Over the past twenty five years rheumatoid arthritis has ceased to be a disease that inevitably ends in deformed hands and disability. Drugs appeared that switch off individual molecules of inflammation with precision, and with them came a realistic goal of treatment: remission.

And with the arrival of reliable treatment a new problem appeared. Investigation shows laboratory and radiological remission: blood tests and joints are normal, there are no new erosions on the images. Yet the person continues to live with pain, exhaustion and the morning sensation that the body does not belong to them.

Let us try to work out together why biological therapy is necessary, and why it is not sufficient.

Rheumatoid arthritis is a chronic systemic autoimmune disease in which the immune system mistakenly attacks the body’s own tissues, affecting the joint linings and the internal organs. According to current understanding, three things take part in the development of RA: hereditary predisposition, epigenetic changes (shifts in gene activity in which the text of the DNA itself does not change, but the way cells read that instruction does) and environmental factors.

It is very important to understand that genetic predisposition is of course highly significant, but genes on their own do not start the disease. What starts it is the meeting between hereditary predisposition and the environment. The strongest of the known external factors is smoking. Next come excess weight, a disturbed microbial composition of the gut, the lungs and the oral cavity, dust inhalation, certain viral infections.

Let us imagine a person who was unlucky. Their hereditary predisposition met unfavourable environmental factors and switched on epigenetic changes. Put simply, they developed rheumatoid arthritis. Autoantibodies appear in the blood on average four and a half years before the first clinical symptoms. That is, by the moment a person first notices swelling and pain in the joints, changes have already been present in the immune system for several years.

Synovitis, the inflammation of the joint lining, is not the beginning of the disease. It is the culmination of a long subthreshold process.

Two important conclusions follow from this.

First: treatment cannot be postponed, every month of delay is a lost window of opportunity.

Second: rheumatoid arthritis is not a local story about inflamed joints, it is a systemic disease and it requires a systemic approach.

The pharmacological foundation

The role of biological anti-inflammatory drugs in the treatment of rheumatoid arthritis

Rheumatoid arthritis is treated with disease-modifying anti-rheumatic drugs, and in active disease this means biological or targeted synthetic therapy.

The current standard is called treat-to-target, treatment until the goal is reached. Disease activity is measured by the DAS28, SDAI and CDAI indices, and therapy is adjusted until remission or low disease activity is achieved.

The first line of treatment is the well known methotrexate. Then, if the response is insufficient, targeted therapy is added:

• tumour necrosis factor alpha inhibitors: adalimumab, etanercept, infliximab, certolizumab;
• interleukin-6 inhibitors: tocilizumab, sarilumab;
• agents against B lymphocytes: rituximab;
• T cell co-stimulation blockers: abatacept;
• Janus kinase inhibitors: baricitinib, upadacitinib, tofacitinib, which require separate attention to cardiovascular and thrombotic risks.

The point of these drugs is one thing: they stop the destruction. Cartilage and bone destroyed by activated synovial fibroblasts and osteoclasts unfortunately cannot be restored. Bone erosion is an irreversible loss of structure, and the only thing proven to prevent it is suppression of the inflammatory cascade with medication.

Therefore, despite the fact that I always favour the most naturopathic choice available in treatment, in the case of an autoimmune disease it has to be admitted: treatment with targeted anti-inflammatory drugs is an absolute necessity.

Three components of pain

The limits of drug therapy

The gap between laboratory well-being and how the person actually feels, the gap this article began with, has a specific name. Pain in rheumatoid arthritis consists not of one component but of three.

The nociceptive component. Classic inflammatory pain. Cytokines and prostaglandins irritate the pain endings in the inflamed joint. It is precisely this component that disease-modifying drugs act upon, and they act well.

The neuropathic component. Pain from damage to or compression of nerve structures by swelling or inflamed tissue, for example in tunnel syndromes, which occur often in rheumatoid arthritis.

The nociplastic component. Pain that arises from a change in the pain processing system itself, without corresponding tissue damage. The mechanism is called central sensitisation.

Central sensitisation means that the nervous system has reset pain perception into amplification mode.

