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Rheumatoid arthritis is chronic, systemic autoimmune disease characterized primarily by chronic symmetrical polyarthritis. Rheumatoid arthritis is a disease in which one’s own immune system “attacks” and causes inflammatory changes in symmetrically affected peripheral joints. The clinical course varies from mild to progressive rheumatoid arthritis that severely damages the joints. Because rheumatoid arthritis is a systemic disease, organs other than the joints, such as the skin, blood vessels, heart, lungs, and muscles, are often affected. Although it has a highly variable course, the most common are symmetrically inflamed peripheral joints (wrist, metacarpophalangeal joints), leading to progressive destruction of joint structures, usually accompanied by systemic symptoms.

Patients with this disease have a higher cardiovascular risk and increased mortality, i.e., shortened life expectancy. Life expectancy is shortened by 8-15 years in the most severely ill. About 40% of patients become permanently disabled after 3 years and in a milder form of the disease after 20 years.  There is a rapid decline in the function of the affected parts of the body in the first year after the onset of the disease, and the first year is an important prognostic indicator for the further course of the disease.

Rheumatoid arthritis affects 0.5-1.0% of the population. Women get sick 2-3 times more often than men. The disease’s onset can be at any age, but the most common time of onset of the disease is between 30 and 50 years.

The exact cause of Rheumatoid Arthritis is not known. It is probably multifactorial. It is known that women are affected three times more often before menopause than men, and after menopause, the frequency of disease onset is similar between the sexes. The disease has a higher incidence in the family, i.e., among relatives in the first generation and with a high incidence in monozygotic twins (up to 15%) and dizygotic twins (3.5%). Occasionally in families, it affects several generations. Genetic factors are thought to contribute up to 60% to disease susceptibility. There is a strong association between susceptibility to rheumatoid arthritis and HLA-DR4  haplotype that occurs in 50-70% of patients and correlates with a poorer prognosis.

Chronic inflammation of the joint envelope is caused by CD4 + type T lymphocytes’ activation.

Genetic and environmental causes of rheumatoid arthritis

The frequency (prevalence) of rheumatoid arthritis is relatively uniform in the population of most countries in Europe and North America and ranges from 0.5-1.0%. A higher frequency in the world was found in the American ethnic group Pima and Chippewa Indians  (5.3-6.8%), while the lowest frequency was found in Southeast Asia, including China and Japan, where it is only 0.2-0.3%. (Picture).

The disease is most common in age groups over 65 years. Women have a higher prevalence of rheumatoid arthritis than men.

Epidemiological studies on rheumatoid arthritis have found that hereditary and environmental factors are important in the disease’s occurrence. 

The disease’s development requires environmental factors or a trigger (“trigger”) in genetically predisposed individuals. Taking oral contraceptives has been shown to have a protective effect. The frequency is restored in the subfertile and postpartum periods. Infections (EBV, CMV, parvovirus, and bacteria such as Proteus mirabilis and mycoplasma ) via HSP (heat shock protein) participate in the rheumatoid formation factor.

Among other reasons, smoking is significant, and to a lesser extent, various dietary, climatic, and geographical influences. Smoking is also associated with poorer efficacy in DMARD treatment and biologic therapy.

As part of the infection, several comorbidities associated with the development of rheumatoid arthritis should be mentioned as possible triggers of the disease, namely periodontal disease, which is a chronic infection that begins as gingivitis and progresses to periodontitis and bone destruction, urinary tract infection: Proteus, gastrointestinal infections caused by salmonella, shigella, campylobacter, yersinia, and chlamydia trachomatis.

The following factors are rheumatoid arthritis.

Several epidemiological studies have shown the importance of genetic factors on the onset of the disease.

1. Research on “migrant” population groups has shown that despite living in countries with a certain prevalence of the disease, the population of other ethnic groups that have immigrated and lived in those countries for generations has maintained the disease frequency characteristic of the countries from which they migrated. Thus, a very low incidence of RA was found in England among the population of the Caribbean and Pakistani origin, which is significantly lower than that in the domicile English population.

2. Familial grouping of diseases. It is estimated that RA’s occurrence is about 2 times more common among family members. However, it is significantly less than in some other chronic diseases such as diabetes or multiple sclerosis. 

