State of Art of Idiosyncratic Drug-Induced Neutropenia or Agranulocytosis, with a Focus on Biotherapies

Introduction: Idiosyncratic drug-induced neutropenia and agranulocytosis is seldom discussed in the literature, especially for new drugs such as biotherapies outside the context of oncology. In the present paper, we report and discuss the clinical data and management of this relatively rare disorder, with a focus on biotherapies used in autoimmune and auto-inflammatory diseases. Materials and methods: A review of the literature was carried out using the PubMed database of the US National Library of Medicine. We searched for articles published between January 2010 and May 2019 using the following key words or associations: “drug-induced neutropenia”, “drug-induced agranulocytosis”, and “idiosyncratic agranulocytosis”. We included specific searches on several biotherapies used outside the context of oncology, including: tumor necrosis factor (TNF)-alpha inhibitors, anti-CD20 agents, anti-C52 agents, interleukin (IL) 6 inhibitors, IL 1 inhibitors, and B-cell activating factor inhibitor. Results: Idiosyncratic neutropenia remains a potentially serious adverse event due to the frequency of severe sepsis with severe deep tissue infections (e.g., pneumonia), septicemia, and septic shock in approximately two-thirds of all hospitalized patients with grade 3 or 4 neutropenia (neutrophil count (NC) ≤ 0.5 × 109/L and ≤ 0.1 × 109/L, respectively). Over the last 20 years, several drugs have been strongly associated with the occurrence of idiosyncratic neutropenia, including antithyroid drugs, ticlopidine, clozapine, sulfasalazine, antibiotics such as trimethoprim-sulfamethoxazole, and deferiprone. Transient grade 1–2 neutropenia (absolute blood NC between 1.5 and 0.5 × 109/L) related to biotherapy is relatively common with these drugs. An approximate 10% prevalence of such neutropenia has been reported with several of these biotherapies (e.g., TNF-alpha inhibitors, IL6 inhibitors, and anti-CD52 agents). Grade 3–4 neutropenia or agranulocytosis and clinical manifestations related to sepsis are less common, with only a few case reports to date for most biotherapies. Special mention should be made of late onset and potentially severe neutropenia, especially following anti-CD52 agent therapy. During drug therapy, several prognostic factors have been identified that may be helpful when identifying ‘susceptible’ patients. Older age (>65 years), septicemia or shock, renal failure, and a neutrophil count ≤0.1 × 109/L have been identified as poor prognostic factors. Idiosyncratic neutropenia should be managed depending on clinical severity, with permanent/transient discontinuation or a lower dose of the drug, switching from one drug to another of the same or another class, broad-spectrum antibiotics in cases of sepsis, and hematopoietic growth factors (particularly G-CSF). Conclusion: Significant progress has been made in recent years in the field of idiosyncratic drug-induced neutropenia, leading to an improvement in their prognosis (currently, mortality rate between 5 and 10%). Clinicians must continue their efforts to improve their knowledge of these adverse events with new drugs as biotherapies.

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Severe Neutropenia and Agranulocytosis Related to Antithyroid Drugs: A Study of 30 Cases Managed in A Single Reference Center

Medicines ◽

10.3390/medicines7030015 ◽

2020 ◽

Vol 7 (3) ◽

pp. 15

Author(s):

Emmanuel Andrès ◽

Noel Lorenzo-Villalba ◽

Rachel Mourot-Cottet ◽

Frédéric Maloisel ◽

Martine Tebacher ◽

...