• Hyperalgesia develops, when a painful stimulus is perceived more strongly than it should be.
• Allodynia develops, when pain is caused by touch that is harmless in itself.
• Receptive fields expand, and the area that hurts becomes larger than the original one.
• The descending pain inhibition system breaks down, the internal mechanism that normally dampens the signal on its way to consciousness.
• Microglia become activated.
• The balance of neurotransmitters shifts: more glutamate, less GABA, less serotonin and noradrenaline.

The key consequence: peripheral anti-inflammatory treatment has almost no effect on this part of the pain. It can extinguish inflammation in the joint completely, yet it cannot change the intensity of pain if that pain is already maintained centrally.

Let us examine rheumatoid arthritis along the familiar scheme:

Axis one

Psychosomatics

Discussing the psychological component with a patient who has a severe autoimmune disease is difficult. The patient feels they are being told that the illness is in their head. That is why in the clinic I always begin the conversation with the words: “Your pain is absolutely real, it is located in the body, and the body and its perception of pain are governed by the brain.”

The first vector, from the psyche to inflammation. Psychological stress activates the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Under chronic stress the sensitivity of tissues to cortisol decreases, its anti-inflammatory effect weakens, and the production of pro-inflammatory cytokines rises. Clinically this looks like a flare of the inflammatory process after a difficult period in life.

The second vector, from inflammation to the psyche. Pro-inflammatory cytokines penetrate the central nervous system and alter the metabolism of neurotransmitters, above all serotonin and dopamine. What research calls sickness behaviour appears: low mood, loss of interest, fatigue, sleep disturbance. This is a direct biological action of inflammation on the brain.

Depression and anxiety occur in fifteen to forty percent of patients with rheumatoid arthritis. The work of Hackshaw and colleagues, published in the Journal of Psychosomatic Research in 2026, showed across a comparison of fibromyalgia, rheumatoid arthritis and systemic lupus erythematosus that depression worsens functional status to a considerable extent through the amplification of pain. That is, depression works through the pain channel rather than in parallel with it.

The circle closes: inflammation intensifies depression, depression intensifies pain, pain limits movement, and immobility intensifies inflammation and depression.

Which psychological methods have evidence behind them

Cognitive behavioural therapy. The most studied method in chronic pain. It works with catastrophising, that is, with the automatic prediction of the worst outcome, which is in itself one of the strongest predictors of pain intensity and disability. It reduces pain and fatigue in rheumatoid arthritis as an addition to drug therapy.

Mindfulness practices. Training of attention in which pain is observed without an immediate emotional reaction to it. Separating the sensory and affective components of pain reduces suffering at the same signal intensity.

Acceptance and commitment therapy. It shifts the goal from reducing the symptom to returning to meaningful activity in spite of the symptom. In chronic conditions this often proves more practical than fighting.

Clinical hypnosis. A method that deserves a paragraph of its own, because its reputation in the Russian speaking world does not correspond to its scientific status.

Hypnosis is not sleep and not a loss of control. It is a state of focused attention with heightened responsiveness to suggestion, in which the perception of pain can be changed with precision. The mechanism was shown as early as the classic work of Rainville and colleagues in 1997: suggestion directed at the unpleasantness of pain altered activity in the anterior cingulate cortex without affecting the somatosensory cortex. That is, hypnosis acts precisely on the affective component of pain, on how tormenting it is rather than on how physically strong it is. For nociplastic pain this is an exact hit on the target.

A systematic review with meta-analysis of randomised trials of hypnosis in chronic musculoskeletal and neuropathic pain, published in 2022, confirms a reduction in pain intensity. In rheumatoid arthritis specifically the data are older and methodologically weaker: the work of Horton-Hausknecht, Mitzdorf and Melchart from 2000 in sixty six patients, ten weekly sessions, a reduction in pain compared with simple relaxation and with a waiting list, an effect that persisted at three and six months. The design was non-randomised, and this should be acknowledged honestly.

A practically important detail: teaching self-hypnosis turns the method from a procedure into a skill. The patient acquires an instrument to use at home, without a therapist and without additional drugs.

None of these methods affects erosions. All of them affect pain, fatigue, sleep, functional status, adherence to treatment and whether the person stays inside their own life or drops out of it.

Axis two

Biochemistry

Diet does not cure rheumatoid arthritis. But it lowers the inflammatory background and regulates the hormonal and neurotransmitter balance, thereby supporting the effectiveness of targeted therapy and the durability of remission.

