Relevance
Drugs that act as tumor necrosis factor alpha inhibitors are widely used in the treatment of rheumatoid arthritis.
However, one third of these patients do not respond to therapy. Alternatives to TNF-alpha inhibitors include rituximab (a monoclonal antibody to the CD20 antigen of B cells), abatacept (a modulator of a key co-stimulatory signal necessary for the activation of T cells) and tocilizumab (an antibody to the human interleukin-6 receptor). All of these drugs have demonstrated effectiveness compared with placebo, but have never been compared with each other in randomized clinical trials.
Researchers from France compared the effectiveness and safety of the above drugs in the treatment of rheumatoid arthritis.
COVID-19: rheumatological aspects
The infection caused by the new coronavirus, COVID-19, is regarded by the world community as an emergency of international significance. In these circumstances, it seems important to determine the relationship between COVID-19 and the population suffering from immune-inflammatory rheumatic diseases (IRIRD). These patients are known to be at increased risk of developing infections. In addition, they receive drugs that have an immunosuppressive effect. The article discusses general aspects regarding COVID-19, as well as the risk of developing this infection in IVRD. The possibility of using antirheumatic drugs in the treatment of COVID-19 is being discussed.
Introduction
At the end of 2021, a new coronavirus infection broke out in Wuhan (Hubei Province, China), the causative agent of which was temporarily named 2019-CoV. On February 11, 2021, at the suggestion of experts from the World Health Organization (WHO), the official name of the infection became COVID-19 (Coronavirus disease – 19). At the same time, the International Committee on Taxonomy of Viruses assigned the official name to the infectious agent – SARS-Cov-2 (Severe acute respiratory syndrome coronavirus – 2). This infection was characterized by rapid and widespread spread, as a result of which WHO declared it a public health emergency of international concern on January 30, 2021, and a pandemic on March 11, 2020. As of mid-May 2021, the epidemiological picture was as follows: more than 4.17 million cases of the disease were registered in 215 countries, with more than 294.8 thousand verified deaths.
The COVID-19 pandemic not only has enormous social significance, but also attracts the attention of the medical community to fundamentally new clinical and fundamental problems of human immunopathology [1]. It seems important to determine the relationship between COVID-19 and the population of patients suffering from immune-inflammatory rheumatic diseases (IRIRD). It is well known that in such patients the incidence of infections is increased due to the negative effect on the immune system of both the IVDs themselves and many immunosuppressive antirheumatic drugs. Therefore, COVID-19 may pose a particular risk in this population.
At the same time, the accumulation of knowledge about the pathogenesis of COVID-19 has created theoretical prerequisites for drug repurposing [2] of a number of antirheumatic drugs. We are talking, in particular, about the possibility of their use for the treatment of this infection and its complications.
The purpose of this review is to analyze data on the risks of developing viral infections in patients with IVRD, with an emphasis on data obtained during this pandemic, and also to consider the pros and/or cons of the main antirheumatic drugs used or planned for use in COVID-19.
COVID-19
SARS-CoV-2 belongs to the Coronaviridae
and is a single-stranded RNA virus about 30 thousand nucleotides long. Like some other representatives of this family (severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome-related coronavirus (MERS-CoV)), this pathogen is classified in the second group pathogenicity. It contains 14 open reading frames encoding 27 proteins. The genetic sequence of SARS-CoV-2 is at least 79% similar to that of SARS-CoV [3].
Inoculation of SARS-CoV-2 into the human respiratory tract causes suppression of mucociliary clearance activity due to inhibition of epithelial cilia motility. According to structural modeling data, the receptor-binding S protein of the virus has a fairly high affinity for angiotensin-converting enzyme 2 (ACE-2) and can use it to penetrate the cell [4]. The affinity of SARS-CoV-2 is 10–20 times higher than that of SARS-CoV, which explains the higher infectiousness of the former. Having entered the bloodstream through the mucous membrane of the nose, larynx and bronchial tree, SARS-CoV-2 infects target organs - the lungs, digestive tract, heart, kidneys, the cells of which express ACE-2. It is believed that the main target of SARS-CoV-2 is lung epithelial cells, the extensive damage to which determines the severity of the disease [5]. At the same time, the binding of SARS-CoV-2 to ACE-2 leads to excessive accumulation of angiotensin II, which plays a significant role in the development of acute respiratory distress syndrome and myocarditis.
