Comparison of the effectiveness of modern antirheumatic drugs

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 and antirheumatic drugs: expectations and reality

Despite the progress made in studying the mechanisms of development of COVID-19, the pathogenesis of the disease is not completely clear. Cytokine dysregulation and hyperinflammation (cytokine storm) have led to the repositioning and off-label use of a wide range of drugs that were being developed to treat immunoinflammatory rheumatic diseases. Although a huge number of clinical studies of these drugs have been conducted, many problems remain unresolved, in particular the development of feasible and cost-effective treatments for patients most at risk of developing hyperinflammation and associated severe outcomes. The article analyzes the results of the use of anti-inflammatory drugs in patients with COVID-19.

Outcomes of COVID-19 during treatment with GCS

Introduction

Since December 2021, when the new coronavirus SARS-CoV-2 (Severe Acute Respiratory Coronavirus 2) was discovered in Wuhan, China, the coronavirus disease (COVID-19) pandemic has spread throughout the world. To date, there are more than 157 million verified cases and more than 3.2 million deaths [1].

Despite the progress made in understanding the mechanisms underlying the disease, the pathogenesis of COVID-19 is not fully established. It is known that the main clinical manifestations and complications are associated with dysregulation of cytokines and hyperinflammation, defined as cytokine storm. Hyperinflammation can lead to acute respiratory distress syndrome (ARDS), multiple organ failure, and death [2].

The development of this severe pathology served as the basis for drug repurposing and off-label use of a wide range of anti-inflammatory drugs that were specifically developed for the treatment of immunoinflammatory rheumatic diseases (IRI) [3–7]. It is no coincidence that today rheumatologists have enormous experience in the use of immunomodulatory anti-inflammatory drugs. It seems particularly relevant since existing antiviral drugs have not shown a significant increase in favorable outcomes in COVID-19 [8–10].

As of mid-June 2021, the PubMed bibliographic system contains more than 3,000 publications covering aspects of the use of various immunomodulatory drugs for the new coronavirus infection. At the same time, in an attempt to repurpose antirheumatic drugs for the treatment of COVID-19, “mandatory collection of all supporting data related to biomarkers, pharmacodynamics and safety in the target population was limited or ignored, although with the best intentions” [11]. As Indian scientists note, the COVID-19 pandemic represents a classic conflict between clinical and academic medicine. Clinical medicine, or bedside medicine, which is based on a broad evidence base, also allows for the prescription of treatments that can be based on preclinical in vitro

or limited clinical results [12].

Hydroxychloroquine

The above primarily applies to hydroxychloroquine (HCQ). The reason for the “enthusiasm” was due to the drug’s in vitro

against SARS-Cov-2, along with data from a small, uncontrolled study conducted in China. HCQ, which has antiviral and immunomodulatory properties, has been widely promoted as a therapeutic and/or prophylactic agent for COVID-19. The resulting surge in demand for HCQ has significantly reduced supply, affecting patients with IVDD (primarily rheumatoid arthritis and systemic lupus erythematosus (SLE)) who have successfully used this drug for decades. However, as the size and requirements of observational studies increased, the evidence became less and less reassuring. Not surprisingly, the results of randomized clinical trials (RCTs) coincided with negative data from observational studies [11].

It is important to note that, compared with standard therapy, the addition of HCQ increased the risk of outcomes such as respiratory failure requiring mechanical ventilation and death, according to the results of the RECOVERY trial [13]. In addition, those receiving HCQ as part of combination therapy, mainly in combination with azithromycin, had a higher incidence of adverse events than when using standard treatment regimens. Thus, in patients with severe COVID-19, during the use of HCQ, a prolongation of the QT interval on the electrocardiogram, increased levels of liver enzymes and a higher risk of death due to cardiovascular complications were recorded [14].