Fatty acids and eicosanoids. From omega-6 fatty acids, which are abundant in sunflower, corn and soybean oil, the body builds predominantly pro-inflammatory mediators. From omega-3, which are abundant in oily sea fish, it builds less inflammatory eicosanoids and, more importantly, specialised pro-resolving mediators: resolvins, protectins, maresins. These are molecules that do not merely suppress inflammation, they actively bring it to an end.

Scientific reviews confirm a consistent effect of omega-3 on disease activity and inflammatory markers in rheumatoid arthritis, including a reduced need for non-steroidal anti-inflammatory drugs.

Extra virgin olive oil. Monounsaturated fats plus polyphenols, among them oleocanthal, which inhibits cyclooxygenase by a mechanism related to the action of ibuprofen, although incomparably weaker in strength.

Fibre. Vegetables, legumes and whole grains feed the gut bacteria, which produce short chain fatty acids, above all butyrate. Butyrate nourishes the cells of the intestinal epithelium, strengthens the barrier and promotes the maturation of regulatory T lymphocytes, the cells whose task is to stop immune aggression against the body’s own tissues. This is a direct link between the plate and the mechanism of autoimmune inflammation.

Adipose tissue. Visceral fat is not a storehouse but an endocrine organ that secretes interleukin-6 and tumour necrosis factor alpha. Obesity in rheumatoid arthritis is associated with higher disease activity and with a poorer response to therapy. Normalising body weight here is an anti-inflammatory measure in the literal sense.

Vitamin D. Deficiency is common in rheumatoid arthritis, and vitamin D itself takes part in the regulation of the T cell response. The VITAL trial showed a reduction in the incidence of autoimmune diseases of about twenty two percent with two thousand units of cholecalciferol daily. Correction of deficiency is recommended, and the dose should be selected on the basis of a blood test rather than at random.

The Mediterranean pattern of eating brings together everything listed above: olive oil as the main fat, fish twice a week, vegetables, legumes, nuts and seeds, whole grains, restriction of red and processed meat and of sugar. It is already included in the British NICE guidelines as a supportive measure in rheumatoid arthritis. The randomised MADEIRA trial in women with rheumatoid arthritis in remission showed improvement in disease activity measures and in body composition over twelve weeks. The telehealth trial by McKellar and colleagues produced improvement in physical function and quality of life. A controlled trial combining the Mediterranean diet with an exercise programme over six months showed a reduction in pain and in C-reactive protein.

During a flare the emphasis shifts towards an anti-inflammatory protocol: priority goes to omega-3, to weight control and to sufficient protein to protect muscle mass, since active inflammation destroys muscle. In remission the Mediterranean pattern works as the foundation, and it works on a second front as well: cardiovascular risk in patients with rheumatoid arthritis is substantially raised, and this is one of the main reasons for the shortened life expectancy in this disease. Diet here protects more than the joints.

Axis two, continued

The microbiome

One of the most convincing hypotheses of the last decade explains the connection between the gut microbiome and autoimmune diseases.

Meta-analyses of randomised trials consistently show a reduction in C-reactive protein with probiotics taken alongside disease-modifying therapy. The work of Sanchez and colleagues from 2022 gave a mean reduction of about three milligrams per litre.

A probiotic capsule does not replace disease-modifying therapy and is not a treatment in its own right. But the presence of dysbiosis not only makes the course of the disease more severe, it also reduces the effectiveness of therapy.

Axis three

Biomechanics

A generation ago patients with rheumatoid arthritis were advised to spare their joints. That recommendation turned out to be mistaken and was refuted by clinical trials. Today physical activity in rheumatoid arthritis belongs to therapy rather than to lifestyle advice.

Contracting skeletal muscle is an endocrine organ: it releases special substances, the myokines. Muscle derived interleukin-6, released during exercise, triggers an anti-inflammatory cascade, raising the level of interleukin-10 and of the interleukin-1 receptor antagonist. Irisin and other myokines are added to this. The concept was formulated by Benatti and Pedersen in Nature Reviews Rheumatology in 2015 and has been confirmed since.