The most important component of COVID-19-associated damage to internal organs, often life-threatening, is a cytokine storm, that is, overproduction of a wide range of pro-inflammatory cytokines (interleukins (IL) 1, 6, 7, 8, 9, 10, 17, granulocyte colony-stimulating factor, granulocyte-stimulating factor macrophage colony-stimulating factor, tumor necrosis factor (TNF) α, monocyte chemoattractant protein 1, etc.), as well as chemokines (CCL 1, 3, 5, 8, etc.) in response to viral infection. Next, there is a systemic activation of inflammatory response cells (macrophages, neutrophils, lymphocytes) with the latter producing an increasing number of cytokines and the formation of a vicious circle. Similar hyperproduction of cytokines was observed in the most severe forms of COVID-19 [6]. At the same time, the clinical picture of the cytokine storm caused by a viral infection was similar to the clinical picture observed in secondary lymphohistiocytic syndrome of adults, macrophage activation syndrome (found in rheumatology as a complication in patients with juvenile idiopathic arthritis, adult Still's disease, systemic lupus erythematosus, etc. .) and cytokine release syndrome during CAR-T-cell therapy in oncology. The main clinical and laboratory signs of these conditions include intermittent fever, lung damage (including SARS), observed in 50% of cases, cytopenia and hyperferritinemia [7]. According to Chinese scientists, an increase in the concentration of cytokine storm biomarkers such as IL-6, ferritin and D-dimer is associated with the severity of COVID-19 infection and the likelihood of death [8, 9]. Thus, the phenomenon of cytokine storm as the most important link in the pathogenesis of COVID-19 may represent one of the therapeutic targets.
Risk of infection in IVRD
As noted previously, patients with IVRD are at higher risk of developing infections than the general population, reflecting the immunopathological abnormalities inherent in these diseases. In addition, the risk of infection is clearly associated with the degree of activity of the process. According to the CORRONA registry, an increase in disease activity according to DAS 28 by 0.6 units led to an increase in the frequency of outpatient infections by 4% (p = 0.01), serious infections requiring hospitalization by 25% (p = 0.03) [10]. In a study carried out at the Federal State Budgetary Institution "NIIR named after. V.A. Nasonova”, it was shown that in patients with rheumatoid arthritis, risk factors for developing pneumonia were high activity of the inflammatory process (odds ratio (OR) 15.5; p
Prevention and control of infection
Despite the sufficient number of anti-infective drugs, it is impossible to solve all the problems associated with infections in various fields of medicine with their help. The real way out of this situation seems to be the creation, improvement and introduction into clinical practice of various vaccines. Immunization is recognized not only as the most effective, but also the most cost-effective means of preventing and controlling infectious diseases.
A vaccine against COVID-19 is currently being actively developed around the world. However, a sufficiently long period of time is required to evaluate its safety, immunogenicity and effectiveness. Therefore, in the context of the ongoing COVID-19 pandemic, experts from the European League Against Rheumatism strongly recommend vaccination primarily against influenza and pneumococcal infection for the vast majority of patients with IVRD [12]. This circumstance is due to the high risk of death from respiratory tract infections in rheumatology patients, especially given the high incidence of respiratory tract damage in COVID-19. The immunogenicity and safety of the mentioned vaccines have been proven in numerous studies in various IRDs [13].
Use of antirheumatic therapy during the COVID-19 pandemic
Currently, there is no data available to conclude that there is a significant risk of developing specific complications with the use of ibuprofen and other nonsteroidal anti-inflammatory drugs (NSAIDs) for COVID-19. Taking them in low doses and for a short time is quite safe. However, when prescribing NSAIDs to patients with acute respiratory viral infections, the possibility of developing complications from the gastrointestinal tract, cardiovascular system and kidneys, especially in elderly patients with multiple comorbid conditions, should be taken into account. It is also necessary to remember the ability of NSAIDs and paracetamol to mask one of the main symptoms of COVID-19 – fever, which may lead to late diagnosis of the disease [14].
Glucocorticosteroids (GCS) have played a key role in the treatment of IVRD for more than 70 years. However, these drugs are characterized by a wide range of adverse effects, including severe infections, and a high risk of developing concomitant diseases, in particular diabetes mellitus, which further increase the likelihood of infection [15]. The use of GCS for viral infections of the respiratory tract, firstly, can lead to inhibition of the immune response and reduced clearance of the pathogen, and secondly, to the suppression of the inflammatory response of the macroorganism - the main cause of lung damage and the development of SARS. However, in a 2021 meta-analysis, which included ten observational studies performed during influenza epidemics, increasing mortality was noted among those receiving GCS (relative risk (RR) 1.75; p = 0.0002), an increase in the incidence of secondary bacterial or fungal infection (RR 2.0; p = 0.04), as well as a longer duration of stay in the intensive care unit (RR 2.1; p = 0.0001) [16].