3. Research on twins has shown that their common genetic characteristics can explain 50-60% of both twins’ disease occurrences. Some genes responsible for the onset of the disease are known today, such as HLA DRB1 and HLA DRB1 * 0404, which are estimated to be responsible for about 50% of RA’s genetic effect.

HLA genes

HLA gene polymorphism plays an important role in developing the disease, and most people have HLA-DR4, HLA-DR1, and HLA-DW15. DR4 is present in most ethnic groups, while, e.g., DRW more important in Japanese.
There is also significant polymorphism for other genes:

• PADI4 – peptidyl arginine deiminase type, present in the bone marrow and peripheral leukocytes
• PTPN22 – Protein tyrosine phosphatase, a nonreceptor type 22, encodes an intracellular tyrosine kinase that is a potent inhibitor of T-lymphocyte activation.
• STAT4 – Signal transducer and activator of transcription 4, a transcription factor that interferes with activation by cytokines IL-12, IL-23, and IL-27.
• CTLA4 – Cytotoxic T lymphocyte-associated antigen 4, from the membrane immunoglobulin family, inhibits T-lymphocyte activation.
• TRAF1 – TNF receptor-associated factor 1 plays an important role in apoptosis, proliferation, and differentiation of inflammatory cells.
• Polymorphism for TNF-α

Environmental factors

The meaning of “environmental” means all the factors that affect the disease’s occurrence, which cannot be explained by heredity or established genes. In a broader sense, environmental factors are outside the person and are related to food, water, air, etc. 
In rheumatoid arthritis, several environmental factors are known that may be more closely related to the onset of the disease:

1. Hormones and pregnancy.

Using birth control pills and your pregnancy are associated with a reduced risk of developing RA. However, in the postpartum period, especially after the first birth, the risk of developing the disease is increased. It is also considered that breastfeeding after the first pregnancy is the riskiest for the disease’s occurrence, compared to breastfeeding after other pregnancies.

2. Infections

There is more indirect epidemiological evidence that previous exposure to infectious agents may cause RA. This attitude stemmed, among other things, from the observation that the incidence of rheumatoid arthritis in the world is constantly decreasing, which is most likely due to the constant decline in the number of infectious diseases. Another indirect evidence is the higher incidence of the disease in persons receiving transfusions, through which the transmission of an infectious agent is also possible.
Epstein-Barr virus, the causative agent of infectious mononucleosis, and Proteus and Mycoplasma bacteria are most commonly associated with RA.

3. Other environmental factors

And. Diet.
Few epidemiological studies on the association of RA with diet have suggested a possible protective role of omega-3 fatty acids in developing the disease.

b. Smoking.
Somewhat more research has shown that people who smoke have a higher risk of developing this disease.

Rheumatoid arthritis continues to be a challenge for epidemiological research, which seeks to detect and elucidate both the hereditary and environmental factors of this disease and their interactions. 

Pathophysiology

The disease’s onset is characterized by infiltration of the synovial membrane lymphocytes, plasma cells, dendritic cells, and macrophages. CD4 lymphocytes, including TH1 cells, which secrete IFN-ϒ, and Th17 cells, which secrete IL-17A, IL-17F, and IL-22, play a central role in pathogenesis because they interact with other cells.

Lymphoid follicles develop within the synovial membrane in which interactions between T and B lymphocytes occur, leading to cytokines and autoantibodies in B lymphocytes (including rheumatoid factor ACPA – anti-citrullinated peptide antibodies).

Immunocomplexes activate synovial macrophages due to local damage, and they begin to produce inflammatory cytokines (TNF, IL-1, IL-6, IL-15).  These secreted inflammatory cytokines act on synovial fibroblasts, leading to synovial membrane edema and soft tissue and cartilage damage.

Activated fibroblasts are a rich source of cytokines, chemokines, leukotrienes, and matrix metalloproteinases that exacerbate local tissue damage and cause remodeling. The synovial membrane becomes hyperplastic.

An important event is the activation of osteoclasts by RANKL (secreted from T-lymphocytes and macrophages). The activation of chondrocytes by IL-1 and TNF exacerbates bone and cartilage destruction.

The joint structures in rheumatoid arthritis become hypoxic, and new blood vessels are formed (neoangiogenesis). The inflammatory altered synovial membrane becomes vascularized with activated endothelial cells that promote further leukocyte chemotaxis and maintain and enhance the joints’ inflammatory response.

