scholarly journals THU0206 А VERY EARLY (7-28 DAYS) RESPONSE ON JAK INHIBITOR TOFACITINIB IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS: EFFECT ON PAIN AND CENTRAL SENSITIZATION.

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 327.3-327
Author(s):  
A. Karateev ◽  
E. Filatova ◽  
E. Pogozheva ◽  
V. Amirdzhanova ◽  
E. Nasonov ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Central Sensitization ◽  
Early Time ◽  
National Registry ◽  
Genetically Engineered ◽  
Pain Severity ◽  
Signal Pathways ◽  
Jak Inhibitor ◽  
Jak Inhibitors ◽  
Biological Drugs

Background:The presence of central sensitization (CS) significantly burdens the course of rheumatoid arthritis (RA). JAK inhibitors block intracellular signal pathways including the ones responsible for synthesis of mediators and cytokines causing pain and CS. The application of JAK inhibitors is supposed to relieve pain and reduce CS severity promptly.Objectives:To evaluate JAK inhibitor effect on pain and signs of CS in patients with active RA 7 and 28 days after the start of therapy.Methods:Study group included 39 patients with RA, their age was 50.9±11.1, 79.5% of women, 89.7% of RF “+”, DAS28 5.8±0.6, receiving DMARDs (methotrexate 82.0% and leflunomide 18.0%), who were administered with tofacitinib 5 mg 2 times a day due to inefficiency or intolerance of genetically engineered biological drugs. There were assessed the pain severity using Brief pain inventory (BPI) questionnaire, the presence of neuropathic pain component (NPC) using PainDETECT questionnaire and signs of CS using Central Sensitisation Inventory (CSI) questionnaire at early time after tofacitinib administration.Results:Patients initially experienced a severe pain – 5.72±2.21 according to the visual analogue scale (VAS), 53.8% had signs of central sensitization (CSI ≥ 40), 17.9% had NPC (PainDETECT ≥18). 7 days after tofacitinib intake there was statistically reliable reduction of pain severity – up to 4.37±2.2 (р=0.01), pain decrease of 29.4±17.9% (BPI), NCP – PainDETECT from 12.9±5.5 to 10.6±5.6 (р=0.047) and CS – CSI from 43.1±12.8 to 35.9±11.2 (р=0.01). The effect had increased after 28 days: pain level (VAS) was 2.84±1.57 (р=0.000), pain decrease of 43.6±29.6% (BPI), PainDETECT 29.8±12.4 (р=0.000), CSI 26.4±13.9 (р=0.000).During this period there were no serious adverse reactions.Conclusion:The application of JAK inhibitor tofacitinib allows to reach a fast analgesic effect, also due to impact on CS and NCP.Source: National Registry patients with RADisclosure of Interests: :Andrey Karateev: None declared, Ekaterina Filatova: None declared, Elena Pogozheva: None declared, Vera Amirdzhanova: None declared, Evgeny Nasonov: None declared, Alexander Lila: None declared, V Mazurov: None declared, N Lapkina: None declared, Galina Lukina Speakers bureau: Novartis, Pfizer, UCB, Abbvie, Biocad, MSD, Roche, Tatiana Salnikova: None declared, Ruzana Samigullina: None declared, Diana Chakieva: None declared, Irina Marusenko: None declared, Olga Semagina: None declared, Marina Semchenkova: None declared

scholarly journals AB0135 A VERY EARLY CLINICAL RESPONSE TO TOFACITINIB IS ASSOCIATED WITH LOW RHEUMATOID ARTHRITIS ACTIVITY AFTER 3 AND 6 MONTHS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1095.3-1096
Author(s):  
A. Karateev ◽  
A. Lila ◽  
E. Nasonov ◽  
V. Mazurov ◽  
D. Chakieva ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Clinical Response ◽  
Central Sensitization ◽  
Intracellular Signaling ◽  
Pain Reduction ◽  
Pain Severity ◽  
Jak Inhibitors ◽  
Significant Pain ◽  
Number Of Patients ◽  
Days Of Therapy

