Treatment of rheumatoid arthritis and its complications with gold preparations: indications and application

Consultation with a rheumatologist – RUB 1,750.

Coronavirus poses a deadly threat to the human body. But even in case of recovery, the danger of damage to various organs and systems remains. Many of those who have suffered a coronavirus infection recover, but for some patients, symptoms persist for a long time, affecting their quality of life. Scientists have found an explanation for the joint and muscle pain that some patients with coronavirus complain about - the infection causes an autoimmune reaction that triggers the development of rheumatoid arthritis.

As American doctors have already found out, the new virus can lead to rheumatological problems requiring long-term treatment. Doctors examined patients with coronavirus who were forced to see rheumatologists from March to December 2020. It turned out that post-Covid musculoskeletal symptoms are often associated with the body's autoimmune reaction. In their opinion, rheumatological problems, characterized by joint pain, arise from the fact that coronavirus infection often forces the body to attack itself. Experts noted that serious complications resulting from infection with COVID-19 include rheumatoid arthritis, which is the result of this particular “attack of the body.”

Rheumatologists know that a virus (mumps, measles, hepatitis B, herpes, and now COVID-19) can serve as a trigger for the development of the disease. Normally, the human immune system produces antibodies (proteins) that help the body fight, destroy viruses, bacteria and other foreign substances. In rheumatoid arthritis, the immune system produces antibodies against healthy cells and tissues of the body's own.

Symptoms

Lesions of the musculoskeletal system during infection with COVID-19 are polymorphic in clinical symptoms. This:

• swelling of the joint
• soreness,
• redness,
• local increase in temperature to subfebrile values
• resting joint pain
• morning stiffness for more than an hour,
• general fatigue
• malaise.

Rheumatoid arthritis affects small joints, most commonly the hands and feet. However, large joints can also be affected. The main sign of rheumatoid arthritis is symmetry. First, inflammation occurs inside the joint, as a result the synovial membrane thickens, then the articular cartilage is damaged, and muscles, ligaments and tendons weaken. Against the background of persistent inflammation, the bones that form the joint are destroyed. In severe cases of the disease, the joints begin to lose their function, permanent deformities may occur and develop, resulting in a decrease in the patient’s functional ability and quality of life.

Biological properties

The exact mechanism of action of gold salts on the body has not been determined. Presumably, the compounds change the morphology and functions of macrophages, inhibiting the development of autoimmune reactions. The altered structure of immunoglobulin cannot stimulate the production of antibodies, that is, the rheumatoid factor is eliminated. In clinical conditions, the ability of gold components to influence the synthesis of collagen and prostaglandins and reduce the migration of leukocytes to joint tissues has been demonstrated.

But research data that confirmed the healing potential of gold does not reveal the reasons for the delayed effect on the pathological process. In the best case, a continuous therapeutic course of aurotherapy takes from 3 to 4 months.

It's worth it - a period of real remission is achieved:

• signs of rheumatoid arthritis disappear;
• pain stops;
• ESR is normalized;
• RF titers decrease.

Gold compounds are located in the reticuloendothelial system and the synovial membrane of the joints and remain there for a long time. Unlike metallic gold, its derivatives are not toxic. Long-term intake of gold salts gives a chance to stop the progress of the disease: destruction of articular elements, formation of cysts and erosions. In this case, the erosive process in the bones can be reversed: the bone structure can be restored, and the mineralization of bone tissue can be improved. Therefore, treatment should not be stopped prematurely.

If at the end of the “golden course” the disease returns in an aggravated form, repeating treatment with this method does not make any sense. This circumstance is why rheumatologists justify long-term therapy with gold salts.

Treatment

Timeliness is important in the treatment of rheumatoid arthritis. Delaying treatment by a year reduces the likelihood of a favorable prognosis.

Medication methods

Basic antirheumatological drugs are prescribed as first-choice therapy: methotrexate, leflunomide (Arava), sulfasalazine, hydroxychloroquine. Taking them slows down the course of the disease, prevents bone deformities, improves the quality of life of patients and the prognosis of the disease. These drugs are prescribed for an indefinite period, sometimes for life. If we are talking about an aggressive and active course of the disease or intolerance to high doses of basic drugs, glucocorticosteroid drugs are prescribed, which very quickly and effectively relieve inflammation. The last group of drugs is the “heavy artillery”, genetically engineered biological drugs. The effectiveness and duration of therapy is assessed by a rheumatologist; his tasks also include dynamic monitoring of the patient.