Cytokines and their influence

Of all the cytokines, they play the most important role in TNF  and IL-6. Interleukin-6 has a role in regulating systemic effects in rheumatoid arthritis through induction of the acute phase of inflammation, anemia, chronic disease, dyslipidemia, fatigue, and reduction of cognitive functions. TNF plays the most important role in endothelial cell activation, fibroblast protection, and neoangiogenesis.

The consequences of the above processes are the formation of granulation tissue, rheumatoid nodules, and hyperplastic lymph nodes and bone marrow:

• Inflammatory granulation tissue (pannus) spreads above and below the articular cartilage, which is progressively damaged. Later, fibrous or bony ankylosis of the joint develops. Muscles adjacent to the inflamed joint may also be affected and infiltrated with lymphocytes.
• Rheumatoid nodules consist of a central region of fibrinoid material surrounded by a palisade of proliferating mononuclear cells. Apart from the joints, such nodules can also be present in the pleura, lungs, pericardium, and sclera.
• Lymph nodes in rheumatoid arthritis are often hyperplastic, with numerous lymphoid follicles with large germinal centers and numerous plasma cells in the lymph node’s sinus and medulla.
• The bone marrow is also hyperplastic.

Pathology of the disease

Rheumatoid arthritis is characterized by widespread, long-term synovitis (inflammation of the joint membrane). As mentioned, the cause is unknown, but the role is certainly played by a rheumatoid factor produced by plasma cells and local inflammation with immune complexes’ formation. The normal joint sheath is thin and comprises several layers of cells.

These cells are synovial cells similar to fibroblasts and macrophages that cover the loose connective tissue. Synoviocytes play a central role in the inflammation of the joint sheath.

In rheumatoid arthritis, the joint sheath thickens greatly, so much so that it can be palpated as a swelling around the joints and tendons. There is a joint envelope’s proliferation into folds, and the tissue is infiltrated by many different inflammatory cells, including polymorphonuclear cells, lymphocytes, and plasma cells. Therefore, the normally thin joint envelope becomes hyperplastic and thickened. There is also a significant proliferation of blood vessels.

Increased permeability of blood vessels and the joint envelope’s inner layer leads to effusion in the joint space, and the effusion contains lymphocytes and dying polymorphonuclear cells.

The hyperplastic joint sheath extends from the joints’ edges to the cartilage surface. This is called “pannus.” The panes of the inflamed envelope damage the underlying cartilage by blocking its normal diet (cartilage feeds passively from the joint fluid) and the direct effect of cytokines on chondrocytes. The cartilage thins and the bone beneath it becomes exposed. Local cytokine production causes juxta-articular osteoporosis during active synovitis.

Fibroblasts from the proliferating joint sheath also grow around the blood vessels between the edge of the joint sheath and the pineal bone and damage the bone. This is seen on MRI in the first 3-6 months after the onset of arthritis before diagnostic bone erosions appear on X-ray.

Therefore, these early lesions justify the use of DMARDs in the first 3–6 months after arthritis onset. Low-dose steroids and anti-TNF-α drugs stop or even reverse the formation of erosions. Erosions lead to various deformities and contribute to long-term disability.

Rheumatoid factor and anti-CCP antibodies

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Rheumatoid factor is a circulating antibody to which the Fc is part of the IgG antibody-antigen. This nature of the antigen means that it independently accumulates in immune complexes and therefore activates complement and promotes inflammation, causing chronic synovitis.

Transient production of rheumatoid factor is an important part of the body’s normal mechanism for eliminating immune complexes. Still, in rheumatoid arthritis, they show much higher affinity, and their production is constant and occurs in the joints. They can be any immunoglobulin class (IgM, IgG, or IgA), and clinical tests usually detect IgM rheumatoid factor.

About 70% of patients with polyarticular rheumatoid arthritis have IgM rheumatoid in serum. Positive titers may precede the onset of rheumatoid arthritis.

The term seronegative rheumatoid arthritis refers to patients whose standard IgM tests for rheumatoid factor are consistently negative. They usually have a more limited pattern of synovitis.

