-related agranulocytosis cases remains unsolved, pharmacovigilance and surveillance are advised. Early detection of agranulocytosis before symptoms of infection occur is important to prevent disease progression and a fatal outcome. Levamisole-induced hematological changes manifest not only agranulocytosis, but also concomitant thrombocytopenia and pancytopenia.1e8 Thrombocytopenia often shows a course similar to agranulocytosis. The hematological recovery is mainly dependent of the neutrophil level and the type of infections or the utilization of hematopoietic growth factors.26 When agranulocytosis or granulocytopenia is identified at a minimum or symptomless via prompt blood count examination, levamisole withdrawal plus intensive infection control measures are started immediately, and even a patient with severe agranulocytosis such as Case 1 whose ANC remained null for several days is able to recover within 1e2 weeks without any serious problems. The utilization of G-CSF since 1991 has improved the prognosis by reducing the granulocyte recovery time in the large majority of agranulocytosis patients, but despite its use, mortality remains high around 5e15%.6,26 Besides, G-CSF was found less effective in the elderly with pancytopenia such as in Case 3.26,27 Symptoms of levamisole-induced agranulocytosis do not differ from those of other causes of agranulocytosis. High fever and sore throat are the most frequent symptoms. Acute pharyngitis and necrotic gingivitis are the common oral manifestations at presentation. Despite the typical presentation of high fever, 15% of agranulocytosis patients can be asymptomatic.27 Under a high degree of diagnostic astuteness and raising patient’s awareness about agranulocytosis, this report demonstrated that a patient with minimum symptoms such as in Case 2 can be detected in the early neutropenic stage. Studies reported that levamisole-induced agranulocytosis occurs most frequently in patients with rheumatic diseases, in women, and in HLA B27 genotypes.32 The number of circulating neutrophils in HLA B27 carriers was significantly reduced during levamisole treatment when compared with those of patients without HLA B27 antigen.32 However, HLA-B27 was not detected in Case 3; indicating HLA-B27 was not an essential requirement for levamisole-induced agranulocytosis. The common characteristic of OLP and thyroid disorders is female preponderance in their prevalence.17e19,22 At the same time, drug-
Levamisole-induced agranulocytosis or pancytopenia induced agranulocytosis is more likely to be female.3,6,22 We witnessed six OLP patients with levamisole-induced agranulocytosis over 30 years in a medical center that showed a higher female-to-male ratio (5:1). A review study including 114 patients with antithyroid drug-induced agranulocytosis in a single Chinese center also revealed a higher female-to-male ratio (10.4:1).22 In the largest published series of antithyroid drug-induced agranulocytosis in Japan, which included 754 cases, females were more affected than males (6.3: 1).22 For adult patients, acquired neutropenia is more common than congenital neutropenia.33 This can be seen after exposure to certain drugs, infections, in the setting of autoimmunity, nutritional deficiency, or as a consequence of a hematologic malignancy. However, drugs and toxins are among the most common causes of acquired neutropenia. Bacterial infections are a rarer cause of neutropenia, with notable exceptions including Brucella and mycobacterial infections.33 Neutropenia with or without other cytopenias can occur in the setting of macrophage activation of hemophagocytosis which is often triggered by an acute viral or bacterial infection. But, supposedly tuberculosis was associated with the first agranulocytosis of Case 3; a bone marrow biopsy only revealed myeloid hypoplasia without hemophagocytic lymphohistiocytosis. Antituberculosis therapy was also prescribed 10 days behind empirical antibiotic treatment during that period. Furthermore, no immunosuppressive agents were given during her second agranulocytosis-related autoimmune disease. Nevertheless, patient neutrophil recoveries within 1e2 weeks have taken a course similar to that of Case 1 with levamisole-induced agranulocytosis. Agranulocytosis induced by non-chemotherapy drugs usually developed within the first 2e3 months following the medication, but it may also develop for the first time following interruption and subsequent resumption of the same drug.1,6,9,22 Nakamura et al. reported that patients with agranulocytosis induced by antithyroid drugs, more than 70% developed within 60 days and nearly 85% within 90 days, but 55 (7%) patients developed agranulocytosis after 4 months and several patients developed agranulocytosis more than 2 years after treatment.22,23 Bai et al. reported a patient with agranulocytosis following the discontinuation of methimazole treatment for 4 months.9 Citrome et al. reported that agranulocytosis can occur several months or even years after withdrawal of clozapine.34 Therefore, it seemed reasonable to assume that the first agranulocytosis in Case 3 developed following the discontinuation of levamisole treatment for 4 months, and then the second and third agranulocytosis occurred quickly within 3e4 weeks after levamisole resumption in the sensitized patient. In other words, this patient had three recurrent episodes of levamisole-induced agranulocytosis with pancytopenia within a four-year period. The study demonstrated that our awareness regarding levamisole-induced blood-cytopenias in OLP patients remains incomplete. Other than a relationship with prolonged high dosage, the pathogenesis of levamisole-induced agranulocytosis remains unresolved.35 Both immune-mediated response and direct toxicity have been described as possible mechanisms. It is usually dose and concentration-dependent, and is associated with continuous administration.33,35 In Case 3,