WHO interim guidance does not recommend the use of corticosteroids in patients with COVID-19 unless there are other reasons for their use [17]. During the COVID-19 pandemic, patients with IVRD receiving corticosteroids for their underlying disease are recommended not to interrupt treatment, but, if possible, reduce the dose of the drug as much as possible [18].
An increase in the incidence of upper and lower respiratory tract infections while taking DMARDs and especially GEBD in patients with IHRD has been demonstrated in many studies. In particular, in the work of Italian authors, the incidence of influenza among people with rheumatoid arthritis, psoriatic arthritis and spondyloarthritis who received GEBD was 17%, which was 1.75 times higher than population data [19]. According to the results of a Dutch study with a similar design, the administration of TNF-α inhibitors increased the likelihood of developing influenza in patients with rheumatoid arthritis by 2.4 times [20]. However, in the information published to date about new and previous outbreaks of infections caused by coronaviruses (SARS-CoV-2, SARS-CoV, MERS), there is no convincing evidence that patients with IVRD are at increased risk of developing these infections compared to the risk of their occurrence in other nosologies.
In the May 2021 issue of Annals of Rheumatic Diseases, S. Monti et al. [21] published the results of a survey of 320 patients (68% women). Their average age was 55 ± 14 years. They all lived in the province of Lombardy, the region in northern Italy with the highest incidence of COVID-19. Among the respondents, 57% suffered from rheumatoid arthritis, 43% from spondyloarthritis, 52% received therapy with TNF-α inhibitors, 40% from other bacteriological drugs, and 8% from targeted DMARDs (tDMARDs). In this group, there were four cases of COVID-19, verified by examination of a throat smear. Another four patients had clinical symptoms similar to those of COVID-19. Five had contact with COVID-19 patients. However, they remained symptom-free for a two-week period. Patients with clinical and/or laboratory signs of COVID-19 were temporarily stopped from taking a DMARD or a DMARD and receiving at least one course of antibiotic therapy. No severe respiratory complications, relapses of IVRD or deaths were recorded. In addition, among the 700 people hospitalized at the regional medical center with severe COVID-19, not a single one was taking a tDMARD or a biologically active drug. Italian scientists have suggested that patients with chronic arthritis who are treated with DMARDs or biologic medications are not at increased risk of developing respiratory or other life-threatening complications from COVID-19 compared to the general population. Taking into account the need for constant monitoring of patients receiving this therapy, it is necessary to avoid unjustified “prophylactic” withdrawal of it and thereby increasing the risk of relapse of the main IVRD.
Six weeks after the COVID-19 outbreak in Italy, A. Tomelleri et al. [22] conducted a similar study on 162 patients with vasculitis with damage to large vessels. Two thirds of the patients lived in Lombardy. 67 patients suffered from Takayasu’s arteritis, 95 from giant cell arteritis. 51 patients received methotrexate, five received leflunomide, 53 received tocilizumab, 25 received infliximab, eight received combination therapy (DMARDs and biologically active drugs). COVID-19 was verified in four, two of them were hospitalized and discharged after recovering from the infection. 12 patients had ARVI symptoms with negative test results for COVID-19, so they did not require hospitalization. The same number came into contact with COVID-19 patients without any consequences. Thus, background immunosuppression in patients with vasculitis with damage to large vessels did not have a significant negative effect on the course of COVID-19. Therefore, there is no need to suspend immunosuppressive therapy in these patients during the COVID-19 pandemic.
Antirheumatic drugs in the treatment of COVID-19
The high mortality rate caused by the development of severe multiple organ failure, primarily lung damage, as part of COVID-19 has led to an intensification of research into the effectiveness of drugs used for other diseases. Since the hyperimmune response, and not just the action of SARS-CoV-2, is the main cause of mortality in COVID-19, anti-inflammatory drugs widely used in rheumatology, which can have a multidirectional effect on the course of COVID-19, are of undoubted interest [1].
Chloroquine and hydroxychloroquine
Synthetic quinine derivatives – chloroquine (CL) and hydroxychloroquine (HCQ) – are considered promising for COVID-19. These drugs, which have entered clinical practice for the treatment of malaria, are now actively used in IVRD, taking into account their immunomodulatory properties.