IgM rheumatoid factor is not diagnostic for rheumatoid arthritis, and its absence does not rule out the disease, but it is a useful indicator of prognosis. A consistently high titer in early disease indicates more consistently active synovitis, greater joint damage, and greater disability eventually, and justifies earlier use of DMARDs.

Antibodies against citrullinated proteins (anti-CCP antibodies) and rheumatoid factor together are more specific for rheumatoid arthritis. Anti-CCP predicts the development of erosions and a worse prognosis.

Clinical picture, symptoms and signs

The typical presentation of rheumatoid arthritis (about 70% of cases) begins as a slowly progressive, symmetrical, peripheral polyarthritis that develops over a period of weeks to months. The patient is usually in his thirties to fifties, but the disease can occur at any age.

Less commonly (15%), rapid onset of the disease may occur over several days, or even overnight, with severe symmetrical polyarticular involvement. These patients often have a better prognosis. A worse prognosis than average (with a predictive accuracy of about 80%) correlates with female gender, gradual onset of the disease over several months, positive IgM rheumatoid factor, and/or anemia within 3 months disease onset.

Most patients complain of pain and stiffness in the hands’ small joints (metacarpophalangeal, proximal, and distal interphalangeal) and feet (metatarsophalangeal). Wrists, elbows, shoulders, knees, and ankles can also be affected. In most cases, multiple joints are affected, but about 10% present with knee or shoulder monoarthritis or carpal tunnel syndrome.

The joints are usually warm and hard, with some degree of swelling. There are limited movement and loss of muscle mass. Typically, joint stiffness lasts more than 60 minutes after waking up but can occur after prolonged physical activity. Light activity can relieve symptoms.

Systemic symptoms include afternoon fatigue and malaise, anorexia, generalized weakness, and occasionally low-grade fever.

Rheumatoindi arthritis joint involvement

The effect of rheumatoid arthritis on the hands is great. In early disease, the fingers are swollen, painful, and stiff. Inflammation of the tendon sheaths increases functional damage and can cause carpal tunnel syndrome. Damage to the joints causes various typical deformities.

The most typical combination is ulnar deviation and palmar subluxation of metacarpophalangeal joints. This deformity may look ugly, but the function can be good when the patient learns to adapt, and the pain is controlled. Fixed flexion (boutonniere deformity) or fixed hyperextension (swan neck) of the proximal interphalangeal joints impairs hand function.

The disease can often affect the shoulders’ rotational ability, with pain in the hands at night. Stiffness also occurs that will interfere with daily activities such as dressing and feeding. 

Elbow synovitis causes swelling and painful flexion deformity.

Swelling of the ankles

One of the earliest manifestations of rheumatoid arthritis is a painful swelling of the foot’s metacarpophalangeal joints. The foot becomes wider, and a “hammer” deformity of the big toe develops. Exposing the metatarsal joint surface to pressure and pushing the protective fat pad forward causes pain. Ulcerations and blisters may develop under the metatarsal heads and the dorsum of the fingers.

Rheumatoid arthritis of the joints of the middle and back of the foot causes a flat medial arch and the foot’s flexibility. The ankle often occupies a valgus position. Therefore, wide, deep, padded shoes are appropriate, but they are rarely fully adequate, and walking is often painful and limited. Surgery may be required.

Knees

Massive synovitis and knee effusions occur but respond well to aspiration and steroid injections. Persistent effusions increase the risk of popliteal cyst formation and rupture. In the later stages of the disease, cartilage and bone erosions cause joint space loss visible on X-ray and damage to the medial or lateral and/or retropatellar section of the knee.

Depending on the involvement pattern, the knees may develop varus or vargus deformities. Secondary osteoarthritis develops. A complete knee endoprosthesis is often the only way to restore mobility and relieve pain.

Hips

The hips are rarely affected in early rheumatoid arthritis and are less commonly affected than the knees in all disease stages. Pain and stiffness are accompanied by radiological loss of joint space and juxta-articular osteoporosis. The latter may allow medial migration of the acetabulum (protrusio acetabulae). Later, secondary osteoarthritis develops. An endoprosthesis is usually needed.

Stiff neck

Painful stiffness of the neck in rheumatoid arthritis is often muscular. Still, it may be due to rheumatoid synovitis involving the upper cervical spine’s synovial joints and bursae that separate the dance from the anterior arch of the atlas. Synovitis leads to bone destruction, damages the ligaments, and causes atlantoaxial or instability of the upper cervical spine.