In the middle of last year, the idea of using HCQ as a means of preventing COVID-19 arose and was widely discussed, given its relatively low cost and good tolerability during long-term therapy, in particular, IVRD [15, 16]. However, according to a number of authors, no positive or negative effect on the course of COVID-19 in patients suffering from IVRD was observed during treatment with HCQ. Thus, A. Mathian et al. (2020) reported on 17 SLE patients who developed COVID-19 despite long-term (median 7.5 years) HCQ use. Viral pneumonia was diagnosed in 13 (76%) patients, including complications such as respiratory failure in 11 (65%) and ARDS in 5 (29%). The authors concluded that there is no preventive effect of HCQ against COVID-19 in patients with SLE [17]. According to M. Konig et al. (2020), of 80 observed SLE patients with COVID-19, 64% received aminoquinoline drugs (hydroxychloroquine or chloroquine (CL)) before infection with SARS-CoV-2. At the same time, the frequency of hospitalizations for COVID-19 did not differ between those who used CL/HC and those who did not use them – 55 and 57%, respectively [18].

A number of RCTs have been carried out to evaluate the use of HCQ for post-exposure prophylaxis of COVID-19 in the hope that this accessible and inexpensive drug could help in the early stages of the disease and prevent hospitalization. The study, conducted by researchers at the University of Minnesota, included 821 people over 18 years of age who were asymptomatic but had been in contact with someone with COVID-19 within 6 feet (1.83 m) for more than 10 minutes. Of these, 87.6% (719/821) belonged to the high-risk group of infection (at the time of contact they were not wearing a mask or eye protection), the rest were in the medium-risk group (wearing a mask but without eye protection). Within four days of exposure, participants were randomized to placebo (n = 407) or HCQ 200 mg tablets (n = 414). The regimen for using GC is 800 mg once, then 600 mg after 6–8 hours and then 600 mg daily for four days. The total duration of therapy was five days. During 14 days of follow-up, 13% (107) of study subjects were diagnosed with COVID-19 based on polymerase chain reaction results or clinical signs. This indicator did not differ significantly in the HC and placebo groups – 11.8 and 14.3% with a 95% confidence interval (CI) -7.0– -2.2 (p = 0.35). Healthcare workers were infected predominantly from patients (76.7%), but not from employees. In other cases - from spouses/partners (46.5%) or parents (17.6%). Adverse events were more often observed in the HCQ group than in the placebo group - 40.1 versus 16.8%. The most common were nausea, stool upset and abdominal discomfort. Thus, the effectiveness of HCQ for post-exposure prophylaxis of COVID-19 was no higher than that of placebo [19].

Other RCTs also did not provide evidence of the effectiveness of HCQ as a means of preventing SARS-CoV-2 infection after contact with sick people [20, 21].

Despite the fact that HCQ as an antiviral agent did not live up to the hopes placed on it, it remains in the arsenal of rheumatologists as the main anti-inflammatory drug for a number of IVRDs. Experts from the American College of Rheumatology emphasize that in the context of drug shortages due to COVID-19, new prescriptions of HCQ for indications not approved by the Food and Drug Administration (FDA) should be avoided [22]. Considering the beneficial pleiotropic effects of HCQ, such as antithrombotic, hypoglycemic, hypolipidemic [23], it can be assumed that the use of this drug would be advisable in patients with COVID-19 who have clinical and laboratory manifestations of coagulopathy in combination with autoimmune disorders (overproduction of antibodies to phospholipids) and comorbid pathology (atherosclerotic vascular disease, metabolic syndrome, etc.), as well as post-COVID-19 syndrome.

Glucocorticosteroids

Glucocorticosteroids (GCS), which have a wide range of anti-inflammatory and immunomodulatory effects, became one of the first groups of drugs that began to be used for COVID-19 [24, 25]. However, in a work by Italian scientists published in June 2020, it was noted that out of 117 patients with rheumatic pathology and confirmed COVID-19, 20 (10%) died, while 7 (58%) of them took more than 30 mg of prednisolone per day. day [26]. At the same time, data were obtained on the positive effect of GCS in patients with COVID-19 (table) [27–32].