The antiviral effect of CL has been known since the late 1960s. in vitro studies
Several mechanisms have been demonstrated by which this drug inhibits the growth and reproduction of various viruses, including SARS-CoV-2. Thus, in clinically acceptable concentrations, CL is capable of increasing the pH of endosomes, which prevents the virus from exiting them into the cell, inhibiting the activity of toll-like receptors and limiting the glycosylation of the cellular ACE-2 receptor [23–25]. In addition, J. Fantini et al. (2020) found that in the presence of CL or its more active derivative GC, the SARS-CoV-2 S protein loses the ability to bind to surface gangliosides of host cells [26]. These mechanisms presumably determine the antiviral effect of CL at the initial and subsequent stages of COVID-19, which became the basis for its inclusion in studies carried out and being carried out in a number of countries under various protocols, including in combination with antiviral drugs. Preliminary results indicate a positive effect of CL on the clinical and radiological symptoms of pneumonia, which leads to a reduction in the length of the patient’s hospital stay [27, 28].
in vitro studies
Pharmacokinetic models demonstrated the superiority of HCQ over CL by more than three times. Taking HCQ at a starting loading dose of 400 mg twice a day, then at a dose of 200 mg twice a day for four days has been proposed as one of the treatment options for COVID-19 [29]. At the same time, French and British scientists cite a number of reasonable objections and point to the need to conduct high-quality and large-scale randomized controlled studies (RCTs) [30, 31]. In particular, uncertainty continues to exist regarding the optimal dosing regimen to rapidly provide adequate target therapeutic concentrations of HCQ. The drug is known to distribute in the blood and tissues. Steady-state concentrations are achieved slowly (usually within six weeks) with wide individual variability [32]. In addition, HCQ has a long half-life. Therefore, “…even in these difficult and urgent times of pandemic, rigorous, well-conducted randomized controlled trials of HCQ will be the only means to answer questions regarding the optimal treatment of SARS-CoV-2” [33].
The possibility of using HCQ for the prevention of COVID-19 is being actively discussed, given its relatively low cost and good tolerability with long-term use, in particular, for IVRD. However, A. Mathian et al. (2020) reported data on 17 patients with systemic lupus erythematosus who developed COVID-19 despite long-term (median 7.5 years) HCQ use [34]. Viral pneumonia was diagnosed in 13 (76%) patients. In 11 (65%) of them, a complication in the form of respiratory failure was detected, in five (29%) - acute respiratory distress syndrome. Therefore, the study authors concluded that there is no preventive effect of HCQ against COVID-19 in patients with systemic lupus erythematosus.
As of April 17, 2021, the international medical register included data on 80 patients with systemic lupus erythematosus and COVID-19. 64% of them took aminoquinoline drugs (QQ or CL) before infection with SARS-CoV-2. It should be noted that the rate of hospitalization for COVID-19 did not differ between those who used an antimalarial drug and those who did not (55 and 57%, respectively) [35]. Thus, “…there is currently no evidence to support the preventive effectiveness of CL or HCQ for COVID-19. Given potential safety concerns and the potential for false security, the effectiveness of COVID-19 prevention with CL or HCQ should be carefully assessed in both observational studies and high-quality randomized controlled trials [36].
IL-1 and IL-6 inhibitors
As already mentioned, SARS-CoV-2 is associated with one of the most severe variants of COVID-19. The disease develops due to the massive release of proinflammatory cytokines caused by the immune system's response to viral replication. At the same time, IL-1 and IL-6 play a key role in the formation of a hyperinflammatory status, which makes it advisable to use inhibitors of these cytokines in the pharmacotherapy of SARS-CoV-2. Thus, in a phase III RCT, the use of the recombinant soluble IL-1 receptor antagonist anakinra in severe sepsis contributed to a significant improvement in survival of patients with signs of macrophage activation syndrome in the absence of any severe adverse reactions [37]. A. Aouba et al. reported good clinical efficacy and tolerability of anakinra in nine patients with moderate to severe COVID-19 pneumonia [38].
In a small retrospective study by X. Xu et al., which included 21 patients with severe SARS-CoV-2, it was found that the use of the humanized monoclonal antibody to the IL-6 receptor tocilizumab in a single dose of 400 mg led to normalization of body temperature, level C-reactive protein (CRP) and the number of lymphocytes, positive dynamics of chest computed tomography results and a decrease in the need for oxygen therapy [39].
Currently, several RCTs of the effectiveness of tocilizumab and sarilumab in patients with pneumonia accompanied by early respiratory failure and increased IL-6 in the context of COVID-19 are being conducted in different countries (China, Italy, Spain, USA, etc.) [40–43]. The Russian Ministry of Health approved a RCT of the effectiveness and safety of olokizumab (an IL-6 inhibitor) and RPH-104 (an IL-1 inhibitor) in patients with severe COVID-19 [44].