The pilot study by Bartlett and colleagues from 2018: ten weeks of high intensity interval walking in older patients with stable rheumatoid arthritis, three sessions a week of thirty minutes. The result: a reduction in disease activity of about thirty eight percent, a nine percent increase in aerobic capacity, improved function of innate immune cells, lower blood pressure and heart rate. The programme was well tolerated. A later study by the same group linked the improvement in disease activity to a reorganisation of energy and amino acid metabolism within the muscle itself, and the greatest gain went to patients who were older, less fit and more inflamed.

Beyond the anti-inflammatory effect, movement solves three further tasks.

The first, rheumatoid cachexia. Chronic inflammation destroys muscle tissue, often while body weight is preserved or even rising. Loss of muscle means loss of function, of stability and of metabolic health, and it is restored only by resistance training combined with sufficient protein.

The second, the joint. Cartilage has no blood vessels and is nourished by diffusion, which is provided by cyclical loading and unloading. An immobile joint is not fed. In addition, movement maintains range of motion, and the strength of the surrounding muscles reduces the load on the joint surfaces themselves.

The third, the central nervous system. Regular aerobic exercise strengthens descending pain inhibition, raises the level of brain derived neurotrophic factor, improves sleep and has an antidepressant effect comparable in magnitude to some pharmacological interventions in mild and moderate depression.

The general principle of dosing is simple: during a marked flare the volume and intensity are reduced, the work is mainly with range of motion and gentle activation, but a complete stop is almost never indicated. The programme must be selected individually, taking into account the state of the cervical spine, which in rheumatoid arthritis requires particular caution.

Axis four

Lifestyle

Sleep and the daily rhythm. Morning stiffness in rheumatoid arthritis has a chronobiological explanation. The level of interleukin-6 begins to rise around midnight and peaks in the early morning hours, and in patients with rheumatoid arthritis it continues to rise and reaches its maximum later in the morning. Cortisol, the natural anti-inflammatory hormone, rises later. On the other hand, lack of sleep in itself raises the level of pro-inflammatory markers and lowers the pain threshold after only a few nights. Sleep in this disease should be regarded not as a domestic habit but as a therapeutic factor.

Stress and the cortisol axis. Chronic stress leads not to an excess of cortisol but to a decrease in the sensitivity of tissues to it. Immune cells stop hearing the signal to stop. Practices that slow the breath and reduce sympathetic activation restore receptor sensitivity and heart rate variability.

The inflammatory reflex. Here lies perhaps the most elegant proof that the nervous system governs the immune system directly. The vagus nerve, through the cholinergic anti-inflammatory pathway, suppresses the production of tumour necrosis factor. Koopman and colleagues showed in PNAS in 2016 that stimulation of the vagus nerve suppresses the production of tumour necrosis factor, interleukin-1 beta and interleukin-6 in humans and reduces the activity of rheumatoid arthritis. In December 2025 Nature Medicine published the results of the large randomised RESET-RA trial: two hundred and forty two patients with an inadequate response to biological and targeted therapy, an implantable vagus nerve stimulator against sham stimulation. The ACR20 response at three months was 35.2 percent against 24.2 percent, and by twelve months of the open label phase it reached 52.8 percent.

It matters that patients with rheumatoid arthritis have reduced heart rate variability at baseline, and that autonomic dysfunction, according to prospective observations, precedes the development of the disease. This does not mean that breathing exercises are equivalent to an implanted stimulator. It means that a real physiological circuit exists linking vagal tone with cytokine production, and that this circuit can be influenced through breathing, regular aerobic exercise and the quality of sleep.

Smoking. The strongest of the modifiable risk factors, affecting the development of the disease, its course and the effectiveness of therapy. In the strength of its effect, giving up smoking is comparable to a pharmacological intervention.

Serotonin and noradrenaline. The system of descending pain inhibition runs on these two neurotransmitters, and its depletion is one of the mechanisms of pain centralisation. The pharmacological answer to this is known: duloxetine, amitriptyline, pregabalin. We have already discussed the low effectiveness of these drugs in the article on the drug treatment of chronic pain. But the same system is supported by regular exercise, stable sleep, daylight and social involvement. Isolation and low socioeconomic status are associated with a worse prognosis in rheumatoid arthritis.