The RECOVERY study showed that the use of dexamethasone (DM) at a dose of 6 mg/day for ten days in patients with COVID-19 led to a significant reduction in the incidence of deaths in those on mechanical ventilation (29.3 and 41.4%, relative risk (RR) ) 0.64 (95% CI 0.51–0.81)) and requiring oxygen support (23.3 vs. 26.2% (RR 0.82 (95% CI 0.72–0.94)). However, among patients who did not require oxygenation, there was no difference in the effectiveness of DM compared with controls [27].

The CoDEX study, in which DM was administered intravenously to 299 patients in the intensive care unit (ICU), found that such therapy was associated with an increase in the number of days without mechanical ventilation (p = 0.04) and a lower mean score of the organ organ assessment scale. failure after seven days (p = 0.004) compared with standard treatment. Mortality from any cause was 53% in the dexamethasone group and 61.5% in the standard therapy group [28].

In the double-blind MetCOVID RCT, the addition of methylprednisolone (MP) to standard therapy reduced 28-day mortality only in patients 60 years and older, but there was no overall reduction in mortality [32].

According to the results of a meta-analysis performed by Dutch researchers (44 studies involving 20,197 patients), GCS contributed to a reduction in 28-day mortality and the need for mechanical ventilation.

At the same time, some studies drew attention to the delay in clearance of SARS-CoV-2, which could probably be due to premature administration of GCS (during the period of active viral replication), and an increase in the number of secondary infections [33].

The use of GCS during the viral load phase, that is, during the first seven to ten days of the disease, can lead to aggravation of the disease with a further increase in the intensity of the inflammatory response and a pronounced deterioration of the condition.

Therefore, GCS can have both negative and positive effects at different stages of SARS-CoV-2 infection, lung damage and ARDS [34].

The optimal time of administration, dose and duration of administration of GCS from the point of view of effectiveness and safety remain the subject of further research. Taking into account the availability of GCS, both in price and in terms of availability in the pharmacy network, this area of research should become a general priority [33].

Tocilizumab

The use of tocilizumab (TCZ), a monoclonal antibody against the human interleukin (IL) 6 receptor, in COVID-19 has had some success, mainly in open studies and case series. However, according to the vast majority of large RCTs and meta-analyses, the drug practically did not reduce the incidence of deaths [35–38]. Thus, in the COVACTA RCT involving patients hospitalized with severe COVID-19 pneumonia, the use of TCZ did not lead to a significant improvement in clinical status or lower mortality after 28 days compared with placebo [39].

The international RCT EMPACTA examined the efficacy and safety of TCZ in 389 hospitalized patients with COVID-19 pneumonia who were not receiving mechanical ventilation. Those receiving TCZ had a significant reduction in the risk of transfer to mechanical ventilation or death compared with those taking placebo – 12.2 and 19.4%, respectively (RR 0.56 (95% CI 0.33–0.97); p = 0.04 ). However, mortality rates between groups at 28 days were not significantly different - 10.4 and 8.6%, respectively. It was concluded that in a certain proportion of patients with COVID-19 pneumonia, TCZ reduces the likelihood of transfer to mechanical ventilation, but does not reduce mortality [40].

The multicenter CORIMUNO-19 RCT enrolled patients with moderate to severe COVID-19 pneumonia who required oxygen support of at least 3 L/min without the need for mechanical ventilation or ICU admission. At day 14, the TCZ group experienced a 33% reduction in invasive/noninvasive ventilation or death. However, mortality rates on day 28 in this group were not significantly different from those in the control group receiving standard therapy [36].

In a retrospective cohort study of patients with severe COVID-19 pneumonia who required respiratory support in the ICU, Russian scientists did not find a decrease in mortality with either earlier (before intubation) or late (after the start of mechanical ventilation) administration of TCZ at a dose 400 mg compared to standard therapy [41].

A retrospective analysis of the medical records of 5,776 patients from the electronic medical database of Northwell Health, the largest private not-for-profit health care system in New York State, found that those receiving the combination of GCS and TCZ had lower mortality compared with those receiving standard treatment (RR 0. 44 (95% CI 0.35–0.55); p

Thus, the search for the place of TCZ in the COVID-19 treatment algorithm continues. New RCTs are needed to define the patient profile and clear indications for the use of TCZ in COVID-19.