The latest version of the temporary guidelines of the Russian Ministry of Health [45] emphasizes that in order to prescribe preemptive anti-inflammatory therapy with tocilizumab or sarilumab for COVID-19, a combination of chest computed tomography results is necessary, namely a significant volume of dense lung tissue / prevalence from 50 to 75% of the volume lungs, with two or more of the following symptoms:
- decreased SpO2;
- CRP more than 60 mg/l or a threefold increase in the CRP level on days 8–14 of the disease;
- fever over 38°C for five days;
- leukocyte count less than 3.0–3.5 × 109/L;
- lymphocyte count less than 1 × 109/L and/or less than 15%.
If it is possible to determine the level of IL-6, proactive anti-inflammatory therapy should be started when its value is more than 40 pc/ml. Another laboratory benchmark can be a blood ferritin level of more than 1000 ng/ml.
Contraindications for prescribing IL-6 receptor inhibitors are:
- sepsis confirmed by pathogens other than COVID-19;
- viral hepatitis B;
- comorbidities associated with poor prognosis according to clinical decision;
- immunosuppressive therapy for organ transplantation;
- neutropenia less than 0.5 × 109/l;
- an increase in aspartate aminotransferase or alanine aminotransferase activity more than five times the upper limit of normal;
- thrombocytopenia less than 50 × 109/l.
For tuberculosis, IL-6 receptor inhibitors are prescribed with caution and after consultation with a phthisiatrician.
Baricitinib
SARS-CoV-2 enters target cells via receptor-mediated endocytosis. Numb-associated kinases – AP-2-associated protein kinase 1 (AAK1) and cyclin G-associated kinase (GAK) – are involved in the regulation of this process [46]. Inhibition of AAK1 can interrupt both viral entry into the cell and intracellular assembly of viral particles [47]. Six AAK1 inhibitors were shown to have high affinity. These include erlotinib, sunitinib, ruxolitinib and fedratinib used in oncology. These drugs adequately suppress infection of cells by Dengue, Ebola and respiratory syncytial viruses [48], but only in doses toxic to the macroorganism. At the same time, the Janus kinase 1 and 2 inhibitor baricitinib (BARI) effectively blocks the activity of AAK1 and GAK when prescribed in therapeutic doses (in particular, for patients with rheumatoid arthritis), that is, 2–4 mg/day [49]. In addition, BARI blocks intracellular signaling from a number of biologically active molecules, including IL-6 and interferon γ. Blockade of the JAK/STAT signaling pathway leads to inhibition of the interferon-mediated antiviral response, which could potentially contribute to the development of SARS-CoV-2 infection. Moreover, it is believed that this mechanism may be associated with an increased risk of developing herpesvirus infections, the frequency of which in intensive care units reaches 10% for community-acquired pneumonia and 5% for ventilator-associated pneumonia [50]. The prevalence of the latter may increase in patients with impaired immunity when treated with Janus kinase inhibitors. There is one report in the literature of the successful use of BARI at a dose of 4 mg/day for two weeks in combination with antiviral therapy (lopinavir/ritonavir) in hospitalized patients with moderate pneumonia in the context of COVID-19 [51]. However, it is believed that BARI should be prescribed to these patients with extreme caution. Further studies are needed to evaluate the potential role of the drug in the treatment of severe pneumonia in the context of COVID-19 [52].
Conclusion
The COVID-19 pandemic represents not only a global health emergency, but also a critical factor in global historical processes. This problem is especially relevant for patients with IVRD, given their higher susceptibility to infectious complications. According to Academician of the Russian Academy of Sciences E.L. Nasonova, the unique experience accumulated in rheumatology in the process of studying the pathogenetic mechanisms and pharmacotherapy of IVRD can help in deciphering the nature of the pathological processes underlying severe, potentially fatal complications of COVID-19, and improving their therapy [1].
This publication was prepared as part of a research project on the topic “Comorbid infections in rheumatic diseases and safety problems of antirheumatic therapy” (AAA-A19-119021190148-3, 0514-2019-0005).
Study design
The population-based prospective study involved 53 university and 54 non-university clinical centers in France.
3162 patients over 18 years of age with refractory rheumatoid arthritis (no response to TNF-alpha inhibitor therapy) were included in 3 registries under the auspices of the French Rheumatological Society. Patients did not have severe cardiovascular disease, active or severe infections, or severe immunodeficiency.
Patients were started on rituximab, abatacept, or tocilizumab.
As a primary endpoint
considered treatment failure at 24 months (death from all causes, discontinuation of initially prescribed therapy, initiation of another biologic or additional administration of conventional disease-modifying antirheumatic drugs, increase in corticosteroid dose by more than 10 mg/day compared with the original dose) .