1199 the first agranulocytosis following the discontinuation of levamisole treatment for 4 months is not in accordance with this. The re-administration of levamisole for recurrent OLP caused exacerbation of the same hematological changes within one month that indicated an immunemediated mechanism in the sensitized patient. A direct toxic reaction by sustained high drug blood levels also could explain the events, particularly since the exacerbation after re-administration may not occur until the second or third dosage. This hypothesis need not exclude a concomitant immunologic process and, indeed, both might be necessary to cause agranulocytosis. However, the patient who will develop idiosyncratic agranulocytosis is not predetermined despite various postulated underlying mechanisms. Levamisole-induced specific immune-mediated response reacted not only with mature granulocytes, but also affected mature blood cells and myeloid progenitor cell growth.35 Bone marrow is not damaged.1e3 The halflife of levamisole is only 5.6 h and remains detectable for 2e3 days after initial exposure.1,2 While on drugs known to cause agranulocytosis at high rates (e.g. clozapine, methimazole or levamisole), regular blood count examination in patients is pivotal.6,22,34 Clozapine prescription for treatment-resistant schizophrenia should follow clear guidelines of regular CBC monitoring by once weekly from initiation to the first 6 months, every 2 weeks from 6 to 12 months, and no less than once a month after 12 months as well as following the discontinuation of clozapine.34 Based on agranulocytosis as a sudden event with low incidence of 0.1e0.5% in Graves’ patients on antithyroid drug therapy, the American Thyroid Association guidelines recommend against regular blood monitoring.22e28 In a case series study of agranulocytosis by Nakamura et al., one patient had a normal ANC in the previous day and some developed over 4 months to 2 years following antithyroid drug treatment.22e28 These facts stand against the need for regular monitoring, as this might not be cost effective. However, this is the best way to detect agranulocytosis patients without symptoms. A periodic granulocyte count measured at each visit within the first 3 months after antithyroid drug treatment has been shown to be useful, since it can identify 64% of agranulocytosis patients and 94% of granulocytopenia with no or minimum symptoms.23,24 Continued vigilance against agranulocytosi is important, in particular during the first 3 months and after a period of discontinuation, especially for patients with poor drug compliance.9,22e28 However, there is no guideline for regular blood monitoring in patients on levamisole treatment. In a case series study of antithyroid drug-induced agranulocytosis, granulocyte counts >1000/ml were confirmed within 1 week before onset in 21.3% (45 of 211) of patients. In the 2 weeks before onset, 52.6% (111 of 211) of agranulocytosis patients had normal granulocyte counts. Even one patient showed normal granulocyte counts just 1 day before onset.21e23,25 This reveals how agranulocytosis develops abruptly and how prediction and prevention are difficult. Regular monitoring of CBC might not be useful for sudden-onset agranulocytosis, though could be beneficial for slowly progressive type onset. Even so, Nakamura recommended a strong warning against overdependence on blood tests every 2 weeks, since more than half of
1200 agranulocytosis patients exhibited normal granulocyte counts in the 2 weeks before onset.21,22 In the end, it could just be labelled as random bad luck. The best way to avoid the mortality-associated druginduced agranulocytosis remains as patient education at time of prescription. Every OLP patient receiving levamisole therapy should be informed of the most common symptoms of agranulocytosis. A suspicious case with high fever, unexplained discomfort, or easy bruising should seek medical help without delay, prescribing all the necessary treatments if blood sampling finds the patient’s ANC is less than 1000/ml and with severe thrombocytopenia. These findings indicate that levamisole is an effective immunomodulator for OLP patients; however, it should be used with caution and administered with regular blood monitoring.
Conflicts of interest
S.-Y. Lu et al.
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10.
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13.
14.
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The author has no conflict of interests relevant to this article.
16.
Acknowledgments
17.
The study was self-funded by our institution after proper Institutional Review Board approval (IRB 201801756B0 to Shin-Yu Lu). The authors would like to thank Mr. Chien-Hao Su, a pharmacist of the Department of Pharmacy in the study hospital for his surveillance in levamisole safety and assistance with identifying patients on Levazol therapy, as well as to thank my colleague Dr. Shui-sang Hsueh for his technical assistance with the statistics of the research.
18.
19. 20.
Appendix A. Supplementary data 21.
Supplementary data to this article can be found online at https://doi.org/10.1016/j.jfma.2019.03.007.
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28.