Keyword(s):

Septic Shock ◽

Growth Factors ◽

Neutrophil Count ◽

Antithyroid Drug ◽

Nodular Goiter ◽

Severe Neutropenia ◽

Antithyroid Drugs ◽

Hematopoietic Growth Factors ◽

Drug Induced ◽

The Mean

Background: The most important series devoted to antithyroid drug-induced severe neutropenia and agranulocytosis are Japanese studies, almost specifically in relation to the intake of methimazole. The clinical data of 30 Caucasian patients followed up for antithyroid drug-induced neutropenia at a third-level hospital are reported. Methods: The data of 30 patients with idiosyncratic antithyroid drug-induced neutropenia and agranulocytosis from a cohort study on drug-induced neutropenia and agranulocytosis conducted at the University Hospital of Strasbourg (France) were retrospectively reviewed. Results: The mean patient age was 61.7 years old (range: 20–87), and the gender ratio (F/M) was 4. Several comorbidities were reported in 23 patients (76.7%), with the mean Charlson comorbidity index of 1. The causative drugs were carbimazole and benzylthiouracil, in 28 (93.3%) and 2 cases, respectively, prescribed primarily for multi-hetero-nodular goiter or thyroid nodule to 18 patients (60%). Sore throat and acute tonsillitis (40%), isolated fever (20%), septicemia (13.3%), documented pneumonia (6.7%), and septic shock (6.7%) were the main clinical features upon admission. The mean neutrophil count at nadir was 0.02 and 0 × 109/L (range: 0–0.3). Regarding the patients’ hospital course: 13 cases (43.3%) worsened during hospitalization, severe sepsis was found in 26.7%, systemic inflammatory response syndrome—in 13.3%, and septic shock—in 3.3% of the cases, respectively. Broad-spectrum antibiotics were indicated for all the patients, and 21 (73.3%) of them received hematopoietic growth factors. Hematological recovery (neutrophil count ≥ 1.5 × 109/L) was seen at 8.3 days (range: 2–24), but faster in those receiving hematopoietic growth factors (4.9 days, p = 0.046). Two patients died during hospitalization, and the rest had a favorable clinical outcome. Conclusions: Antithyroid drug-induced neutropenia represents a serious complication resulting from the rates of severe infections especially in those cases severe neutropenia. In this setting, an established procedure for the management of patients seems useful or even indispensable in view of potential mortality.

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Safety and efficacy of rifabutin among HIV/TB-coinfected children on lopinavir/ritonavir-based ART

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkz219 ◽

2019 ◽

Vol 74 (9) ◽

pp. 2707-2715 ◽

Cited By ~ 4

Author(s):

Holly E Rawizza ◽

Kristin M Darin ◽

Regina Oladokun ◽

Biobele Brown ◽

Babatunde Ogunbosi ◽

...

Keyword(s):

Adverse Events ◽

Absolute Neutrophil Count ◽

Neutrophil Count ◽

Treatment Options ◽

Severe Neutropenia ◽

Laboratory Monitoring ◽

Safety And Efficacy ◽

Cell Percentage ◽

Grade 3 ◽

Cd4 Cell

Abstract Background TB is the leading cause of death among HIV-infected children, yet treatment options for those who require PI-based ART are suboptimal. Rifabutin is the preferred rifamycin for adults on PI-based ART; only one study has evaluated its use among children on PIs and two of six children developed treatment-limiting neutropenia. Methods Since 2009, rifabutin has been available for HIV/TB-coinfected children requiring PI-based ART in the Harvard/APIN programme in Nigeria. We retrospectively analysed laboratory and clinical toxicities at baseline and during rifabutin therapy, and examined HIV/TB outcomes. Results Between 2009 and 2015, 48 children received rifabutin-containing TB therapy with PI (lopinavir/ritonavir)-based ART: 50% were female with a median (IQR) baseline age of 1.7 (0.9–5.0) years and a median (IQR) CD4+ cell percentage of 15% (9%–25%); 52% were ART experienced. Eighty-five percent completed the 6 month rifabutin course with resolution of TB symptoms and 79% were retained in care at 12 months. Adverse events (grade 1–4) were more common at baseline (27%) than during rifabutin treatment (15%) (P = 0.006). Absolute neutrophil count was lower during rifabutin compared with baseline (median = 1762 versus 2976 cells/mm3, respectively), but only one instance (2%) of grade 3 neutropenia occurred during rifabutin treatment. Conclusions With clinical and laboratory monitoring, our data suggest that rifabutin is a safe option for TB therapy among children on PI-based ART. By contrast with the only other study of this combination in children, severe neutropenia was rare. Furthermore, outcomes from this cohort suggest that rifabutin is effective, and a novel option for children who require PI-based ART. Additional study of rifabutin plus PIs in children is urgently needed.