In addition to taking medications, non-drug therapy methods are recommended:

• Exercise therapy (not contraindicated even in the highly active phase of the disease);
• physiotherapy,
• massage
• hydrotherapy.

In the later stages of the disease, with inadequate or late therapy, or with an aggressive course of the disease, surgical treatment methods are sometimes necessary:

• synovectomy (removal of the synovial membrane of the affected joint);
• reconstructive plastic surgery on bones, ligaments, tendons of large and small joints;
• endoprosthetics.

INTERFERON THERAPY FOR RHEUMATIC DISEASES

RM Balabanova, ON Yegorova Thanks to advances in molecular biology, our understanding of the pathogenetic mechanisms of rheumatic diseases (RD) is being refined. In the treatment of RD, so-called drugs that affect the disease are used, which to one degree or another affect the immune processes. However, the development of quite serious adverse reactions when using these drugs limits the possibility of their use in RD. Now there are several approaches to solving this problem: the creation of monoclonal antibodies (mAb) to the receptors of T-, B-lymphocytes, antigen-presenting cells, mAb to CD18 and CD54, mAb to cytokines; search for natural cytokine inhibitors; the use of cytokines, including recombinant interferons (IFNs). To date, encouraging results have been obtained from the clinical use of IFN in RD. Our experience with the use of recombinant forms of a- and g-IFN in RD is consistent with these data.

Advances in molecular biology form a true notion of the pathogenetic mechanisms of rheumatic diseases (RD). To treat the latter, the drugs which affect the disease itself, as well as immune processes in some way or another are used. However, many serious side effects due to the use of these agents restrict their application in RD. Nowadays there are several evident approaches to solving this problem: the advent of monoclonal antibodies (MAbs) to the receptors of T and B Iymphocytes, antigen-presenting cells, MAbs to CD18 and CD54 and those to cytokines; search for natural cytokine inhibitors, the use of cytokines, including recombinant interferons (IFN). The encouraging results of clinical use of IFN in RD have been obtained to date. The authors' findings while using the recombinant forms of a- and g- interferons in RD are in agreement with these data.

IN

In the drug therapy of rheumatic diseases (RD), certain successes have been achieved in recent years by expanding the arsenal of drugs and rationalizing treatment regimens, however, data regarding the role of cytokines in the processes of immune and non-immune inflammation dictate the need to search for new ways of pathogenetic therapy of RD.