Subluxation and swelling of the local synovial membrane can damage the spinal cord, creating pyramidal and sensory signs. The best way to visualize this damage is by MRI. In the later stages of the disease, walking difficulties can occur. Joint diseases cannot explain that weakness of the legs or loss of bowel or bladder control can occur due to the spinal cord’s compression and is a neurosurgical emergency.

Imaging of the cervical spine in flexion and extension in patients with rheumatoid arthritis before surgery or upper gastrointestinal endoscopy is required to check for instabilities and reduce the risk of spinal cord injury during intubation. 

Other joints affected by the disease are temporomandibular, acromioclavicular, sternoclavicular, cricoarytenoid, and any other synovial joint.

Extraarticular manifestations Rheumatoid arthritis

Subcutaneous nodules are solid, intradermal, and generally occur over pressure areas, typically the elbows, finger joints, and Achilles tendon. Histologically, a necrotic center is surrounded by rows of activated macrophages, resembling synovitis without synovial space. Nodules can ulcerate and become infected but usually disappear when the disease comes under control. The doctor can remove the nodules surgically, or a corticosteroid can be injected into them if they cause problems. They often come back. 

Olecranon and other bursae may be swollen (bursitis).

Tenosynovitis of the affected flexor tendon in hand can cause stiffness and curl of the finger. Swelling of the extensor tendon and dorsum of the wrist is common. 

Loss of muscle mass around the joints is also common. Muscle enzyme concentrations are normal. Myositis is sporadic. Corticosteroid-induced myopathy may occur.

Peripheral intrapulmonary nodules are usually asymptomatic but may cavitate. When pneumoconiosis (Caplan’s syndrome) is present, large cavitation lung nodules may develop. Other manifestations may be serositis causing pleural effusions, pleural nodules, fibrosing alveolitis (pulmonary fibrosis), obstructive bronchiolitis, infectious lesions (e.g., tuberculosis in patients on drugs that modify the immune response).

Vasculitis is caused by immune complexes deposited in the artery walls, which is not common. Smoking is a risk factor. Other manifestations are nail bed infarctions due to cutaneous vasculitis, widespread cutaneous vasculitis with skin necrosis seen in patients with the highly active and highly seropositive disease, mononeuritis multiplex, intestinal infarction due to necrotizing arteritis of mesenteric blood vessels (which is difficult to distinguish from polyacid nodules).

Elevated CRP

Poorly controlled rheumatoid arthritis with long-term elevated CRP is a risk factor for premature atherosclerosis of the coronary and cerebral arteries independent of traditional risk factors. Clinical pericarditis is rare. In severely seropositive rheumatoid arthritis, a post-mortem echocardiogram shows that 30-40% of patients have pericardial involvement. Endocarditis and myocardial disease are rarely seen clinically, but 20% of cases are also found post-mortem. It also occurs  Reynaud’s syndrome.

Amyloidosis causes nephrotic syndrome and renal failure. It is presented by proteinuria. It occurs mainly in severe, long-term rheumatoid disease due to the deposition of stable serum amyloid A protein (SAP) in various organs’ intercellular matrix. SAP is an acute phase reactant normally produced by the liver. Amyloidosis is rare, and disease-modifying drugs more commonly cause proteinuria in RA. 

Felty’s syndrome is splenomegaly and neutropenia in patients with rheumatoid arthritis. Complications are ulcerations on the legs and sepsis. HLA-DR4 is found in 95% of patients, compared with 50-75% of patients with rheumatoid arthritis alone. Lymph nodes can be palpable, usually in the distribution of affected joints. It may be peripheral lymphedema of the arm or leg. 

Anemia is almost universal and is usually normochromic, normocytic anemia of chronic disease. There may also be iron deficiency due to gastrointestinal blood loss due to taking nonsteroidal antirheumatic drugs, or even rarely hemolytic (positive Coombs test). There may be pancytopenia due to hypersplenism in Felty syndrome or as a complication of DMARD treatment. High platelet counts occur with active disease.

Diagnosis

The diagnosis is based on the ACR (The American College of Rheumatology) criteria. Their diagnostic algorithm is shown in the figure and the table’s criteria.