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A Case of Antithyroid Drug-Induced Agranulocytosis Pre-Covid 19 Era

10.52916/jmrs204031 ◽

2020 ◽

pp. 1-4

Author(s):

MosabNouraldein Mohammed Hamad

Keyword(s):

Side Effects ◽

Neutrophil Count ◽

Antithyroid Drug ◽

Drug Effects ◽

Medical Advice ◽

Antithyroid Drugs ◽

Graves Disease ◽

Drug Induced ◽

Immunological Mechanisms ◽

Noticeable Reduction

Agranulocytosis is an infrequent and serious side effect of antithyroid drugs characterized by a noticeable reduction in granulocyte and neutrophil count, it usually occurs within the first 2-3 months of treatment. There is a variety of mechanisms by which ATD can induce agranulocytosis, direct drug effects, and immunological mechanisms. We present 33 years old female attended Atbara teaching hospital who has developed agranulocytosis 2 weeks after starting ATD to treat relapsed Graves' disease. What was unusual about this patient is that symptoms have occurred in a period less than 15 days of starting treatment and with a dose of 45 mg /day. The physician must educate the patient about the possibility of early onset of serious side effects of ATD and to seek medical advice as soon as possible.

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Psychopharmacological Treatment, Intraocular Pressure and the Risk of Glaucoma: A Review of Literature

Journal of Clinical Medicine ◽

10.3390/jcm10132947 ◽

2021 ◽

Vol 10 (13) ◽

pp. 2947

Author(s):

Adela Magdalena Ciobanu ◽

Vlad Dionisie ◽

Cristina Neagu ◽

Otilia Maria Bolog ◽

Sorin Riga ◽

...

Keyword(s):

At Risk ◽

Intraocular Pressure ◽

Adverse Effects ◽

Current Knowledge ◽

Glaucoma Patient ◽

New Drugs ◽

Extensive Literature ◽

Drug Induced ◽

Psychopharmacological Treatment ◽

Pubmed Database

Through the years, the available psychopharmacological treatments have expanded with numerous new drugs. Besides weight gain, gastro-intestinal problems or Parkinson-like symptoms, ocular adverse effects of psychiatric drugs have been reported. These adverse effects are not common, but can be dangerous for the patient. This review summarises the current knowledge on the risk of raised intraocular pressure and glaucoma entailed by psychopharmacological treatment. Also, it provides updated data for clinicians involved in the treatment of patients with glaucoma or glaucoma risk factors. For this purpose, we performed an extensive literature search in the PubMed database using specific terms. Selective serotonin and noradrenaline reuptake inhibitors are the best evidenced as having no association with glaucoma. Antipsychotics, and especially first generation, seem to have no correlation with an increased intraocular pressure and therefore possibly with a risk of glaucoma, although a special attention should be paid when using ziprasidone. Tricyclic antidepressants, benzodiazepines and topiramate should be avoided in patients diagnosed with glaucoma or at risk. Clinicians should be aware of the possible psychotropic drug induced glaucoma and monitor at risk patients closely in order to prevent this condition. Irrespective of the psychopharmacological regimen taken into consideration, the glaucoma patient should be under the strict supervision of the ophthalmologist.