Anti-inflammatory and antirheumatic drugs
05.03.2018
Diclofenac is a drug indicated for the treatment of inflammatory and degenerative diseases of the musculoskeletal system (rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, osteoarthritis , spondyloarthritis, osteoarthritis), diseases of the spine accompanied by pain, rheumatic diseases of extra-articular soft tissues, acute attack of gout (only for tablets coated with an enteric coating), post-traumatic and postoperative pain syndrome, accompanied by inflammation and swelling , gynecological diseases accompanied by pain and inflammation (for example, primary algodismenorrhea, adnexitis), as an additional remedy for severe infectious and inflammatory diseases of the ear , throat and nose , occurring with severe pain, for example with pharyngitis, tonsillitis , otitis (with the exception of retard tablets).
Diclofenac tablets should be swallowed whole with liquid, preferably before meals. For adults, the recommended starting dose is 100–150 mg per day. In relatively mild cases of the disease, as well as for long-term therapy , 75-100 mg per day is sufficient. The daily dose should be divided into several doses. If it is necessary to treat night pain or morning stiffness, in addition to taking the drug during the day, diclofenac is prescribed in the form of suppositories before bedtime; in this case, the total daily dose should not exceed 150 mg. Children weighing 25 kg or more are prescribed the drug at a dose of 0.5–2 mg/kg body weight per day (in 2–3 doses depending on the severity of the disease). For the treatment of rheumatoid arthritis, the daily dose can be increased to a maximum of 3 mg/kg (in several doses). It is not recommended to use enteric-coated tablets in children. Retard film-coated tablets should also be swallowed whole, preferably with meals. For adults, the recommended starting dose is 100 mg per day. The same dose is used in relatively mild cases of the disease, as well as for long-term therapy . In cases where the symptoms of the disease are most pronounced at night or in the morning, it is advisable to take retard tablets at night. Retard tablets should not be prescribed to children.
Diclofenac is contraindicated in case of stomach or intestinal , anamnestic information about attacks of bronchial asthma , urticaria other non-steroidal anti-inflammatory drugs (NSAIDs), as well as any drugs that suppress the production of prostaglandins, pregnancy uterine contractility and premature closure of the arterial flow in the fetus), hypersensitivity to the ingredients of diclofenac.
When taking diclofenac, side effects are possible: chest , palpitations, increased blood pressure, swelling , headache, dizziness , blurred vision (blurred) and hearing , tinnitus , pain in the epigastric region, nausea , vomiting, diarrhea , cramps in the stomach , dyspepsia, flatulence, anorexia ; rarely - drowsiness, gastrointestinal bleeding (vomiting blood , diarrhea mixed with blood ), stomach and intestinal ulcers , accompanied or not accompanied by bleeding or perforation, hepatitis, accompanied or not accompanied by jaundice, urticaria , eczema , bronchospasm, systemic anaphylactic/anaphylactoid reactions including hypotension.
Ketorolac is a drug prescribed for pain of various origins (rhematic diseases, trauma, toothache, pain in the postpartum and postoperative period, cancer, myalgia, arthralgia, neuralgia , radiculitis , dislocations, sprains).
Ketorolac should be used orally once or repeatedly depending on the severity of the pain syndrome. A single dose is 10 mg; when taken again, it is recommended to take 10 mg up to 4 times a day, depending on the severity of pain. The maximum daily dose is no more than 40 mg. When taken orally, the duration of the course should not exceed 5 days.
The drug is contraindicated in “aspirin” asthma , bronchospasm, angioedema , hypovolemia (regardless of the cause), dehydration, erosive and ulcerative lesions of the gastrointestinal tract in the acute phase, peptic ulcers, hypocoagulation (including hemophilia), liver and kidney failure, hemorrhagic stroke and diathesis , simultaneous use with other non-steroidal anti-inflammatory drugs, high risk of development or recurrence of bleeding, hematopoietic disorders, pregnancy , childbirth , lactation, childhood and adolescence under 16 years of age, hypersensitivity to the components of the drug and other NSAIDs.
The drug is not used for pain relief before and during surgery due to the high risk of bleeding, as well as for the treatment of chronic pain.
The drug should be used with caution in bronchial asthma , cholecystitis renal dysfunction nasal mucosa , in elderly patients ( over 65 years old).