Background:JAK inhibitors block intracellular signaling pathways responsible for the synthesis of cytokines and mediators involved in the development of chronic pain and central sensitization (CS). This determines a very rapid clinical response to JAK inhibitors. However, it is not clear how the significant pain reduction in the first weeks of therapy is associated with the achievement of low rheumatoid arthritis (RA) activity.Objectives:to assess the relationship between the early clinical response to tofacitinib and the decrease in RA activity after 3 and 6 months.Methods:Study group included 88 patients with RA, their age was 53±11,5, 79.3% of women, 89.8% of RF “+”, DAS28 5.2±1.2, receiving DMARDs (methotrexate 59.5% and leflunomide 19.8%), who were administered with tofacitinib 5 mg 2 times a day due to inefficacy or intolerance of biological DMARDs. There were assessed the pain severity using Brief pain inventory (BPI) questionnaire, the presence of neuropathic pain component (NPC) using PainDETECT questionnaire and signs of CS using Central Sensitisation Inventory (CSI) questionnaire at early time after tofacitinib administration, RA activity using DAS28 after 3 and 6 months.Results:The mean pain severity at baseline was 5.3±2.0 according to the visual analogue scale (VAS 0-10), 51.1% of patients had signs of central sensitization (CSI ≥ 40), 15.9% had NPC (PainDETECT ≥18). 7 days after tofacitinib intake there was statistically reliable reduction of pain severity – up to 4.1±1.8 (р<0.05) and CS – CSI from 40.4±13.5 to 36.5±12.5 (р=0.01). After 28 days, the effect was higher: the pain level (VAS) was 2.8±1.6 (p=0.000), PainDETECT decreased from 11.8±5.6 to 6.8±3.1 (p=0.000), CSI – to 31.6±13.9 (p=0.000). DAS28 after 3 and 6 months was 3.7±1.3 and 3.6±1.2. The number of patients with pain decrease of ≥50% after 28 days of therapy was 59.9%. Low RA activity after 3 months. (DAS28 ≤3.2) was achieved in 64.4% of patients. There was a clear correlation between the number of patients with significant pain reduction at 28 days and the number of patients with low RA activity after 3 and 6 months (rS=0.548, p=0.000; rS=0.790, p=0.000). Six patients withdrew from the study due to inefficacy or social reasons. There were no serious adverse reactions.Conclusion:The application of JAK inhibitor tofacitinib allows to reach a fast analgesic effect and reduce CS signs. An early clinical response to tofacitinib (pain relief) predicts a decrease in RA activity after 3 and 6 months of the therapy.Limitation: Open-label observatory study.Disclosure of Interests:None declared

scholarly journals P460 Evaluation of potential mechanisms underlying the safety observations of filgotinib in clinical studies in rheumatoid arthritis

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S409-S409
Author(s):  
A Clarke ◽  
J Di Paolo ◽  
B Downie ◽  
A Meng ◽  
N Mollova ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Cell Proliferation ◽  
Clinical Studies ◽  
Nk Cell ◽  
Janus Kinase ◽  
Jak Inhibitor ◽  
Jak Inhibitors ◽  
Erythroid Progenitor ◽  
Cell Counts

Abstract Background Inhibitors of the Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway have demonstrated efficacy in the treatment of rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). Differences in selectivity of JAK inhibitors for JAK1, JAK2, JAK3 and TYK2 may influence their respective safety profiles, and the mechanisms responsible are not currently known. Filgotinib (FIL), a JAK1 inhibitor, did not negatively impact haemoglobin, LDL:HDL ratios or natural killer (NK) cell counts in clinical trials. Here, we compare the in vitro mechanistic profiles of four JAK inhibitors at clinically relevant doses. Methods JAK inhibitors (FIL, FIL metabolite [GS-829845], baricitinib [BARI], tofacitinib [TOFA], and upadacitinib [UPA]) were evaluated in vitro in human-cell-based assays. Growth of erythroid progenitors from human cord blood CD34+ cells was assessed using a HemaTox™ liquid expansion assay, NK cell proliferation was induced by IL-15 and LXR agonist-induced cholesteryl ester transfer protein (CETP) expression was assessed in the hepatic cell line, HepG2. Using assay-generated IC50 values and the reported human plasma concentrations from clinical studies, we calculated the target coverage for each JAK inhibitor at clinically relevant doses. The activity of FIL in humans was based on PK/PD modelling of FIL + GS-829845. Results Inhibition of cellular activity was calculated for each JAK inhibitor based on in vitro dose-response data, human exposure data and modelled PK/PD relationships. At clinically relevant doses, FIL resulted in lower calculated inhibition of NK cell proliferation compared with other JAK inhibitors. FIL 100 mg and 200 mg also reduced CETP expression, whereas other JAK inhibitors had no effect. There was no difference in the effect of FIL vs. other JAK inhibitors on erythroid progenitor cell differentiation or maturation. Conclusion FIL, a JAK1 inhibitor, resulted in less inhibition of NK cell proliferation compared with BARI, TOFA, and UPA. FIL also reduced LXR agonist-induced CETP expression, while the other inhibitors did not alter these levels. These results provide a potential mechanistic link between the observed reduction of CETP concentration following FIL treatment and the previously observed reduction in the LDL:HDL ratio in RA patients.