and aplastic anemia study. Pharmacoepidemiol Drug Saf 1993; 2:525e9. Bai XS, Liu JH, Xiao SM. A patient with agranulocytosis following the discontinuation of methimazole treatment for 4 months: a case report. Exp Ther Med 2014;8:823e5. Moertel C, Fleming T, MacDonald J. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 1990;322:352e8. Lewinski U, Mavligib G, Hersh E. Cellular immune modulation after a single high dose of levamisole in patients with carcinoma. Cancer 1980;46:2185e94. Redondo JM, Lopez-Guerrero JA, Fresno M. Potentiation of interleukin-2 activity by levamisole and imidazole. Immunol Lett 1978;4:31e41. Veys E, Mielants H. Experience and recommendations for treatment schedule of levamisole to rheumatoid arthritis. J Rheumatol 1978;4:31e41. Lozoda F. Levamisole in the treatment of erythema multiforme: a double-blind trial in 14 patients. Oral Surg Oral Med Oral Pathol 1982;53:28e31. Lozoda F, Silverman Jr S, Cram D. Pemphigus vulgaris: a study of six cases treated with levamisole and prednisone. Oral Surg Oral Med Oral Pathol 1982;54:161e5. Olson J, Silverman Jr S. Double-blind study of levamisole therapy in recurrent aphthous stomatitis. J Oral Pathol 1978;7: 393e9. Lu Shin-Yu, Chen Weu-Jen, Eng Hock-Liew. Dramatic response to levamisole and low-dose prednisolone in 23 patients with oral lichen planus, A 6-year prospective follow-up study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1995;80:705e9. Lu Shin-Yu, Chen Weu-Jen, Eng Hock-Liew. Response to levamisole and low-dose prednisolone in 41 patients with chronic oral ulcers, A 3-year open clinical trial and follow-up study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;86: 435e45. Won TH, Park SY, Kim BS, Seo PS, Park SD. Levamisole monotherapy for oral lichen planus. Ann Dermatol 2009;21:250e4. Sun A, Chiang CP, Chiou PS, Wang JT, Liu BY, Wu YC. Immunomodulation by levamisole in patients with recurrent aphthous ulcers or oral lichen planus. J Oral Pathol Med 1994;23:172e7. Chiang CP, Yu-Fong Chang J, Wang YP, Wu YH, Lu SY, Sun A. Oral lichen planus-Differential diagnoses, serum autoantibodies, hematinic deficiencies, and management. J Fla Med Assoc 2018;117:756e65. Nakamura H, Miyauchi A, Miyawaki N, Imagawa J. Analysis of 754 cases of antithyroid drug-induced agranulocytosis over 30 years in Japan. J Clin Endocrinol Metab 2013;98:4776e83. Nakamura H, Ide A, Kudo T, Nishihara E, Ito M, Miyauchi A. Periodic granulocyte count measuring is useful for detecting asymptomatic agranulocytosis in antithyroid drug-treated patients with Graves’ disease. Eur Thyroid J 2016;5:25e60. Tajiri J, Noguchi S, Murakami T, Murakami N. Antithyroid druginduced agranulocytosis. The usefulness of routine white blood cell count monitoring. Arch Intern Med 1990;150:621e4. Tajiri J, Noguchi S. Antithyroid drug-induced agranulocytosis: special reference to normal white blood cell count agranulocytosis. Thyroid 2004;14:459e62. Maloisel F, Andres E, Kaltenbach G, Noel E, Martin-Hunyadi C, Dufour P. Prognostic factors of hematological recovery in lifethreatening nonchemotherapy drug-induced agranulocytosis, A study of 91 patients from a single center. Presse Med 2004; 33:1164e8. Vicente N, Cardoso L, arros L, Carrilho F. Antithyroid druginduced agranulocytosis: state of the art on diagnosis and management. Drugs R 2007;17:91e6. Andres E, Weitten T, Mourot-Cottet R, Keller O, Zulfiqar AA, Serraj K, et al. Antithyroid agents related agranulocytosis: literature review. Rev Med Interne 2016;37:544e50.
Levamisole-induced agranulocytosis or pancytopenia 29. Swertick RA, Campbell CF. Medication dyes as a source of drug allergy. J Drugs Dermatol JDD 2013;12:99e102. 30. Shilpa P, Chaudhari PSP. Pharmaceutical excipients: a review. Int J Pharm Biol Chem 2012;1:22e34. 31. Strauss J, Greeff OBW. Excipient-related adverse drug reactions: a clinical approach. Curr Allergy Clin Immunol 2015; 28:24e7. 32. Hodinka L, Ge ´her P, Mere ´tey K, Gyo ´di EK, Petra ´nyi GG, Bozso ´ky S. Levamisole-induced neutropenia and agranulocytosis: association with HLA B27 leukocyte agglutinating and
1201 lymphocytotoxic antibodies. Int Arch Allergy Appl Immunol 1981;65:460e4. 33. Gibson C, Berliner N. How we evaluate and treat neutropenia in adults. Blood 2014;124:1251e8. 34. Citrome L, McEvoy JP, Saklad SR. A quide to the management of clozapine- related tolerability and safety concerns. Clin Schizophrenia Relat Psychoses 2016;10:163e77. 35. Pisciotta AV. Immune and toxic mechanisms in drug-induced agranulocytosis. Semin Hematol 1973;10:279e310.
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Original Article
Treatment effectiveness of levamisole plus prednisolone on oral lichen planus patients with emphasis on levamisole-induced agranulocytosis or pancytopenia Shin-Yu Lu*, Tzu-Fan Chang, Chih-Jen Lin Oral Pathology and Family Dentistry Section, Department of Dentistry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan Received 9 February 2019; received in revised form 2 March 2019; accepted 6 March 2019
KEYWORDS Levamisole; Agranulocytosis; Pancytopenia; Oral lichen planus
Background/Purpose: Physicians’ and dentists’ knowledge of levamisole-induced agranulocytosis or pancytopenia remains incomplete. This study aimed to evaluate the treatment effectiveness of levamisole plus prednisolone on oral lichen planus (OLP) patients with emphasis on levamisole-induced hematological changes. Methods: Ninety patients with erosive OLP were given 120 mg/day new levamisole (Levazol) and 15 mg/day prednisolone for three consecutive days each week. Three cases with levamisole-induced blood-cytopenias were assessed and treated within one year. Results: Most patients reported significant pain relief and showed no evidence of erosive OLP after 4e8 weeks of treatment with few side effects; nevertheless, three female patients developed agranulocytosis or granulocytopenia with concomitant thrombocytopenia or pancytopenia within 2e6 weeks after levamisole (Levazol) treatment. One case with previously unknown double episodes of agranulocytosis revealed her first episode following interruption of levamisole (Decaris) treatment for 4 months. High fever and sore throat were the most common symptoms, but two agranulocytosis cases remained asymptomatic one week before diagnosis, and were treated with levamisole withdrawal and empiric antimicrobial initiation as well as utilization of granulocyte colony-stimulating factors. Neutrophil recovery took about 1 week, but over 4 weeks in one of the cases (an elderly patient) with septic shock. Conclusion: Agranulocytosis or pancytopenia usually developed within 2 months after levamisole treatment, but it might be delayed. Agranulocytosis was more likely to occur in females and onset was acute. Levamisole is an effective immunomodulator for OLP patients; however, it should be used with caution and administered with regular blood monitoring.