Interleukin 1 inhibitors

It is assumed that in addition to IL-6, IL-1 plays an important role in the pathogenesis of inflammation in COVID-19. On this basis, attempts have been made to treat severe and critically ill patients with COVID-19 using anakinra, a recombinant antagonist of the human IL-1 receptor.

A meta-analysis of non-randomized cohort studies involving 184 patients showed that mortality in the anakinra group was significantly lower than in the control group - 10 and 41%, respectively (p

At the same time, the multicenter, open-label CORIMUNO-ANA-1 trial, which compared anakinra treatment with standard therapy in patients with mild to moderate pneumonia as part of COVID-19, was stopped early by the Data Monitoring Committee in the absence of a positive effect in the stage analysis results of 116 patients (59 received anakinra, 57 received standard treatment). There were no significant differences between groups in terms of four-day improvement, incidence of ventilation requirements, or deaths within two weeks, suggesting that there was no benefit from anakinra treatment in this category of COVID-19 patients [44]. The study was later criticized for inclusion criteria that did not include parameters indicating hyperinflammation. Overall, the Danish researchers suggest that IL-1 inhibition is reasonable in selected patients with COVID-19 and clear evidence of hyperinflammation [45].

Baricitinib

The drug baricitinib (BARI), an inhibitor of Janus kinases types 1 and 2 with an anti-inflammatory effect, attracted the attention of researchers at the beginning of 2021 due to its ability to suppress the activity of certain enzymes (AP-2-associated protein kinase and cyclin G-associated kinases) that regulate the process of receptor-mediated endocytosis, that is, the main route of penetration of SARS-CoV-2 into target cells. In addition, BARI's minimal interaction with P450 enzymes allowed it to be used in combination with antiviral drugs such as lopinavir/ritonavir and remdesivir. In November 2021, the FDA issued an emergency use authorization for BARI in combination with remdesivir for the treatment of suspected or laboratory-confirmed COVID-19 in hospitalized adults and children two years of age or older who required supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation. The FDA's decision was based on the results of the ACTT-2 RCT, conducted by the National Institute of Allergy and Infectious Diseases (USA), which included 1,033 patients with moderate or severe COVID-19. 515 patients (first group) received BARI (4 mg/day for 14 days) plus remdesivir, 518 patients (second group) received placebo plus remdesivir. The duration of observation was 29 days. Recovery was defined as the patient being ready for discharge (not requiring supplemental oxygen or constant medical supervision) or having already been discharged from the hospital by the end of the observation period. The median time required for recovery was seven days in the first group and eight in the second (p = 0.04). In addition, in the first group, by the 15th day of treatment, there was a 30% increase in the likelihood of improvement in clinical status on an eight-point ordinal scale (p = 0.04). The frequency of deaths in both groups did not differ significantly - 5.1 and 7.8%, respectively (p = 0.09). However, the risk of deterioration to the point of transfer to mechanical ventilation or death on day 29 was lower in the first group (RR 0.77 (95% CI 0.60–0.98)) [46].

At the same time, as FDA experts emphasize, the above regulatory verdict was made as part of the emergency authorization procedure, but not full approval. The emergency authorization status means a wider introduction of the specified combination of drugs into clinical practice, while the evidence base for their effectiveness still remains incomplete, which does not allow an unconditionally positive decision to be made in favor of their use in COVID-19. Therefore, BARI is not approved as a stand-alone treatment for COVID-19. Research into the safety and effectiveness of this experimental treatment for COVID-19 is ongoing [47].

Anticomplementary therapy

Complement activation may be one of the mechanisms of thromboinflammation and hypercoagulation during SARS-CoV-2 infection, which brings COVID-19 closer to other thrombotic microangiopathies, including those developing in SLE and antiphospholipid syndrome. The drug eculizumab, recently introduced into clinical practice, suppresses the terminal activity of human complement, having high affinity for its C5 component. As a consequence, the cleavage of the C5 component into C5a and C5b and the formation of the terminal complement complex C5b-9 are completely blocked.