AB0345 EFFICACY OF JAK INHIBITORS IN REFRACTORY RHEUMATOID ARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1472.1-1472
Author(s):  
M. Kamiya
Keyword(s):  
Rheumatoid Arthritis ◽  
Disease Activity ◽  
Disease Duration ◽  
Inhibitor Therapy ◽  
Cumulative Number ◽  
Jak Inhibitor ◽  
Continuation Rate ◽  
Jak Inhibitors ◽  
Refractory Rheumatoid Arthritis ◽  
Continuation Rates

Background:Disease-modifying antirheumatic drugs (DMARDs) have been the main agents for treating rheumatoid arthritis (RA) unless there are serious clinical restrictions or contraindications such as comorbidities. With inefficacy of conventional synthetic DMARDs (e.g., methotrexate), biological DMARDs (bDMARDs) are now available to suppress progression of joint destruction. However, bDMARDs cannot control disease activity in some patients, so JAK inhibitors targeting different cytokines are expected to be beneficial.Objectives:This study investigated factors associated with the efficacy and continuation of JAK inhibitor therapy in patients with refractory RA for whom disease activity was not adequately controlled even with multiple sequentially administered bDMARDs with different targets.Methods:We obtained the number of bDMARDs used and the various reasons for discontinuing therapy in our hospital from January 2005 to December 2019. Kaplan–Meier analysis was used to obtain the therapy continuation rate, and the log-rank test was used to examine the difference in therapy continuation rate. Refractory RA was defined as RA with inefficacy with 3 or more bDMARDs with different targets (1 or more tumor necrosis factor inhibitor, a selective costimulation modulator abatacept, and an interleukin 6 receptor inhibitor tocilizumab). We then examined patients with refractory RA who had received tofacitinib (TOF) or baricitinib (BAR) therapy after discontinuation of a series of bDMARDs due to unsatisfactory response. Various statistical tests were performed to identify predictors of ≥ 6-month continuation of JAK inhibitor therapy that achieves low disease activity without increases in prednisolone (PSL) use. Explanatory variables included characteristics of patients at initiation of TOF or BAR therapy: age, sex, disease duration, number of bDMARDs previously used, concomitant methotrexate dose, concomitant PSL dose, DAS28-ESR value, presence of rheumatoid factor or anti-CCP antibodies, and MMP-3 level.Results:A cumulative number of 782 bDMARDs were administered to 362 RA patients by December 2019. The most common reason for discontinuation was inefficacy (51.8%), followed by adverse events including deaths (30.1%), patients’ circumstances such as hospital transfer (9.2%), switch to biosimilars (5.2%), and remission (3.7%). The bDMARDs continuation rate and the number of bDMARDs used were 69.6% and 2.17 for 5 years and 53% and 2.83 for 10 years, respectively, if the switch was considered to be continuous due to insufficient effect. The 6-month continuation rates were not significantly different between TOF and BAR (60 patients [62.3%] vs. 39 patients [81.3%], respectively; P = 0.147). In patients with refractory RA, continuation rates were not significantly different between TOF and BAR (19 patients [42.1%] vs. 11 patients [54.5%], respectively; P = 0.86). Only TOF-treated patients, not BAR-treated patients, showed significant differences in disease duration (226.1 months in the continued group vs. 111.8 months in the discontinued group; P = 0.035) and concomitant PSL dose (0.71 mg vs. 4.0 mg, respectively, P = 0.045).Conclusion:There are not a few patients with refractory rheumatoid arthritis. These findings, albeit retrospective, suggest that low concomitant PSL dose and long disease duration at the time of TOF therapy initiation were factors for TOF continuation. Therapy continuation rate was decreased in patients with refractory RA, and further study on switching therapy between different JAK inhibitors is anticipated.References:[1]Souto A, Maneiro JR & Gomez-Reino JJ. Rate of diccontinuation and drug survival of biologic therapies in rheumatoid arthritis: a systematic review and meta-analysis of drug registries and health care database. Rheumatology (Oxford), 55, 523-534, 2016Disclosure of Interests:None declared