* Corresponding author. Kaohsiung Chang Gung Memorial Hospital, 123 Dapi Road, Niaosong District, Kaohsiung, 833, Taiwan (R.O.C).Fax: þ886 7317123x8288. E-mail address: [email protected] (S.-Y. Lu). https://doi.org/10.1016/j.jfma.2019.03.007 0929-6646/Copyright ª 2019, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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S.-Y. Lu et al. Copyright ª 2019, Formosan Medical Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/).
Introduction Agranulocytosis or pancytopenia is a rare but lifethreatening complication of levamisole, and an up-to-date understanding of the subject is important. Agranulocytosis is characterized by a marked reduction of circulating granulocytes with an absolute neutrophil count (ANC) less than 500/ml (normal reference>1500/ml). Pancytopenia is defined when in addition to agranulocytosis, patients show total leukocyte count <4000/ml, hemoglobin <11 gm/dl and a platelet count <100,000/ml.1e6 The lower the neutrophil count and the longer it remains low, the greater risk of serious infections or sepsis. Agranulocytosis patients often experience ANC under 100/ml at greatest risk.6e8 Agranulocytosis usually occurs within the first two months following levamisole treatment; however, certain cases have demonstrated that agranulocytosis might occur after interruption or long-term treatment.1e9 Levamisole (Decaris) has been used as an anthelmintic in both human and veterinary since 1966. It attracted interest as an effective immunomodulator for diseases in which cellular immune deficiency was suspected, such as chronic and recurrent oral ulcers, primary and secondary immune deficiencies, rheumatoid arthritis, and in stabilization of tumor remission in cancer.10e21 When used with low-dose prednisolone therapy for patients with oral lichen planus (OLP), erythema multiforme, pemphigus vulgaris or pemphigoid, levamisole has been shown to be effective and relatively safe in comparison with high-dose prednisolone.14e21 Significant side effects from levamisole are skin rash, headache, palpitation and insomnia that were typically mild, whereas agranulocytosis was serious.1e6,13e21 Studies have reported that the hematologic toxicity is a significant and disturbing consequence of long-term levamisole administration, approaching in frequency and severity as agranulocytosis induced by antithyroid drugs, in particular for methimazole.1e6,22e28 In causality assessments of 980 reported cases with agranulocytosis induced by non-chemotherapy drugs in MEDLINE (1966e2006), 10 cases (1.0%) were associated with levamisole; however, case reports cannot provide rates of drug-induced complications.6 Sun et al. reported that the incidence of agranulocytosis was about 0.2% in OLP patients on Decaris therapy.20 In over 30 years of managing almost three thousands of OLP patients in a medical center, the present researchers have experienced three patients with agranulocytosis following Decaris plus prednisolone treatment in 1986e2017 and three patients with agranulocytosis or neutropenia and concomitant thrombocytopenia or pancytopenia after the addition of new levamisole (Levazol) to prednisolone during 2018, with an incidence near 0.2%. However, widespread clinical trials of levamisole as an immunopotentiating agent in rheumatoid arthritis,
metastatic carcinoma, and immunodeficiency states have been complicated by agranulocytosis in 2.5%e13% of patients.2,10e13 Symoens et al. reported that 88 of 3900 patients on levamisole therapy had agranulocytosis, an incidence of 2.3% with 8 recorded deaths exhibited most frequently in rheumatoid arthritis patients.1,2 A much higher incidence of 13% was found in a small series of women receiving combined chemotherapy and levamisole for breast cancer.2 Agranulocytosis often occurs abruptly and patients present with signs of infection together with high fever. Clinical suspicion is therefore important and immediate blood sampling is needed. In a case series study of 754 Graves’ patients with antithyroid drug-induced hematologic complications, agranulocytosis was diagnosed in 670 (88.9%) patients, whereas 84 (11.1%) were reported with pancytopenia or aplastic anemia.22 Tajiri et al. reported that 12 Graves’ patients with antithyroid drug-induced agranulocytosis revealed normal white blood counts (WBC).25 We witnessed six OLP patients with agranulocytosis or granulocytopenia and concomitant thrombocytopenia or pancytopenia after levamisole therapy. Thus, monitoring of complete blood counts (CBC) and not only granulocyte counts or WBC is necessary. The aim of this report is to evaluate the treatment effectiveness of Levazol pus prednisolone on OLP patients with emphasis on characteristics of levamisole-induced blood-cytopenias.
Patients and methods The study was approved by the Institutional Review Board. A total of 90 consecutive patients (79 women and 11 men, mean age 58.1 years, range 30e87 years) with sore mouth visiting the Oral Medicine Clinic of the study hospital between November 2017 and October 2018 and finally diagnosed as having OLP were included in this study. Upon the terminated supply of Decaris since November 2017, Levazol (40 mg) and prednisolone (5 mg) administered three times a day for 3 consecutive days each week were used as long as evidence of symptomatic OLP was seen. Patients were monitored once every two weeks for the first 3 months and once a month thereafter for recording of clinical responses and side effects. Data were retrieved from the chart notes made at each visit. The clinical effectiveness across treatment periods was analyzed by using JMP statistical package, version 14.0.0 (SAS Institute Inc., Cary, NC, USA). A p-value <0.05 was considered statistically significant.
Results As shown in Table 1, 84 patients reported significant pain relief and showed no evidence of erosive OLP after 4e8 weeks of treatment. They also remained free from
Levamisole-induced agranulocytosis or pancytopenia Table 1
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Disease activity during the treatment of levamisole (Levazol) plus prednisolone on 90 patients with oral lichen planus.