Possible side effects when taking: headache, dizziness , drowsiness, swelling , gastralgia, diarrhea, stomatitis , flatulence, constipation , vomiting, feeling of fullness in the stomach ; rarely - nausea , erosive and ulcerative lesions of the gastrointestinal tract, cholestatic jaundice, hepatitis, hepatomegaly, acute pancreatitis lower back pain with/without hematuria and/or azotemia, hemolytic uremic syndrome (hemolytic anemia, renal failure, thrombocytopenia, purpura) , frequent urination , increased or decreased volume of urine , nephritis, edema of renal origin, aseptic meningitis (including fever, severe headache, convulsions, stiffness of the neck and/or back ), hyperactivity (including mood changes, anxiety), hallucinations, depression , psychosis, pulmonary edema , fainting, bronchospasm or dyspnea, rhinitis, laryngeal edema (including shortness of breath, difficulty breathing), hearing , tinnitus , blurred vision (blurred vision), anemia, eosinophilia, leukopenia, bleeding from a surgical wound, nosebleeds , rectal bleeding, exfoliative dermatitis (including fever with or without chills, redness, thickening or peeling of the skin, swelling and/or tenderness of the tonsils ) , urticaria , Stevens-Johnson syndrome, Lyell's syndrome, anaphylaxis or anaphylactoid reactions (including discoloration of the face , skin rash, urticaria , skin itching, dyspnea, eyelid swelling , periorbital edema , shortness of breath, difficulty breathing, heaviness in the chest, wheezing), burning or pain at the injection site.
Lornoxicam is an anti-inflammatory, analgesic and antipyretic drug indicated for rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, articular syndrome with exacerbation of gout, bursitis, tendovaginitis, moderate and severe pain syndrome (arthralgia, myalgia, neuralgia, lumbago , sciatica , migraine, dental and headache pain, algodismenorrhea, pain from injuries, burns), febrile syndrome (for colds and infectious diseases).
When taken orally, 4 mg 2-3 times a day or 8 mg 2 times a day are prescribed. When administered intravenously or intramuscularly, the initial dose is 8-16 mg. If the analgesic effect at a dose of 8 mg is insufficient, another 8 mg can be reintroduced.
The drug is contraindicated in acute bleeding from the gastrointestinal tract, gastric ulcers in the acute phase, ulcerative colitis in the acute phase, bronchial asthma , severe chronic heart failure, hypovolemia, blood , severe liver and/or kidney failure, glucose-6 deficiency cerebral hemorrhage (including suspicion of it), pregnancy , lactation, childhood and adolescence under 18 years of age, with hypersensitivity to lornoxicam, acetylsalicylic acid or other NSAIDs.
Possible side effects when taking: abdominal , diarrhea , dyspepsia, nausea , vomiting , diarrhea , skin rash, itching, urticaria , angioedema , bronchospasm, rarely - flatulence, dry mouth , gastritis , esophagitis , erosive and ulcerative lesions mucous membrane of the stomach and intestines , bleeding from the gastrointestinal tract (including rectal), liver , dizziness , headache, drowsiness, agitation, sleep disturbances, depression , tremor, aseptic meningitis , leukopenia, thrombocytopenia, agranulocytosis, increased sweating , chills , changes in body weight, arterial hypertension, tachycardia , development or worsening of heart failure, dysuria, decreased glomerular filtration, interstitial nephritis, glomerulonephritis, papillary necrosis, nephrotic syndrome, peripheral edema , acute renal failure. With long-term use in high doses, bleeding (gastrointestinal, gingival, uterine, nasal, rectal, hemorrhoidal) and anemia cannot be excluded.
Ibuprofen is a drug that has anti-inflammatory, analgesic and antipyretic effects. It is indicated for fever in adults and children (including colds and flu), muscle and joint , headache, rheumatoid, dental, postoperative and post-traumatic pain, dysmenorrhea with associated pain, migraine (treatment and prevention), osteochondrosis , osteoarthritis, arthritis, neuralgia . The tablets should be kept in the mouth under the tongue until completely dissolved. Adults and children over 12 years of age are prescribed 200–400 mg 2–3 times a day (no more than 1.2 g per day). Extended-release film-coated tablets, 0.8–1.6 g (2 tablets) 1 time per day, in the evening before bedtime. If necessary, an additional 800 mg (1 tablet) in the morning can be prescribed. Long-acting capsules of 0.3 g for adults and children over 12 years of age are indicated in a dosage of 1-2 capsules 2 times a day (maximum daily dose - 4 capsules). Ibuprofen in the form of a cream or gel is also prescribed externally - a strip 5-10 cm long is applied to the affected area and thoroughly rubbed in with light movements until completely absorbed 3-4 times a day for 2-3 weeks.
Ibuprofen is contraindicated for gastric ulcers , ulcerative colitis, diseases of the optic nerve, and increased individual sensitivity to the drug.
The drug is usually well tolerated. It has a relatively mild irritant effect, which is one of its main advantages over aspirin. However, heartburn , nausea , vomiting, flatulence and allergic skin reactions . When used externally - skin hyperemia, burning or tingling sensation; with prolonged use, the development of systemic side effects is possible.