Initial searches include:

• complete blood count. Anemia may be present. Erythrocyte sedimentation rate and CRP are elevated in proportion to the inflammatory process activity and are useful for monitoring treatment.
• Serological tests. Anti-CCP is positive earlier in the disease, and in early inflammatory arthritis indicates the likelihood of progression to RA. Rheumatoid factor is present in about 70% of cases, and low titer ANA in about 30% of cases.
• X-ray of affected joints. Only soft tissue swelling is seen in early disease. MRI can show early erosions but is rarely sought.
• Aspiration joint if the effusion is present. The aspirate appears cloudy due to the presence of white blood cells. Septic arthritis may be suspected in a suddenly painful joint.

Differential diagnosis

Many disorders can mimic rheumatoid arthritis:

• crystal-induced arthritis
• osteoarthritis
• the systemic lupus erythematosus (SLE)
• sarcoidosis
• reactive arthritis
• psoriatic arthritis
• ankylosing spondylitis
• arthritis associated with hepatitis C.

Rheumatoid factor may be nonspecific and is often present in several autoimmune diseases; as already mentioned, anti-CCP is more specific for RA. For example, hepatitis C may be associated with RA-like arthritis clinically, and RF is positive. However, anti-CCP is negative.

Some patients with arthritis-induced crystals may meet the RA’s diagnostic criteria, but an examination of synovial fluid should clarify the diagnosis. The presence of crystals makes RA amazing. Joint involvement and subcutaneous nodules can result from gout, cholesterol, and amyloidosis as well as RA; you may require aspiration and nodule biopsy.

SLE can usually be distinguished if there are skin lesions on light-exposed areas of the skin, hair loss, lesions of the oral and nasal mucosa, absence of joint erosions even in long-term arthritis, synovial fluid often having less than 2000 white blood cells per microliter (predominantly mononuclear cells), antibodies to double-stranded DNA, renal disease, and low serum complement levels.

Unlike RA, deformities in SLE can usually be reduced due to lack of erosions and damage to cartilage or bone. RA-like arthritis can also occur in other rheumatic disorders (e.g., polyarteritis, systemic sclerosis, dermatomyositis, or polymyositis). There may be features of more than one disease, indicating an overlap syndrome.

Sarcoidosis, Whipple’s disease, multicentric reticulohistiocytosis, and other systemic diseases can affect the joints. Acute rheumatic fever has a migratory joint involvement pattern and evidence of previous streptococcal infection.

Reactive arthritis

Previous gastrointestinal or genitourethral symptoms can distinguish reactive arthritis; asymmetrical grip and pain on the grip of the Achilles tendon, sacroiliac joints, and ankles; conjunctivitis, iritis, painless buccal ulcers; circulatory balanitis; keratoderma blennorhagicum on the soles and elsewhere. 

Psoriatic arthritis

Psoriatic arthritis is usually asymmetric and usually not associated with RF, but differentiation can be difficult without nail or skin lesions. Involvement of the distal interphalangeal joints and arthritis mutilans strongly indicates the diagnosis and the presence of diffusely swollen fingers (“sausage” fingers). Ankylosing spondylitis can be distinguished by the spinal and axial joints’ involvement, absence of subcutaneous lesions, and negative RF.

Osteoarthritis

Osteoarthritis can be distinguished by affected joints, the absence of rheumatoid nodules, systemic manifestations, significant amounts of RF, and less than 2,000 white blood cells per microliter of synovial fluid. Osteoarthritis of the hands most typically affects the distal interphalangeal joints, the thumbs’ bases, and the proximal interphalangeal joints. Rheumatoid arthritis does not affect the distal interphalangeal joints.

Treatment

The diagnosis of rheumatoid arthritis inevitably causes concern and fear, and the patient requires a lot of explanation and support. Early diagnosis with early referral to a rheumatologist is the most important component. You should note that most patients will continue a more or less normal life with the help of medication despite arthritis; 25% fully recover.

The earliest years are often the most difficult, and people should be encouraged to stay at work during this phase if possible. Planning is hampered by uncertainties about when the disease will have remission or worsening, when and whether medications will work, and whether they will produce side effects. People learn to adapt very well, but it takes time and support. 