Response within 2 weeks Response within 4 weeks Response within 6 weeks Response within 8 weeks Remission period (months)
Remarkable response
Partial response
No response
P
46 66 81 84 4.3 1.8
44 (2 þ Case 2) 21 (Case 3)c 5 (Case 1)c 1 3.3 1.4
0 0 0 0 0
0.054 0.045a 0.023 0.012
b
Remarkable response (80%e100% remission of symptoms and signs). Partial response (50%e75% remission of symptoms and signs). No response (unchanged or worsening of symptoms and signs). a The treatment effectiveness was statistically significant after 4 weeks (P < 0.05). b Levamisole was discontinued after 2 weeks due to skin rash in two patients and granulocytopenia combined with thrombocytopenia in Case 2 (Table 2). c Upon the onset of agranulocytosis and pancytopenia, levamisole was discontinued after 3 weeks in Case 3 and after 6 weeks in Case 1 (Table 2).
symptoms months after the treatment ended. Levazol was discontinued in five patients with adverse reactions, although there were otherwise improved OLP symptoms. Significant side effects were minor skin rash and headache in two cases, but three female patients subsequently developed agranulocytosis or granulocytopenia with concomitant thrombocytopenia or pancytopenia within 2 months following medications during January to May 2018. Raising patient education at time of prescription was carried out and prompt blood sampling was taken just the day before and 2e4 weeks after Levazol therapy; no new agranulocytosis case was found until the end of 2018. The results of blood-cytopenias in three patients are summarized in Tables 2 and 3 and Fig. 1. The first case of a 46-year-old female presented to the Emergency Department (ED) complaining of high fever up to 40 C, sore throat and general weakness for two days in February, 2018. Her past medical history was unremarkable except for hyperthyroidism with subtotal thyroidectomy and she had received thyroxin therapy for nine years. She reported no
drug allergy history. Six weeks previously, she had begun to take 120 mg/day Levazol plus 15 mg/day prednisolone 3 days a week for erosive OLP and desquamative gingivitis. Her physician obtained a CBC as part of a new patient visit, and the WBC of 300/ml and calculated ANC of 12/ml demonstrated severe leukopenia with agranulocytosis. The metabolic profile revealed elevated inflammatory marker C-reactive protein (CRP), 101.78 mg/L (reference range <5 mg/L) and mild abnormal liver function. No deficiency of iron, B12 or folate was found. Blood cultures and chest xray showed no abnormalities, but abdominal ultrasonography revealed fatty liver. Medications were carefully reviewed and levamisole as the culprit drug was favored. Accordingly, in stopping levamisole, empirical antibiotic initiation and supportive care were undertaken immediately. The granulocyte-colony stimulating factor (G-CSF) was also given at the first admission date. Her ANC remained low, 8/ml in the sixth hospital day, but dramatically rose to 3762/ml in the eighth day. She was discharged without any complications.
Table 2 Analysis of agranulocytosis or granulocytopenia with concomitant thrombocytopenia or pancytopenia in three oral lichen planus patients receiving levamisole plus prednisolone therapy. No.
1 2 3 3aa 3ba
Age /Sex
46/F 57/F 87/F 83/F 83/F
Lev mg per day /wks
AG or GP onset wks
120/6 120/2 120/3 150/6 150/4
6 2 3 22b 4
Hematological changes Before therapy WBC 1000 /ul 3.5e11
Neu ratio % 42e47
ANC /ul
_ 4.9 4.6 4.8 4.7
_ 47.6 50.7 50.0 62.7
AG/GP at diagnosis WBC 1000 /ul 3.5e11
Neu ratio % 42e47
ANC /ul
>1500
Plt 1000 /ul 150-400
_ 2332 2332 2400 2947
_ 252 159 127 148
0.3 3.6 <0.2 0.5 0.7
4.0 40.1 25.0 0.0 0.0
Neu Recover within days
>1500
Plt 1000 /ul 150e400
12 1443 <50 0 0
152 98 11 76 48
8 <7 33 16 14
Abbreviation: AG, agranulocytosis; ANC, absolute neutrophil count; GP, granulocytopenia; Lev, Levamisole; Neu, Neutrophil; Plt, Platelets; WBC, White blood count; wks, weeks. AG is defined by ANC below 500/ul. GP is defined by ANC<1500/ul. Thrombocytopenia is defined by platelets<150 1000/ul. a Case 3 had the previous double episodes (3a and 3b) of agranulocytosis with pancytopenia within 2014. In other words, she had three recurrent episodes of AG within a four-year period. b 22 weeks in Case 3a indicated her first agranulocytosis following Decaris and prednisolone treatment 3 days each week for 6 weeks and the discontinuation of the same drug for 16 weeks.
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Table 3 The selective indices of hematological changes in three oral lichen planus patients with agranulocytosis or neutropenia combined thrombocytopenia or pancytopenia before treatment (day-), on the day of diagnosis (day 0) and after levamisole withdrawal. No.