System of interferon and cytokines in RD

Despite the obvious clinical uniqueness of RD, there are general patterns of development of the pathological process, in which the leading role is given to cytokines of immune and non-immune cells: T- and B-lymphocytes, neutrophils, mononuclear phagocytes, causing tissue destruction [1]. Tissue damage occurs either directly through cytotoxic reactions, or indirectly through the activation of autoreactive and inflammatory cells that induce the production of inflammatory cytokines, proteases and other components involved in the inflammatory response [1]. Thus, in rheumatoid arthritis (RA), tissue destruction initially appears in the area where T lymphocytes are in close contact with monocytes and fibroblast-like synovial cells, which suggests direct cell contact. At the same time, activated T lymphocytes, having received a signal from antigen-presenting cells, begin to secrete cytokines, the effect of which is manifested both in situ and through the microcirculation system. More than 80 cytokines are known, including interleukins (IL), tumor necrosis factor (TNF), colony-stimulating factor, interferons (IFN), etc. In maintaining the homeostasis of the macroorganism, along with the immune system, a large role is played by the INF system, which, in addition to specific (antiviral) has and immunomodulatory effects, manifested by regulation of the expression of genes of the major histocompatibility system, modulation of cell differentiation and maturation, suppression of cell proliferation, and also affecting the endocrine system [2]. There is evidence indicating an interaction between the immune system and IFN. Thus, TNF and g-IFN potentiate each other’s action in terms of stimulating neutrophil migration and the secretion of oxygen radicals [3]. b-IL-1 and TNF induce the synthesis of a 26 kDa protein, which is b-IFN, also known as IL-6 [4]. Pretreatment of macrophages with a-, b-, g-IFN promotes hyperproduction of IL-1 by these cells, which may explain the feverish reaction of the body in response to non-administration of IFN [5]. There is a direct and inverse relationship between the synthesis of IL-2 and g-IFN, at the same time g-IFN induces the secretion of IL-2 by activated T cells [6]. IFN is able to inhibit the differentiation of B cells, while at the same time stimulating their proliferative response [2]. Interesting data show that g-IFN, along with IL-4, suppresses cytokine-stimulated bone resorption, exerting a calcitonin-like inhibitory effect on mature osteoclasts [1]. The study of the features of the IFN system in RD allowed us to identify similar changes in the IFN status in RA, systemic lupus erythematosus (SLE) and Behçet's disease (BD): hypoproduction of α-IFN by leukocytes in vitro in 89% of patients with RA and SLE and in 60% of patients with BD, pronounced inhibition of the production of g-IFN in 96% of patients with RA and SLE and in 80% of patients with BD, hyperproduction of serum IFN in RA and SLE, tested as a-acid-labile IFN - a-KLI (O.N. Shcheglovitova and A.N. Kulieva, 1989). Similar results were obtained by Hooks et al. (1979), who found in the serum of patients with SLE, RA and patients with Sjogren's syndrome an increased level of serum IFN, represented by a high content of a-CLI, against the background of hypoproduction of a- and g-IFN (J. Barnier et al., 1984; Y. Kim and al., 1987). Researchers differ in their assessment of the ability of leukocytes to produce IFN in response to specific induction. Thus, T. Stolzenburg et al. (1988) in a study of serum from patients with RA, SLE, systemic scleroderma (SSc), Reiter's disease (RD) and osteoarthritis (OA) revealed a defect in the production of g-IFN in patients with SLE, RA, SSc, and in BD and OA the level of the studied IFN has not been changed. Others, on the contrary, note a decrease in the production of a-IFN in patients with SLE and RA (A. Renter et al., 1989; M. Seitz, 1987). The above indicates that complex therapy for RD must include drugs that can modulate the patient’s immune response and restore the normal functioning of the INF system.

INF drugs in the treatment of RD

Existing and widely used in clinical practice IFN medications are divided according to the type of active component into a, b and g, as well as according to the production technology and time of creation - into natural (1st generation IFN) and recombinant (2nd generation IFN). Human leukocyte-derived IFN (1st generation IFN) was first used in SLE; a number of researchers (V.A. Galenok, 1971; O.V. Sinyachenko, 1975; Z.S. Alekberova et al., 1980) showed the positive effect of this drug on the course of cutaneous vasculitis and lupus nephritis.

Scheme of the acute phase of inflammation in rheumatic joint damage.