Possibilities of personalized approach to genetically engineered biological therapy of rheumatoid arthritis

2021 ◽  
pp. 35-40
Author(s):  
L. N. Shilova ◽  
S. S. Spitsina
Keyword(s):  
Rheumatoid Arthritis ◽  
Biological Therapy ◽  
Predictive Biomarkers ◽  
Empirical Therapy ◽  
Pathological Process ◽  
Genetically Engineered ◽  
Patient Centered ◽  
Biological Drugs ◽  
Potential Association ◽  
Personalized Approach

Rheumatoid arthritis is the most common rheumatic disease characterized by damage to the synovium, progressive destruction of cartilage and bone tissue. As a result of the establishment of the biological role of cytokines, it became possible to intervene in the main links of the pathogenesis of the disease, which led to inhibition of the main pathological process in RA – autoimmune inflammation.The aim. To consider the possibilities of optimizing the biological therapy of rheumatoid arthritis by identifying predictors of anti-inflammatory efficacy among clinical and laboratory markers.Basic provisions. Despite the success of genetically engineered biological drugs in the treatment of inflammatory arthritis, due to the lack of predictive biomarkers, the use of a trial and error approach, empirical therapy, is inevitable, which does not always lead to satisfactory results. The study of the main biomarkers of RA provides new insights into their potential association with various clinical phenotypes.Conclusion. This patient-centered approach offers the prospect of improving treatment outcomes through the use of specific drugs in certain patient groups.

scholarly journals Janus kinase inhibitors for the treatment of rheumatoid arthritis

2021 ◽  
Vol 64 (2) ◽  
pp. 105-108
Author(s):  
Sun Hee Jang ◽  
Ji Hyeon Ju
Keyword(s):  
Rheumatoid Arthritis ◽  
Kinase Inhibitors ◽  
Interleukin 1 ◽  
Janus Kinase ◽  
Jak Inhibitor ◽  
Jak Inhibitors ◽  
Biologic Dmards ◽  
Signal Transducers ◽  
Refractory Rheumatoid Arthritis ◽  
Stat Signaling

Rheumatoid arthritis is a chronic inflammatory destructive disorder that affects the joints, muscles, and tendons accompanying various extra-articular manifestations. Traditional disease-modifying anti-rheumatic drugs (DMARDs) represent the basic treatment for rheumatoid arthritis. Over the last 20 years, biologic DMARDs (tumor necrosis factor inhibitors, interleukin-1 inhibitors, interleukin-6 inhibitors, T cell inhibitors, and B cell inhibitors) have been widely used as a novel class of DMARDs that have efficacy and efficiency. Discovery of the underlying pathogenesis of autoimmune disease enables us to develop new target therapies such as a Janus kinase (JAK) inhibitor. Activated JAK is known to activate signal transducers as well as activators of transcription (STAT) signaling. A JAK inhibitor is a type of medication that functions by inhibiting the JAK-STAT signaling pathway. In addition, it is easy to take a JAK inhibitor orally. In Korea, several JAK inhibitors have been approved. This review describes the types of JAK inhibitors, recommended doses, side effects, and updated European Alliance of Associations for Rheumatology guidelines. Clinicians should more often consider JAK inhibitors in the treatment of refractory rheumatoid arthritis in current rheumatology clinics

scholarly journals Evaluation of the effectiveness of Tofacitinib in rheumatoid arthritis in real clinical practice: The relationship between pain relief in the first 4 weeks and disease activity after 3–6 months