Time course
WBC /ml (4000e11000)
Neutrophil % (42e74)
ANC /ml (>1500)
Lymphocyte % (20e56)
Hb g/dl (12.5e17)
Platelet 1000/ml (150e400)
1
Day 0 Day 3 Day 6 Day 8 Day 10 Day 16 Day-14a Day 0 Day 30 Day-180c Day -21b Day 0 Day 10 Day 14 Day 21 Day 33 Day 63 Day-135c Day 0 Day 3 Day 16 Day 23 Day-80b Day 0 Day 4 Day 14 Day 20
300 500 800 5700 14400 10300 4900 3600 9400 4600 3900 <200 300 700 2000 7200 5600 4800 500 800 4900 5300 4700 700 300 3300 6500
4.0 0.0 1.0 66.0 29.0 60.0 47.6 40.1 53.3 50.7 79.8 25.0 72.0 78.0 73.0 71.4 73.0 74.0 0.0 1.0 67.0 77.0 62.7 0.0 0.0 53.0 67.7
12 0 8 3762 4147 6180 2332 1443 5010 2332 3112 <50 216 546 1460 5140 4088 3552 0 8 3283 4081 2947 0 0 1749 4401
78.0 84.0 88.0 6.0 8.0 28.0 43.0 42.8 39.4 41.5 11.4 75.0 28.0 18.0 23.0 20.1 19.0 20.0 98.0 94.0 22.0 17.0 27.1 98.6 93.3 28.0 23.1
12.7 10.4 11.1 11.0 11.6 13.4 12.4 11.6 12.6 12.2 12.7 9.6 8.2 8.4 7.8 8.9 9.5 13.4 11.3 11.7 11.2 11.5 11.7 11.7 11.4 9.8 10.3
152 194 459 405 394 299 252 98 231 159 142 11 22 73 42 40 93 127 76 130 445 387 148 48 63 84 233
2
3
3a
3b
Abbreviation: ANC, absolute neutrophil count; WBC, white blood count; Hb, hemoglobin. a In Case 2, the day-14 indicated blood test just in the day (2 weeks) before levamisole treatment. b In Case 3, the day-21 indicated blood test just in the day (3 weeks) before levamisole treatment. c In Case 3 of day-180, case 3a of day-135 and case 3b of day-80 indicated the available blood indices 180 days, 135 days and 80 days before the start of levamisole treatment respectively.
The second case of a fifty-seven-year-old female had a past medical history of rheumatic heart disease and denied any drug allergy. Her erosive OLP was diagnosed and treated with Levazol plus prednisolone during April, 2018. Patient’s CBC with differential and serum iron, B12 and folate were taken just the day before medication and all showed normal reference ranges. Two weeks later, OLP response demonstrated much improvement, but she complained about occasional mild fever and discomfort after medications. Prompt CBC test was taken and the hematological changes within 2 weeks demonstrated mild neutropenia with severe thrombocytopenia. Immediate decisions of stopping levamisole and starting oral amoxicillin were taken to prevent infection. Without hospitalization, the patient was reviewed by telephone call 48 h later. No fever or any complaint was reported. Her available time for further CBC test was taken one month later. Her blood counts have recovered. She requested continuous levamisole therapy under mild neutropenia if there were otherwise improved OLP symptoms. However, while on a drug known to cause agranulocytosis, any patient with early
neutropenia should have such drug be immediately discontinued without rechallenge. The third case of an eighty-seven-year-old female patient had many medical diseases including hypertension, diabetes, gouty arthritis and pulmonary tuberculosis that were under control for many years. In April 2018, she asked for management of recurrent OLP which had been previously treated with Decaris plus prednisolone for 6 weeks during December 2013 to January 2014 and 4 weeks during September 2014. She denied any drug allergy history and began to take Levazol plus prednisolone 3 days a week in April 2018. Patient’s CBC with differential was taken just the day before medication and the results showed a mild leukopenia and thrombocytopenia. There was no deficiency of iron, B12 or folate. Three weeks later, she presented to ED with high fever and malaise for 3 days in May, 2018. Four days prior to ED, associated symptoms including sore throat, left neck pain and leg bruise occurred. Further CBC test was taken and the changes within 3 weeks demonstrated a severe agranulocytosis (ANC of <50/ml) with pancytopenia. Medications were reviewed carefully and
Levamisole-induced agranulocytosis or pancytopenia Figure 1 Case 3 with three recurrent episodes of levamisole-induced agranulocytosis with pancytopenia within a four-year period. The profile of hematological changes include absolute neutrophil count (ANC), platelet and hemoglobin (Hb). (3a) Left, the first episode in May 2014 developed following the discontinuation of levamisole treatment for 4 months. (3b) Middle, the second episode in October 2014 developed following 4 weeks of levamisole treatment. (3) Right, the third episode in May 2018 developed following 3 weeks of levamisole treatment.
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1198 levamisole as the culprit drug was favored. A further test of HLA-B27 was taken but the result was negative. Unexpectedly, this was her third episode of agranulocytosis, but her memory and knowledge about the causes of the previous double episodes of agranulocytosis within 2014 was poor. In May 2014, she presented to ED complaining of dizziness and fever for 3 days, as well as intermittent night sweating and weight loss of 10 kg within one year, but with no cough, shortness of breath or diarrhea. The first agranulocytosis (ANC of 0/ml) combined with severe thrombocytopenia was diagnosed that had developed following the discontinuation of Decaris treatment for 4 months. Her ANC showed progressive improvement after antibiotic initiation, and then the addition of anti-tuberculosis therapy 10 days later, because the chest x-ray showed pulmonary infiltrates and abdominal computed tomography revealed multiple nodular patches in bilateral lower lungs as pulmonary tuberculosis. Tuberculosis-related agranulocytosis was favored. Bone marrow biopsy revealed marked myeloid hypoplasia. Sixteen days later, her ANC had risen to 3283/ml (Case 3a in Table 3). She was discharged without complications but continued anti-tuberculosis therapy. Her second agranulocytosis (ANC of 0/ml) with concomitant severe thrombocytopenia was diagnosed in October 2014 that had developed following 4 weeks of Decaris treatment (Case 3b in Table 3). The primary care physician did not consider levamisole as the culprit drug, but suspected associated autoimmune disease. Supportive care and empirical antibiotic treatment were undertaken immediately, but no immunosuppressive drugs were prescribed. Two weeks later, her ANC had risen to 1749/ml. She was discharged without complications. Her third episode of agranulocytosis (ANC< 50/ml) with pancytopenia developed following 3 weeks of Levazol treatment favored as the main cause in May 2018. The bacterial culture from blood revealed polymicrobial septicemia that rapidly resulted in septic shock with acute respiratory failure, kidney injury, myocardial infarction, and hypoxic encephalopathy. She was sent to the intensive care unit (ICU) for supportive care, parenteral broad-spectrum antibiotic initiation and G-CSF treatment. However, the utilization of G-CSF did not provide improvement in the recovery time, because recurrent sepsis and pancytopenia resulted in more prolonged neutropenia from exhaustion of marrow granulocyte. Her ANC slowly rose to 546/ml two weeks later, then to 1460/ml three weeks later, and to normal ranges after almost four weeks (Case 3 in Table 2). After two months of struggle with serious infections, she was discharged with complications of neurological dysfunction from hypoxic encephalopathy. The severity of three patients ranked from modest (Case 2), severe (Case 1) to very complicated (Case 3, multiple episodes with diverse complications).