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Prediction of Severe Cisplatin-Induced Neutropenia Using Serum Albumin Concentration: A Retrospective Study

10.21203/rs.3.rs-79322/v1 ◽

2020 ◽

Author(s):

Yusuke Nakazawa ◽

Akira Kageyama ◽

Masaki Kitamura ◽

Norio Mitsumori ◽

Takashi Kawakubo

Keyword(s):

Gastric Cancer ◽

Retrospective Study ◽

Serum Albumin ◽

Neutrophil Count ◽

Safety Issue ◽

Characteristic Curve ◽

Severe Neutropenia ◽

Albumin Concentration ◽

Serum Albumin Concentration ◽

Grade 3

Abstract Background: Hypoalbuminemia may occur in patients with gastric cancer because of reduced food intake and gastric dysfunction. Cisplatin that is used in the treatment of gastric cancer not only has gastrointestinal side effects but also has a high serum protein-bound fraction, which causes alteration in pharmacokinetics, especially reduction of serum albumin concentration that may increase the risk of cisplatin-induced neutropenia. Hence, alteration of serum albumin concentration poses a major safety issue during anticancer therapy. We examined whether fluctuations in serum albumin concentration is a risk factor for predicting the development of severe neutropenia.Methods: This retrospective study included patients with gastric cancer undergoing cisplatin plus S-1 combination therapy to analyze their serum albumin concentration and the frequency of grade 3–4 neutropenia. We then investigated the relationship between the serum albumin concentration before cisplatin administration in the treatment course during which the neutrophil count reached nadir and the neutrophil count fluctuation after cisplatin administration.Results: Grades 3–4 and 0–2 neutropenia developed in 24 and 48 patients, with a mean serum albumin concentration of 3.60 ± 0.54 and 3.77 ± 0.51 g/dL, respectively, before chemotherapy (P = 0.23). During chemotherapy when the neutrophil count reached nadir, the serum albumin concentration levels before cisplatin administration were 3.39 ± 0.60 and 3.85 ± 0.59 g/dL, respectively; the grade 3–4 neutropenia group had a significantly lower concentration of serum albumin than the grade 0–2 neutropenia group (P = 0.006). Lower serum albumin concentrations before cisplatin administration were significantly correlated with a decrease in neutrophil count after cisplatin administration (r = 0.463, P < 0.001). According to the receiver operating characteristic curve analysis, patients with serum albumin concentrations below 3.25 g/dL before cisplatin administration exhibited a significantly higher incidence of grade 3–4 neutropenia (odds ratio: 4.33). Conclusions: The risk of cisplatin-induced neutropenia is significantly high in patients with hypoalbuminemia. Thus, serum albumin concentration should be evaluated before cisplatin administration to anticipate the development of severe neutropenia.

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Neutropenia in adults – significant diagnostic issue

Pielegniarstwo XXI wieku / Nursing in the 21st Century ◽

10.2478/pielxxiw-2018-0006 ◽

2018 ◽

Vol 17 (1) ◽

pp. 37-43

Author(s):

Paulina Stefaniuk ◽

Agnieszka Szymczyk ◽

Monika Podhorecka

Keyword(s):

Neutrophil Count ◽

Fungal Infections ◽

Drug Induced ◽

Over The Counter ◽

Blood Tests ◽

Pubmed Database ◽

Serious Infections ◽

Therapeutic Procedures ◽

Life Threatening ◽

Clinically Significant

Abstract Introduction. Neutropenia, a disorder quite commonly encountered in blood tests, is defined as a decrease in the absolute neutrophil count below 1500/µl. Neutropenia may not be clinically significant, whereas it sometimes indicates serious haematological, infectious or rheumatic diseases. The reduction of the number of neutrocytes below 500/µl is referred to as ’agranulocytosis’. Such decrease in neutrophil count impairs host defense and makes the patient more vulnerable to bacterial and fungal infections, which may lead to life-threatening sepsis. Aim. This review presents the causes of congenital and acquired neutropenia, with particular attention to drug-induced neutropenia, which may occur due to the intake of the broad spectrum of drugs, including over-the-counter drugs. The article also attempts to answer the question of how the neutropenia and agranulocytosis should be diagnosed and treated. Methods. The publication is based on the analysis of the literature (PubMed database). Results. It has to be emphasized that a thorough physical examination and appropriate additional tests make it possible to diagnose a disease that causes neutropenia. This allows for the implementation of appropriate therapeutic procedures, and consequently, leads to avoidance of serious infections.