2021 ◽  
Vol 59 (4) ◽  
pp. 394-400
Author(s):  
A. E. Karateev ◽  
E. Yu. Pogozheva ◽  
V. N. Amirjanova ◽  
E. S. Filatova ◽  
A. M. Lila ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Pain Relief ◽  
Clinical Response ◽  
Central Sensitization ◽  
Analgesic Effect ◽  
Intracellular Signaling ◽  
Pain Reduction ◽  
Jak Inhibitor ◽  
Number Of Patients ◽  
The Relationship

The JAK inhibitor tofacitinib (TOFA) blocks the intracellular signaling pathway that activates the synthesis of cytokines and mediators involved in the development of pain and central sensitization (CS), which determines the rapid analgesic effect. However, it is not clear how pain reduction is associated with achieving low activity in rheumatoid arthritis (RA).The aim of the study was to assess the relationship between the early clinical response to tofacitinib and a decrease in rheumatoid arthritis activity after 3 and 6 months.Material and methods. The study group consisted of 88 RA patients (age – 53±11.5 years; 79.3% of women) who received basic anti-inflammatory drugs (59.5% – methotrexate, 19.8% – leflunomide) and who were prescribed TOFA in a dose 10 mg/day. Seropositivity for rheumatoid factor was 89.8%; the value of the DAS28 index is 5.2±1.2. The severity of pain was assessed using the Brief Pain Inventory questionnaire, the neuropathic component of pain (NCP) – using the PainDETECT questionnaire, signs of CS – using the Central Sensitization Inventory (CSI) questionnaire in the early stages after the administration of TOFA, RA activity – using the DAS28-CRP index after 3 and 6 months.Results. The mean severity of pain at baseline was 5.3±2.0 on the visual analogue scale (VAS); 51.1% of patients had signs of CS (CSI>40), 15.9% had NCP (PainDETECT>18). 7 days after the start of therapy, there was a significant decrease in pain – to 4.1±1.8 according to VAS (p<0.05) and CS – 40.4±13.5 to 36.5±12.5 according to CSI (p=0.01). After 28 days, the effect was even more significant: the level of pain according to the VAS was 2.8±1.6 (p=0.000), the NCP decreased from 11.8±5.6 to 6.8±3.1 (p=0.000), CS – up to 31.6±13.9 (p=0.000). The value of the DAS28-CRP index after 3 and 6 months was 3.7±1.3 and 3.6±1.2, respectively. The number of patients with pain relief ≥50% after 28 days was 59.9%, low RA activity after 3 months. (DAS28-CRP≤3.2) was acieved in 64.4% of patients. There was a clear correlation between the number of patients with a pain reduction of ≥50% at 28 days and the number of patients who achieved low RA activity at 3 and 6 months. (rS=0.548, p=0.000 and rS=0.790, p=0.000). 6 patients dropped out of the study due to inefficiency or social reasons. No serious adverse reactions were noted.Conclusions. The use of the JAK inhibitor TOFA allows achieving a quick analgesic effect and reducing the signs of CS. An early clinical response to TOFA (pain relief) predicts a decrease in RA activity after 3 and 6 months of therapy.

scholarly journals Rheumatoid Arthritis: A Novel Approach in Diagnosis and Treatment

2018 ◽  
Vol 0 (0) ◽  
Author(s):  
Marina Kostic
Keyword(s):  
Rheumatoid Arthritis ◽  
Structural Changes ◽  
Interleukin 1 ◽  
Treat To Target ◽  
Signal Pathways ◽  
Biological Drugs ◽  
Safety Issues ◽  
Novel Approach ◽  
Post Marketing ◽  
Factor Α