Discussion During the last two decades, we have demonstrated successful results of levamisole (Decaris) used with low-dose prednisolone on OLP patients with few side effects.17,18 In the study, treatment with Levazol and low-dose
S.-Y. Lu et al. prednisolone may produce similar improved results as before in most treated OLP patients. However, the extraordinary emergence of these new agranulocytosis cases alerted us to the potential danger of levamisole therapy. The active ingredient dosage of levamisole in a Levazol tablet (40 mg) was less than that in a Decaris tablet (50 mg), but the inactive ingredients between them were almost different. Various drug manufacturers generally do not suddenly change the active ingredient in a medication, while they may change the inactive ingredients like pill color or excipients, which can cause side effects or spur an allergic reaction.29e31 The effects and side effects of generic drugs vs. brand-name drugs as well as strategies to increase drug safety were discussed in the Pharmacy & Therapeutics Committee of the study hospital. As the cause of unexpected Levazol-related agranulocytosis cases remains unsolved, pharmacovigilance and surveillance are advised. Early detection of agranulocytosis before symptoms of infection occur is important to prevent disease progression and a fatal outcome. Levamisole-induced hematological changes manifest not only agranulocytosis, but also concomitant thrombocytopenia and pancytopenia.1e8 Thrombocytopenia often shows a course similar to agranulocytosis. The hematological recovery is mainly dependent of the neutrophil level and the type of infections or the utilization of hematopoietic growth factors.26 When agranulocytosis or granulocytopenia is identified at a minimum or symptomless via prompt blood count examination, levamisole withdrawal plus intensive infection control measures are started immediately, and even a patient with severe agranulocytosis such as Case 1 whose ANC remained null for several days is able to recover within 1e2 weeks without any serious problems. The utilization of G-CSF since 1991 has improved the prognosis by reducing the granulocyte recovery time in the large majority of agranulocytosis patients, but despite its use, mortality remains high around 5e15%.6,26 Besides, G-CSF was found less effective in the elderly with pancytopenia such as in Case 3.26,27 Symptoms of levamisole-induced agranulocytosis do not differ from those of other causes of agranulocytosis. High fever and sore throat are the most frequent symptoms. Acute pharyngitis and necrotic gingivitis are the common oral manifestations at presentation. Despite the typical presentation of high fever, 15% of agranulocytosis patients can be asymptomatic.27 Under a high degree of diagnostic astuteness and raising patient’s awareness about agranulocytosis, this report demonstrated that a patient with minimum symptoms such as in Case 2 can be detected in the early neutropenic stage. Studies reported that levamisole-induced agranulocytosis occurs most frequently in patients with rheumatic diseases, in women, and in HLA B27 genotypes.32 The number of circulating neutrophils in HLA B27 carriers was significantly reduced during levamisole treatment when compared with those of patients without HLA B27 antigen.32 However, HLA-B27 was not detected in Case 3; indicating HLA-B27 was not an essential requirement for levamisole-induced agranulocytosis. The common characteristic of OLP and thyroid disorders is female preponderance in their prevalence.17e19,22 At the same time, drug-
Levamisole-induced agranulocytosis or pancytopenia induced agranulocytosis is more likely to be female.3,6,22 We witnessed six OLP patients with levamisole-induced agranulocytosis over 30 years in a medical center that showed a higher female-to-male ratio (5:1). A review study including 114 patients with antithyroid drug-induced agranulocytosis in a single Chinese center also revealed a higher female-to-male ratio (10.4:1).22 In the largest published series of antithyroid drug-induced agranulocytosis in Japan, which included 754 cases, females were more affected than males (6.3: 1).22 For adult patients, acquired neutropenia is more common than congenital neutropenia.33 This can be seen after exposure to certain drugs, infections, in the setting of autoimmunity, nutritional deficiency, or as a consequence of a hematologic malignancy. However, drugs and toxins are among the most common causes of acquired neutropenia. Bacterial infections are a rarer cause of neutropenia, with notable exceptions including Brucella and mycobacterial infections.33 Neutropenia with or without other cytopenias can occur in the setting of macrophage activation of hemophagocytosis which is often triggered by an acute viral or bacterial infection. But, supposedly tuberculosis was associated with the first agranulocytosis of Case 3; a bone marrow biopsy only revealed myeloid hypoplasia without hemophagocytic lymphohistiocytosis. Antituberculosis therapy was also prescribed 10 days behind empirical antibiotic treatment during that period. Furthermore, no immunosuppressive agents were given during her second agranulocytosis-related autoimmune disease. Nevertheless, patient neutrophil recoveries within 1e2 weeks have taken a course similar to that of Case 1 with levamisole-induced agranulocytosis. Agranulocytosis induced by non-chemotherapy drugs usually developed within the first 2e3 months following the medication, but it may also develop for the first time following interruption and subsequent resumption of the same drug.1,6,9,22 Nakamura et al. reported that patients with agranulocytosis induced by antithyroid drugs, more than 70% developed within 60 days and nearly 85% within 90 days, but 55 (7%) patients developed agranulocytosis after 4 months and several patients developed agranulocytosis more than 2 years after treatment.22,23 Bai et al. reported a patient with agranulocytosis following the discontinuation of methimazole treatment for 4 months.9 Citrome et al. reported that agranulocytosis can occur several months or even years after withdrawal of clozapine.34 Therefore, it seemed reasonable to assume that the first agranulocytosis in Case 3 developed following the discontinuation of levamisole treatment for 4 months, and then the second and third agranulocytosis occurred quickly within 3e4 weeks after levamisole resumption in the sensitized patient. In other words, this patient had three recurrent episodes of levamisole-induced agranulocytosis with pancytopenia within a four-year period. The study demonstrated that our awareness regarding levamisole-induced blood-cytopenias in OLP patients remains incomplete. Other than a relationship with prolonged high dosage, the pathogenesis of levamisole-induced agranulocytosis remains unresolved.35 Both immune-mediated response and direct toxicity have been described as possible mechanisms. It is usually dose and concentration-dependent, and is associated with continuous administration.33,35 In Case 3,