In an observational study of 80 patients with COVID-19 in the ICU, treatment with eculizumab (n = 35) led to a significant reduction in mortality at 28 days compared with standard treatment - 51.1% and 80.0%, respectively (p = 0.04). Changes in laboratory parameters and biomarkers during eculizumab therapy indicated inactivation of complement components, reduction of hypoxia and inflammation [48].

The PANAMO study, a phase II study of another C5a inhibitor, vilobelimab, in patients with severe COVID-19, also found a trend toward reductions in oxygen requirements, deaths at day 28, and severe pulmonary embolisms compared with supportive care. [49].

Therefore, anticomplementary therapy may have dual benefits in both treating the inflammatory process and reducing thromboembolic risk in patients with COVID-19. Therefore, the urgent need to find biomarkers to identify patients for this complex therapy is emphasized [45].

Colchicine

Colchicine has a powerful anti-inflammatory effect by inhibiting the NLRP3 inflammasome and thereby suppressing the release of IL-1β, IL-18, and subsequently IL-6.

In an open-label, non-randomized study of patients hospitalized with COVID-19, higher 21-day survival was observed among those receiving colchicine (n = 122) compared with those receiving standard therapy (n = 140) - 84.2% and 63.6% respectively (p = 0.001).

In multivariate analysis, treatment with colchicine was significantly associated with a reduction in mortality (HR 0.15 (95% CI 0.06–0.37)), although there were notable limitations, notably an imbalance in the use of corticosteroids between groups (patients taking colchicine received more corticosteroids) and lack of clear information about the time elapsed from the onset of symptoms to the use of colchicine [50].

In January 2021, the results of the COLCORONA RCT, which included 4488 outpatients with COVID-19, were published in preprint form. The authors noted a reduction in the risk of hospitalization or death in those receiving colchicine (0.5 mg twice daily for three days and then once daily for 30 days), which, however, was not statistically significant - 4.7%. in the colchicine group and 5.8% in the placebo group (RR 0.79 (95% CI 0.61–1.03)). Serious adverse events were reported in 4.9 and 6.3% of patients in the colchicine and placebo groups, respectively (p = 0.05). Overall mortality in this outpatient cohort was very low, 0.2% in the colchicine group and 0.4% in the placebo group (RR 0.56 (95% CI 0.19–1.66)) [51].

Overall, the potential benefit of colchicine against COVID-19 remains unclear.

Conclusion

COVID-19 has presented a serious challenge to humanity and an unprecedented opportunity to gain insight into the real achievements of modern biology and medicine. The development of COVID-19-associated hyperinflammatory syndrome served as the basis for the repositioning of drugs used to treat IVRD. At the same time, within the framework of the topic under consideration, there is still a range of problems that require further research. These include:

deciphering the mechanisms and searching for biomarkers of the heterogeneity of COVID-19-associated hyperinflammatory syndrome in order to personalize anti-inflammatory therapy;
selection of optimal doses, start time and duration of anti-inflammatory therapy;
studying the effectiveness of combined (with antiviral drugs) and escalation therapy with targeted anti-inflammatory drugs;
predicting the risk of complications associated with bacterial infection.

In general, we can hope that the efforts of scientists and doctors around the world will not only improve the prognosis for COVID-19 and gain new knowledge to successfully combat epidemics of viral infections in the future, but will also contribute to the improvement of pharmacotherapy for widespread IVRDs [52].

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

Basic antirheumatic drugs that modify the course of rheumatoid arthritis

Treatment of rheumatoid arthritis with disease-modifying antirheumatic drugs (DMARDs)

In the treatment of rheumatoid arthritis, medications are used to slow the progression of joint erosion. These are disease-modifying antirheumatic drugs (DMARDs) that are an important component of the overall treatment program. What are these drugs and how do they work?