AbstractThe rheumatoid arthritis is chronic disease with progressive course and deteriorations of joints as well as other organs. The pathogenesis of rheumatoid arthritis is characterized with chronic synovitis and inflammation. The main roles in development of rheumatoid arthritis have auto-reactive T cells and inflammatory cytokines, especially tumor necrosis factor α, interleukin 1 and interleukin 6. The management of rheumatoid arthritis has evolved significantly in the past twenty years, especially with introduction new diagnostic criteria by European League for Rheumatoid Arthritis which are very sensitive for early arthritis. The main goal of treating rheumatoid arthritis is to start with therapy in the phase of the disease when destruction of joints can still be prevented. Therapeutic strategies for rheumatoid arthritis involve wide palette of different drugs which can be divided into conventional and biological Disease Modifying Anthirheumatic Drugs. The use of methotrexate in combination with biological drugs provide targeting not only structural changes in rheumatoid arthritis but also and immunological pathways in development of rheumatoid arthritis. These drugs synergistically provide clinical remission and low activity of rheumatoid arthritis in the majority of patients. The uses of biological drugs are limited due their high costs or safety profile. In order to reduce costs and toxicity in the treatment of rheumatoid arthritis, new treat- to –target concept is established. The new class of drugs which modulate signal pathways and activity of tyrosine kinase are under investigations in post marketing surveys in patients with rheumatoid arthritis as in efficacy as in safety issues.

Selected problems in the use of genetic engineering biological therapy in patients with rheumatoid arthritis

2021 ◽  
Vol 6 (4) ◽  
pp. 36-39
Author(s):  
K. Leonova
Keyword(s):  
Rheumatoid Arthritis ◽  
Biological Therapy ◽  
Pharmacological Therapy ◽  
Genetically Engineered ◽  
Biological Drugs ◽  
Inflammatory Drugs ◽  
The Moment ◽  
Attending Physician

Rheumatoid arthritis, like any chronic non-infectious disease, requires constant pharmacological therapy and monitoring of treatment. To relieve exacerbation, maintain long-term remission and improve the quality of life of patients, basic anti-inflammatory drugs are used, which have passed many years of testing for efficacy and safety and are available for patients. But there is a group of drugs that have appeared relatively recently - genetically engineered biological drugs. At the moment, their use is somewhat limited due to the presence of a number of problems. With the accumulation of data on the study of the safety of genetically engineered drugs in the treatment of rheumatoid arthritis, it will be possible to solve many practical issues that arise in the attending physician during the supervision of patients.

scholarly journals Baricitinib exposure during pregnancy in rheumatoid arthritis

2020 ◽  
Vol 12 ◽  
pp. 1759720X1989929 ◽  
Author(s):  
Giulia Costanzo ◽  
Davide Firinu ◽  
Francesca Losa ◽  
Margherita Deidda ◽  
Maria P. Barca ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Adverse Drug Reaction ◽  
Drug Reaction ◽  
First Trimester ◽  
Continuous Exposure ◽  
Jak Inhibitor ◽  
Jak Inhibitors ◽  
Study Program ◽  
Drug Registration ◽  
Exposure During Pregnancy

We here describe the case of a 43-year-old White woman who was diagnosed with rheumatoid arthritis treated with anti-tumour necrosis factor drugs that caused an adverse drug reaction. The objective of this study was to describe the outcome of a pregnancy under baricitinib, a JAK-inhibitor drug, in a woman affected by rheumatoid arthritis. Scant data are available about the safety of JAK inhibitors during pregnancy. A case report and review of literature about JAK-inhibitor exposure during pregnancy were conducted. After the failure of biologic disease-modifying antirheumatic drugs due to a loss of efficacy and adverse drug reaction, the patient was started on baricitinib when it was marketed. During the fifth month of this treatment, she reported missing her period and a pregnancy was confirmed, despite a previous recommendation of adequate contraception. Thus, she had been exposed to baricitinib for several weeks before conception and during the whole first-trimester until the 17th week of gestation. The treatment with baricitinib was promptly discontinued and she was regularly examined. Foetal growth was normal throughout pregnancy and ultrasound examination did not detect any macroscopic abnormality. This is the first report of exposure to baricitinib during pregnancy outside the drug registration study program. We report the positive pregnancy outcome of a continuous exposure to baricitinib during the first 17 weeks of pregnancy. Small molecules, such as JAK inhibitors, are increasingly being used in clinical practice in rheumatoid arthritis and in other diseases. Hence, more broad and focused studies are required to have an insight of safety for this drug class in the case of accidental exposure before or during pregnancy.

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