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Oral Melphalan, Prednisone, and Lenalidomide for Newly Diagnosed Multiple Myeloma Patients: Kinetics of Neutropenia/Thrombocytopenia and Time to Event Results

Blood ◽

10.1182/blood.v112.11.2768.2768 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2768-2768 ◽

Cited By ~ 2

Author(s):

Antonio Palumbo ◽

Patrizia Falco ◽

Francesca Gay ◽

Paolo Corradini ◽

Claudia Crippa ◽

...

Keyword(s):

Multiple Myeloma ◽

Platelet Count ◽

Adverse Events ◽

Dose Reduction ◽

Neutrophil Count ◽

Severe Neutropenia ◽

Severe Thrombocytopenia ◽

Newly Diagnosed ◽

The Mean ◽

Grade 3

Abstract Background: The association of Melphalan, Prednisone and Lenalidomide (MPR) has shown significant anti-myeloma activity in newly diagnosed Multiple Myeloma (MM) patients. In this phase I/II study, the more frequent adverse events were neutropenia and thrombocytopenia. Non-hematologic toxicities were unusual. Methods: We analyzed the kinetics and risk factors for neutropenia and thrombocytopenia in 21 patients (median age 69 years) who received nine four-week cycles of MPR at the maximum tolerated dose (melphalan 0.18 mg/Kg d 1–4, lenalidomide 10 mg d 1–21, prednisone 2 mg/Kg d 1–4, followed by maintenance period with lenalidomide 10 mg/day for 21 days every 4 weeks). We also up-dated efficacy end-point. At the occurrence of grade-3 neutropenia, G-CSF was administered for 5–7 days. The occurrence of grade-4 neutropenia despite G-CSF administration or any other grade-4 hematological toxicities required withholding of treatment and subsequent dose reduction at the start of the following cycle. A new cycle was allowed if the neutrophil count was >1×109/L and platelet count >50×109/L. A delay of 2 weeks was allowed, a delay beyond 2 weeks required dose reduction and a delay beyond 4 weeks required therapy discontinuation. Results: Grade-3 neutropenia occurred in 38.1% of patients, grade-4 neutropenia in 14.2% of patients, but febrile neutropenia was 9.5%. G-CSF was administered in 42.3% of patients. The mean neutrophil count at the start of each MPR cycle was 2.69 × 109/L (SD 1.4). The mean neutrophil count at nadir (day 15–21) of each cycle was 1.43 × 109/L (SD 1.0). The incidence and depth of neutropenia did not increase with the number of cycles. The mean neutrophil count during maintenance was 2.11 × 109/L (SD 1.0). Grade-3 thrombocytopenia occurred in 14.2% of patients and grade-4 thrombocytopenia in 9.5%; one patient required platelet transfusion. The mean platelet count at the start of each MPR cycle was 174 × 109/L (SD 63.9). The mean platelet count at nadir (day 15–21) of each cycle was 121 × 109/L (SD 56.3). Thrombocytopenia was more pronounced after 9 cycles of treatment. The mean platelet count after 9 cycles was 109 × 109/L (SD 53). The mean platelet count at the end of 6 months of lenalidomide maintenance therapy was 158 × 109/L (SD 79.2). One patient required lenalidomide dose reduction for severe neutropenia. Three patients discontinuated therapy for severe thrombocytopenia and neutropenia. Grade 3–4 hematologic toxicity was more frequent in patients with low baseline neutrophil count and in those with Bence-Jones myeloma. Neutropenic fever (9.5%), cutaneous reaction (9.5%), thromboembolism (4.8%) were the most frequent grade 3–4 non-hematologic adverse events. After a median follow-up of 29.5 months, the median time-to-progression was 28.5 months, the median progression-free survival was 28.5 months and the 2-years overall survival was 90.5%. No death was reported in the first 18 months of treatment. Conclusions: MPR is a promising first line regimen for elderly MM patients. Hematologic adverse events were frequent but manageable with the use of G-CSF.