Previously, an attempt was made to treat RA patients with human leukocyte IFN, which helped to reduce the duration of morning stiffness, the number of inflammatory joints and a slight decrease in the activity of the process according to laboratory studies (R.M. Balabanova et al., 1988; M. Peddinani et al., 1986 ). However, the impossibility of complete technical purification and the associated severe side effects, the danger of HIV infection, as well as the shortage of raw materials—donor blood leukocytes—limited the use of INF generation. A method has been developed for the production, isolation and purification of various IFN preparations using genetic engineering methods: a2a-IFN - reaferon, viferon, roferon-A; a2b-IFN - intron-A, inrek, realdiron; a2c-IFN—berophore; b-IFN – feron; g-IFN - inflagen, polyferon, imukin. To date, a large number of open, placebo-controlled and prolonged (12 months) trials have been conducted, indicating the effectiveness of IFN drugs. Researchers used various methods (subcutaneous, intramuscular, rectal) and schemes (daily, intermittent courses, etc.) of administration, as well as different doses of drugs - from 40,000 to 9,000,000 IU. G. Firestein et al. (1987) using recombinant g-IFN at a dose of 1,800,000 IU/day in 12 RA patients, improvement was observed in only two. In 6 patients there was a severe febrile reaction. E. Lemmel et al. (1988) attempted to treat patients with RA with recombinant g-IFN in relatively low doses (40,000 IU once a week), which allowed them to obtain a positive effect in half of the patients and avoid adverse reactions, but no pronounced immunological effect was noted. In Germany in 1996, a multicenter trial of g-IFN (polyferon) was conducted with subcutaneous administration of 2,000,000 IU, 7 injections for 3 weeks, in the next 4 weeks, 3 injections per week (every other day) and another 5 weeks, 2 injections per week. As a result of the therapy, a decrease in morning stiffness, a decrease in the number of inflammatory joints, and a decrease in immunological activity were noted. In juvenile RA, a-IFN (Reaferon), which was administered rectally at a dose of no more than 2,000,000 IU/day in combination with antioxidants for the first 10 days every 12 hours, then 3 times a week once for 6 months, contributed to a reduction in systemic manifestations and positive dynamics articular and INF status, normalization of laboratory parameters (N.N. Kuzmina and M.K. Shcherbakova, 1991). Recently, reports have appeared in the literature on the use of recombinant forms of INF in BD. Thus, G. Fierlback et al. (1989) revealed an inverse correlation between BB activity and the level of endogenous IFN, which gave rise to the use of g-IFN for the treatment of this disease; the drug was prescribed at a dose of 100 mcg subcutaneously daily for 2 weeks to 10 patients, then at the same dose once a week. As a result of therapy, aphthae disappeared in 4 of 8 patients, papular rashes or erythema nodosum in 4 of 7, and polyarthralgia in 3 of 4 patients. The most resistant to treatment were ocular manifestations, which did not disappear in any of the 4 patients. Vedat Hamuryudan et al. (1994) also used to treat 20 patients with BD a2b-IFN at a dose of 5,000,000 IU 3 times a week for 6 weeks, then at the same dose once a week for 10 weeks. A pronounced effect on articular syndrome and a weak effect on the course of ulcerative vasculitis was noted. J. Sanchez-Roman et al. (1995) used a2b-IFN in 2 patients with the intestinal form of BD at a dose of 5,000,000 IU/day for 12 days, then at the same dose weekly. During treatment, abdominal symptoms normalized, which was confirmed by colonoscopy, and genital aphthae decreased or disappeared. Since the mid-80s, we have been conducting open, uncontrolled treatment of patients with RA and SLE with recombinant forms of IFN: g-IFN (reaferon, realdiron) and g-IFN (inflagen) produced by Biofa, Lithuania, in combination with both non-steroidal anti-inflammatory drugs, as well as with drugs that affect the disease, mainly with cytostatic immunosuppressants and corticosteroids (for SLE), using various administration regimens and doses:

• intramuscular injection of 1,000,000 IU of a- or g-IFN every other day for 1 month, in the next 2 months - once a week;
• intramuscularly at 3,000,000 IU a- or g-IFN according to the above-described scheme;
• 3,000,000 IU intravenously every other day for 10 injections, and then intramuscularly once a week as maintenance therapy;
• 3,000,000 IU intravenously 3 days in a row (pulse therapy type) with an interval of 1 month.
• 3,000,000 IU intravenously for 3 days in a row, then for 1 month the same dose once a week intramuscularly, the courses are repeated.

The inclusion of recombinant forms of IFN in the complex therapy of RA and SLE primarily contributed to the normalization of IFN status and thereby prevented the exacerbation and development of chronic intercurrent infections. We noted a decrease in the frequency of adverse reactions, especially when using cytostatic immunosuppressants. The effect of the therapy was expressed in a decrease in systemic manifestations and positive dynamics of joint status in RA and regression of peripheral vasculitis, lupus nephritis in SLE. Assessing the long-term results of IFN therapy in patients with RA and SLE, we noted the insufficiency of a single course of treatment with these drugs: respiratory viral and other infections recurred in 53% of patients, complications of immunosuppressant therapy developed in 20%, and the disease took a typical course in 55%. In 87.8% of patients who received repeated courses of IFN drugs (22 with RA and 12 with SLE), it was possible to stabilize the activity of the process. To date, we have obtained encouraging results from the use of realdiron or inflagen in BD, SSc and Sjögren's syndrome, however, further accumulation of clinical material is necessary for a final assessment of the role of IFN therapy in these diseases. When administering IFN, as with the use of other biological drugs, mainly flu-like adverse reactions are observed. To date, a consensus has not yet formed on the advisability of using IFN in the complex therapy of RA, which is explained by the low availability of these drugs for a wide range of practicing rheumatologists. However, research in this direction is necessary, since the use of selective immunomodulatory drugs and biological immunomodulators becomes possible.