Disease-modifying drugs act on the immune system to slow the progression of rheumatoid arthritis, which is where their name comes from. The DMARD category includes many different drugs, but some are the most commonly used:

Revmatex (Methotrexate)
is the main drug in the DMARD category. It works equally as other drugs and in many cases is more effective. In addition, it is relatively inexpensive and mostly safe. Like other DMARDs, methotrexate has a number of side effects: it can cause stomach upset, can be toxic to the liver or bone marrow, and affect pregnancy. In rare cases, it causes difficulty breathing. Good blood circulation is essential when taking methotrexate. Concomitant use of folic acid may reduce some side effects. The most important advantage of methotrexate is the possibility of its use over a long period. The drug can also be prescribed to children.
Biological agents: Enbrel (etanercet), Humira (adalimumab), Kineret (anakinra), Orencia (abatacet), Remicade (infliximab), and Rituxan (rituximab).
These are newer drugs for the treatment of rheumatoid arthritis, administered subcutaneously or intravenously. They neutralize the activity of the immune system that destroys joints. When combined with methotrexate, these drugs help most people overcome the symptoms of rheumatoid arthritis. According to research, these drugs have fewer side effects than other DMARDs. One of the complications is increased susceptibility to acute infectious diseases. These drugs may have adverse effects on the liver and blood and should be used with caution in the presence of chronic heart problems. Other possible side effects may only appear after long-term use of the drugs.
Plaquenil (hydroxychloroquin)
and
Azulfidine
(sulfazaline
)
are used for moderate rheumatoid arthritis. They are not as effective as other DMARDs, but have fewer side effects. In rare cases, Plaquenil may have negative effects on the eyes. Patients taking this drug should be examined annually by an ophthalmologist.
Minocin (minocycline)
– an antibiotic that can stop the inflammatory process in RA. Its effect appears after a few months. In other cases, it may take a year for the full spectrum of side effects to appear. With long-term use, minocycline may cause skin pigmentation.
Arava (leflunomide)
acts like methotrexate and is more effective in combination with it. The drugs have similar side effects. Arava may cause diarrhea, in which case its use should be discontinued. Since Arava has a negative effect on the fetus, it is contraindicated in women during pregnancy.
Neoral (azathioprine)
used for various diseases accompanied by inflammation, including rheumatoid arthritis. However, due to its negative effect on kidney function and other side effects, it is usually used to treat exacerbations of rheumatoid arthritis when other drugs are ineffective.
Imunar (azathioprine)
used for various inflammatory conditions, including rheumatoid arthritis. The most common side effects are nausea and vomiting, sometimes stomach pain and diarrhea. Long-term use of azathioprine increases the likelihood of developing cancer.

DMARDs slow the progression of rheumatoid arthritis and help many people improve their quality of life. In some cases, remission may occur. Basically, the drugs slow down the rate of progression of the disease.

The use of one DMARD or their combination can prolong the asymptomatic course of rheumatoid arthritis and mitigate the acute manifestations of the disease. Your joints will need less time for morning “swinging”. At your next check-up, your rheumatologist may tell you that your most recent x-rays show no new lesions. Also, regular use of DMARDs reduces the likelihood of developing a long-term destructive process in the joints.

Are DMARDs safe? All DMARDs are approved by the US Food and Drug Administration. Many people take these medications without experiencing any side effects.

However, while DMARDs affect the symptoms of rheumatoid arthritis throughout the body, their powerful effects tend to cause some side effects. The following are typical side effects of DMARDs:

Stomach upset. DMARDs often cause nausea and sometimes vomiting and diarrhea. These symptoms can be managed with other medications. Complications also go away as your body gets used to the drug. If your symptoms are unduly bothersome, your rheumatologist will prescribe another remedy.
Liver dysfunction. This complication is less common than indigestion. You will need to have regular blood tests to check for liver damage.
Blood condition. DMARDs can cause problems with the immune system and increase the risk of infectious diseases. The level of white blood cells, which protect the body from infections, may also decrease. Low levels of red blood cells (anemia) increase fatigue. A simple test done regularly will help monitor your red blood cell levels.

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.