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Clinical Particularities of Drug-Induced Agranulocytosis or Severe Neutropenia in Elderly Patients

Pharmacovigilance and Pharmacoepidemiology ◽

10.33805/2638-8235.101 ◽

2015 ◽

pp. 1-4 ◽

Cited By ~ 1

Author(s):

Emmanuel Andrès ◽

Rachel Cottet Mourot ◽

Olivier Keller ◽

Khalid Serraj ◽

Thomas Vogel

Keyword(s):

Rare Event ◽

Antiplatelet Agents ◽

The Elderly ◽

Severe Neutropenia ◽

Elderly Subjects ◽

Antithyroid Drugs ◽

Hematopoietic Growth Factors ◽

Drug Induced ◽

New Agents ◽

Life Threatening

Agranulocytosis is a life-threatening disorder in any age and also in the elderly subjects who are receiving on the average a larger number of drugs than younger subjects. This disorder frequently occurs as an adverse reaction to drugs, particularly to antibiotics, antiplatelet agents, antithyroid drugs, neuroleptics or anti-epileptic agents and nonsteroidal anti-inflammatory agents. Although patients experiencing drug-induced agranulocytosis may initially be asymptomatic, the severity of the neutropenia usually translates into the onset of severe sepsis that requires intravenous broad-spectrum antibiotherapy. In this setting, hematopoietic growth factors have been shown to shorten the duration of neutropenia. Thus with appropriate management, the mortality rate of idiosyncratic drug-induced agranulocytosis is now of 5 to 10%. Today, drug-induced agranulocytosis still remains a rare event with an annual incidence from 3 to 12 cases per millions of people. However, given the increased life expectancy and subsequent longer exposure to drugs, as well as the development of new agents, physicians should be aware of this complication and its management.

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A possible interaction between favipiravir and methotrexate: Drug-induced hepatotoxicity in a patient with osteosarcoma

Journal of Oncology Pharmacy Practice ◽

10.1177/10781552211031304 ◽

2021 ◽

pp. 107815522110313

Author(s):

Emre Demir ◽

Osman Sütcüoğlu ◽

Beril Demir ◽

Oktay Ünsal ◽

Ozan Yazıcı

Keyword(s):

Drug Interactions ◽

Toxic Hepatitis ◽

Antiviral Agents ◽

Antiviral Agent ◽

Aldehyde Oxidase ◽

Chemotherapeutic Agents ◽

High Dose ◽

Drug Induced ◽

Metastatic Osteosarcoma ◽

Grade 3

Introduction Favipiravir is an antiviral agent that is recently used for SARS-CoV2 infection. The drug-drug interactions of favipiravir especially with chemotherapeutic agents in a patient with malignancy are not well known. Case report The patient diagnosed with metastatic osteosarcoma was given high dose methotrexate treatment, and favipiravir was started on the third day of the treatment with suspicion of SARS-CoV2 infection. Grade 3 hepatotoxicity developed after favipiravir. Management & outcome: The acute viral hepatitis panel and autoimmune liver disease panel were negative. The ultrasound of the abdomen was unremarkable for any hepatobiliary pathology. The all viral and hepatobiliary possible etiological factors were ruled out. The patient’s liver enzymes increased just after (12 hours later) the initiation of favipiravir, and we diagnosed toxic hepatitis caused by favipiravir-methotrexate interaction. Therefore, methylprednisolone 1 mg/kg dose was started for a presumed diagnosis of toxic hepatitis. Hepatotoxicity completely regressed after favipiravir was discontinued. Discussion Favipiravir may inhibit methotrexate elimination by inhibiting aldehyde oxidase and its sequential use may cause hepatotoxicity in this case. The clinicians should keep in mind possible drug interactions while using new antiviral agents against SARS-CoV2 like favipiravir.