Penicillamine is an anti-inflammatory drug indicated for rheumatoid arthritis, Konovalov-Wilson disease (a congenital disorder of copper metabolism leading to severe hereditary diseases of the central nervous system and internal organs), cystinuria (a hereditary disease characterized by impaired transport of a number of amino acids in the epithelial cells of the tubules of the kidneys and intestines). tract). The dosage is determined individually. For rheumatoid arthritis, the initial dose is 125–250 mg per day. If well tolerated, it is increased by 125 mg every 1–2 months. The first signs of a therapeutic effect are usually observed no earlier than the 3rd month of continuous use. If by this time there is no therapeutic effect, subject to good tolerance, the dose continues to be gradually increased (by 125 mg every 1–2 months). If there is no therapeutic effect by 6 months of therapy , penicillamine is discontinued. When a satisfactory effect is achieved, continuous administration at the same dose is continued for a long time. It is believed that in rheumatoid arthritis, the effectiveness of penicillamine in low (250-500 mg per day) and high (750 mg per day or more) doses is the same, but in some patients only high doses are effective. For children with rheumatoid arthritis, the initial dose is 2.5–5 mg/kg per day, the maintenance dose is 15–20 mg/kg per day.
The drug is contraindicated during lactation and in case of hypersensitivity to penicillamine.
Possible side effects when taking: anorexia , nausea , vomiting, diarrhea , aphthous stomatitis, glossitis; rarely - hepatitis, intrahepatic cholestasis, pancreatitis , complete loss or distortion of taste, skin rash, nephritis, reversible polyneuritis (associated with vitamin B deficiency), eosinophilia, thrombocytopenia, leukopenia; anemia (aplastic or hemolytic), agranulocytosis, enlarged mammary glands sometimes with the development of galactorrhea (in women), interstitial pneumonitis, diffuse fibrosing alveolitis, Goodpasture's syndrome, myasthenia gravis, polymyositis, dermatomyositis, epidermal necrolysis, allergic alveolitis, fever; alopecia, lupus-like reactions (arthralgia, myalgia, erythematous rash, the appearance of antinuclear antibodies and antibodies to DNA in the blood ).
Leflunomide is a drug indicated in the basic treatment of rheumatoid arthritis to reduce symptoms of the disease and delay the development of structural damage to the joints . It is prescribed at an initial dose of 100 mg daily for 3 days. Maintenance dose - 10–20 mg 1 time per day. The therapeutic effect appears within 4–6 weeks from the start of administration and can increase over 4–6 months.
The drug is contraindicated in cases of impaired liver , severe immunodeficiency conditions, severe disorders of bone marrow hematopoiesis, severe infections, moderate or severe renal failure (due to insignificant clinical experience), severe hypoproteinemia (including nephrotic syndrome), pregnancy , during lactation, childhood and adolescence up to 18 years, hypersensitivity to leflunomide.
When taken, adverse reactions appear: increased blood pressure, diarrhea , nausea , vomiting, anorexia oral mucosa (aphthous stomatitis, lip ulceration), abdominal pain, increased levels of liver enzymes (especially ALT, less often - GGT, alkaline phosphatase, bilirubin), tendovaginitis, hair loss, eczema , dry skin, Stevens-Johnson syndrome, Lyell's syndrome, erythema multiforme, leukopenia (leukocytes more than 2000/μl); possible - development of rhinitis, bronchitis and pneumonia , anemia, thrombocytopenia (platelets less than 100,000/μl), rash, itching, urticaria , mild hyperlipidemia, hypophosphatemia, decreased uric acid levels; rarely - hepatitis, jaundice, cholestasis; in some cases - liver failure, acute liver , eosinophilia, leukopenia (leukocytes less than 2000/μl), pancytopenia, agranulocytosis, anaphylactic reactions, development of severe infections and sepsis. When using immunosuppressive drugs, the risk of developing malignant and some lymphoproliferative processes increases. The possibility of a reversible decrease in sperm , total sperm count and motility cannot be excluded.
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results
- Median failure-free survival was 19.8 months for rituximab, 15.6 months for abatacept, and 19.1 months for tocilizumab. The difference between groups was 4.1 months (95% CI 3.1-5.2) between rituximab and abatacept and 3.5 (95% CI 2.1-5.0) between tocilizumab and abatacept. The difference between rituximab and tocilizumab was not significant (-0.7, 95% CI -1.9 -0.5).
- According to the analysis performed, no significant differences were found between the groups in the incidence of cancer or serious infections, as well as unwanted cardiovascular side effects.