Literature:

1. Dayer IM, Burger D. Rheumat in Europe 1995;12:24-6. 2. F.E. Ershov. The interferon system is normal and pathological. – M.,: Medicine, 1996;11-120. 3. Old L.J. Science 1985;230:630. 4. Van Damme J., Opdenakker G., Simpson RJ. et al. Exp Med 1987;165:515-21. 5. Dinarello Ch. A. Horizon in cytokine research. The 3d Internat. Mochida memor. symp. - Tokyo, 1993;49. 6. Staeheli P, Horisberger MA, Haller O. Virology 1984;132:456-68.

Medicines and uses

Now let’s take a closer look at what these drugs are: patented names of drugs.

Tauredon (Myocrisin, Aurothiomalate, Sanocrisin). The active substance is sodium aurothymalate. The liquid for intramuscular administration contains 46% gold compounds. At the initial stage of treatment, 2 doses per week are used. The first 3 applications are 10 mg, 4 – 6 are 20 mg. For a full course – 2000 mg. To maintain the accumulated effect - 100 mg once a month or 50 mg twice.

Krizanol . The active element is aurothioprol. Oil solution with a gold concentration of 35%. The minimum amount of drug administered during the week is 17 mg. The course includes 20–25 doses.

Auranofin (Auropan, Actil, Riadura) is a tableted gold-containing drug. Oral dosage is 6 mg daily. If there is no result within 4–6 months, the dosage is increased by 3 mg.

Treatment with gold preparations is divided into several stages:

• trial – determines the tolerability of the drug and dosage;
• saturated – a long period for the accumulation of a healing effect;
• maintenance therapy.

The treatment regimen and dosage are selected by the attending physician strictly individually, taking into account all the features of the development of the disease after excluding possible contraindications.

Homeopathy for arthritis and arthrosis

Homeopathic treatment of arthritis, as opposed to traditional methods of treatment, uses non-synthetic agents. For example, in the initial forms, traditional medicine recommends the use of NSAIDs, and homeopathy stimulates the adrenal cortex with natural components, thereby forcing them to independently produce the hormone obtained in finished form using traditional methods of treatment. Homeopathic treatment also makes extensive use of the placebo effect, based on self-hypnosis. Both approaches to treatment have their place, which one to choose is up to you.

Homeopathic remedies are also used to treat arthritis

Aurotherapy possibilities

The appearance of methotrexate on the pharmacological market transferred gold salts to the category of second-line drugs. This is largely due to the fact that the cytostatic agent is more convenient to use and does not cause a large number of adverse reactions. But the current circumstances did not affect the prescription of aurotherapy to patients who do not have obvious contraindications to this type of treatment.

The group of potential candidates for the prescription of gold preparations includes:

• patients who do not tolerate methotrexate well or do not receive the expected result;
• patients with rapidly progressing pathological changes, susceptible to the early development of bone erosions, with high levels of rheumatoid factor in the blood.

The advantage of gold treatment is the possibility of its use in persons with identified chronic infections and cancer, which is due to the antifungal and antibacterial effects of the drugs.

Aurotherapy is especially effective in the initial stages of the disease, which has signs of a severe course. There was no positive effect on persistent joint changes and fibrous contractures.

Gold compounds have an active effect on rheumatoid synovitis and its extra-articular manifestations: nodules, anemia, weight loss. In patients with developing complications of RA (Sjogren's syndrome, Felty's syndrome), the spread of the therapeutic effect to joint manifestations was recorded.

The relevance of aurotherapy in the treatment of seropositive RA and childhood juvenile rheumatoid arthritis has been proven.

Contraindications

The category of general contraindications to the use of gold salts includes:

• severe damage and diffuse changes in the kidneys and liver parenchyma;
• pathologies of blood and hematopoiesis;
• scleroderma, systemic lupus erythematosus - diffuse connective tissue diseases;
• diabetes;
• tuberculosis;
• increased sensitivity to several types of allergens.

Aurotherapy is not used if a woman is in the period of gestation. This is more of a safety net measure, since there is no exact data on the negative effects of gold compounds on the embryo.