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AB0304 IMMUNOGENICITY OF BIOLOGIC DRUGS IN THE CLINICAL PRACTICE IN THE BULGARIAN POPULATION OF PATIENTS SUFFERING FROM RHEUMATOID ARTHRITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.923 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1451.3-1451

Author(s):

K. Kraev ◽

M. Geneva-Popova ◽

S. Popova

Keyword(s):

Rheumatoid Arthritis ◽

Clinical Practice ◽

Disease Activity ◽

Clinical Response ◽

Neutralizing Antibodies ◽

Tnf Alpha ◽

Drug Bioavailability ◽

Drug Induced ◽

Etanercept Treatment ◽

Markers Of Inflammation

Background:Biological drugs are protein derivatives that, as such, are highly immunogenic. In recent years there have been many conflicting opinions about the role of drug immunogenicity in clinical practice.Objectives:To evaluate the drug immunogenicity of TNF-alpha blocking drugs (etanercept and adalimumab) used to treat patients with rheumatoid arthritis. To determine whether their presence can alter the effect of treatment and to evaluate their role in the clinical practice of rheumatologists.Methods:121 patients with rheumatoid arthritis, as well as 31 healthy controls, similar in sex and age, were examined. They were all monitored at 0, 6, 12 and 24 months from the start of TNF-alpha blocker treatment. Demographics, vital signs, markers of inflammation such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and disease activity indices were examined at each visit, respectively. Drug-induced neutralizing antibodies, as well as drug bioavailability in patients treated with adalimumab, were examined by ELISA.Results:Drug-induced neutralizing antibodies to adalimumab were detected in 11.57% of patients at 6 month, in 17.64% of patients at 12 month, and 24.8% at 24 month. Drug-induced neutralizing antibodies to etanercept were not detected at 6 months, at 7.77% at 12 months, at 9.63% of patients at 24 months. Of the adalimumab patients who were having drug-induced antibodies, 92.59% had low drug bioavailability, while the remaining 7.41% of patients showed normal drug bioavailability despite the presence of drug-induced neutralizing antibodies. In terms of worsening of the disease activity, a positive correlation was found with the presence of drug antibodies - Pearson Correlation = 0.701, p = 0.001. Patients with poor clinical response and available drug antibodies receiving adalimumab were slightly more than those treated with etanercept at 12 and 24 months but the difference is non-significant-U = 0.527, p> 0.05 and U = 0.623, p> 0.05, respectively.Conclusion:Presence of drug-induced neutralizing antibodies in patients treated with adalimumab and etanercept has been associated with poor clinical response and worsening of the patient’s condition. Testing of drug-induced neutralizing antibodies as well as the drug bioavailability of the drug used can be used as reliable biomarkers in clinical rheumatology.References:[1]Benucci M., F.Li Gobbi, M. Meacii et al., “Antidrug antibodies against TNF-blocking agents: correlations between disese activity, hypersensitivity reactions, and different classes of immunoglobulins”, Biologics and Targets and Therapy, 2015: 9 7 -2.[2]Chen D., Y. Chen, W. Tsai et al., “ Significant associations of antidrug antibody levels with serum drug trough levels and therapeutic response of adalimumab and etanercept treatment in rheumatoid arthritis”, Ann Rheum Dis. 2015 Mar; 74 (3).[3]Kalden J. and H. Schulze-Koops, “ Immunogenicity and loss of response to TNF inhibitors: implications for rheumatoid arthritis treatment ”, Nature Reviews Rheumatology, 2017 volume 13, 707–718.[4]Wolf-Henning Boehnck, N. Brembilla, “ Immunogenicity of biological therapies: causes and consequences, ” Expert Review of Clinical Immunology, Vol 14, 2018, Issue 6, 513-523Disclosure of Interests:None declared

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