1199 the first agranulocytosis following the discontinuation of levamisole treatment for 4 months is not in accordance with this. The re-administration of levamisole for recurrent OLP caused exacerbation of the same hematological changes within one month that indicated an immunemediated mechanism in the sensitized patient. A direct toxic reaction by sustained high drug blood levels also could explain the events, particularly since the exacerbation after re-administration may not occur until the second or third dosage. This hypothesis need not exclude a concomitant immunologic process and, indeed, both might be necessary to cause agranulocytosis. However, the patient who will develop idiosyncratic agranulocytosis is not predetermined despite various postulated underlying mechanisms. Levamisole-induced specific immune-mediated response reacted not only with mature granulocytes, but also affected mature blood cells and myeloid progenitor cell growth.35 Bone marrow is not damaged.1e3 The halflife of levamisole is only 5.6 h and remains detectable for 2e3 days after initial exposure.1,2 While on drugs known to cause agranulocytosis at high rates (e.g. clozapine, methimazole or levamisole), regular blood count examination in patients is pivotal.6,22,34 Clozapine prescription for treatment-resistant schizophrenia should follow clear guidelines of regular CBC monitoring by once weekly from initiation to the first 6 months, every 2 weeks from 6 to 12 months, and no less than once a month after 12 months as well as following the discontinuation of clozapine.34 Based on agranulocytosis as a sudden event with low incidence of 0.1e0.5% in Graves’ patients on antithyroid drug therapy, the American Thyroid Association guidelines recommend against regular blood monitoring.22e28 In a case series study of agranulocytosis by Nakamura et al., one patient had a normal ANC in the previous day and some developed over 4 months to 2 years following antithyroid drug treatment.22e28 These facts stand against the need for regular monitoring, as this might not be cost effective. However, this is the best way to detect agranulocytosis patients without symptoms. A periodic granulocyte count measured at each visit within the first 3 months after antithyroid drug treatment has been shown to be useful, since it can identify 64% of agranulocytosis patients and 94% of granulocytopenia with no or minimum symptoms.23,24 Continued vigilance against agranulocytosi is important, in particular during the first 3 months and after a period of discontinuation, especially for patients with poor drug compliance.9,22e28 However, there is no guideline for regular blood monitoring in patients on levamisole treatment. In a case series study of antithyroid drug-induced agranulocytosis, granulocyte counts >1000/ml were confirmed within 1 week before onset in 21.3% (45 of 211) of patients. In the 2 weeks before onset, 52.6% (111 of 211) of agranulocytosis patients had normal granulocyte counts. Even one patient showed normal granulocyte counts just 1 day before onset.21e23,25 This reveals how agranulocytosis develops abruptly and how prediction and prevention are difficult. Regular monitoring of CBC might not be useful for sudden-onset agranulocytosis, though could be beneficial for slowly progressive type onset. Even so, Nakamura recommended a strong warning against overdependence on blood tests every 2 weeks, since more than half of
1200 agranulocytosis patients exhibited normal granulocyte counts in the 2 weeks before onset.21,22 In the end, it could just be labelled as random bad luck. The best way to avoid the mortality-associated druginduced agranulocytosis remains as patient education at time of prescription. Every OLP patient receiving levamisole therapy should be informed of the most common symptoms of agranulocytosis. A suspicious case with high fever, unexplained discomfort, or easy bruising should seek medical help without delay, prescribing all the necessary treatments if blood sampling finds the patient’s ANC is less than 1000/ml and with severe thrombocytopenia. These findings indicate that levamisole is an effective immunomodulator for OLP patients; however, it should be used with caution and administered with regular blood monitoring.
Conflicts of interest
S.-Y. Lu et al.
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13.
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The author has no conflict of interests relevant to this article.
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Acknowledgments
17.
The study was self-funded by our institution after proper Institutional Review Board approval (IRB 201801756B0 to Shin-Yu Lu). The authors would like to thank Mr. Chien-Hao Su, a pharmacist of the Department of Pharmacy in the study hospital for his surveillance in levamisole safety and assistance with identifying patients on Levazol therapy, as well as to thank my colleague Dr. Shui-sang Hsueh for his technical assistance with the statistics of the research.
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19. 20.
Appendix A. Supplementary data 21.
Supplementary data to this article can be found online at https://doi.org/10.1016/j.jfma.2019.03.007.
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