No drug will cure rheumatoid arthritis, but drugs are available that prevent the disease from getting worse. Symptoms are controlled with analgesics and nonsteroidal antirheumatic drugs. Studies now support the use of disease-modifying drugs (DMARDs) in early disease to prevent irreversible damage due to arthritis, and drugs that block TNF-α and IL-6, and the use of rituximab B-cell ablation revolutionize the management of rheumatoid arthritis.

Non-steroidal anti-inflammatory drugs (NSAIDs)

Most patients cannot cope with night pain and stiffness without nonsteroidal antirheumatic drugs. NSAIDs do not reduce the underlying inflammatory process. Everyone acts on the cyclooxygenase pathway. The individual response to nonsteroidal antirheumatic drugs varies greatly, so it is advisable to try several different medications to find the one that suits the person the most. Each of these drugs should be given for at least a week. It makes sense to start with cheaper NSAIDs that have fewer side effects and that you are more familiar with. Regular doses are needed for therapy to be effective.

If gastrointestinal side effects are present and the patient is older than 65, it is not bad to add a proton pump inhibitor. Slow-release formulations (e.g., diclofenac slow-release 75 mg, after dinner) usually work well and can be given with other therapies if needed. For additional analgesia, a simple analgesic (e.g., paracetamol or a combination of codeine or dihydrocodeine and paracetamol) may be taken as needed. Many patients need night sedation.

Corticosteroids

Some studies suggest that early use of corticosteroids slows the disease’s course. Intraarticular injections of semi-crystalline steroids have a powerful but sometimes only short-lived effect. Intramuscular depot injections (40-120 mg methylprednisolone depot) help control severe disease exacerbations but should not be used frequently. The use of oral corticosteroids causes many problems. They are powerful in controlling the disease but should be avoided for a long time because of the inevitable side effects. 

Disease-modifying antirheumatic drugs (DMARDs)

Traditional DMARDs, which mainly act by inhibiting cytokines, reduce inflammation, reduce joint inflammation, reduce acute phase reactants in plasma, and slow the development of joint erosion and irreversible damage. Their effect is not rapid and can only be partial or transient.

DMARDs often have a partial effect, achieving between 20 and 50% improvement in ACR criteria for disease remission (morning stiffness lasts less than 15 min, no fatigue, joint pain, soft tissue swelling; erythrocyte sedimentation less than 30 in women and less than 20 in men). Drugs that block TNF-α and rituximab achieve almost 70% improvement in about 20% of patients and act faster. Sulfasalazine, methotrexate, leflunomide, TNF-α blockers, cyclosporine, and rituximab all show a reduction in the rate of progression of joint damage in early and late disease.

Generally, DMARDs are used after symptomatic treatment. However, patients positive for rheumatoid and anti-CCP with persistent joint swelling have a poor prognosis. They should be treated early with DMARDs – preferably before X-ray erosions appear on the hands and feet.

Studies in early cases of RA suggest that DMARD intervention 6 weeks to 6 months from the onset of the disease improves outcome. The use of combinations of three or four drugs (steroids, methotrexate, sulfasalazine, and hydroxychloroquine) in early RA, with a reduction in the number of drugs, when remission is achieved, is not widely accepted, and the efficacy of such therapy has yet to be proven. Effective DMARD treatment reduces cardiovascular risk in RA patients.

People who will not develop erosions should not be over-treated. Most prognostic estimates in early disease are only 80% accurate for the risk of erosions and consequent disability. Clinicians’ estimates remain the most important link in rheumatoid arthritis management.

Sulfasalazine

Sulfasalazine is a combination of sulfapyridine and 5-aminosalicylic acid, where sulfapyridine is probably the active ingredient. It is well-tolerated, and for most, DMARDs are the first choice, especially in younger patients and women planning a pregnancy. It generates a response in about half of patients in the first 3-6 months. Serious side effects are rare, mostly leukopenia and thrombocytopenia.

Methotrexate

Methotrexate is, according to many, the first option. It is strictly contraindicated in pregnancy. Therefore, you should delay conception for at least 3-6 months after taking methotrexate for both partners. It is given in an initial weekly dose of 2.5-7.5 mg orally, increasing to 15-25 mg if needed. It is well-tolerated, and this therapy can be used early in the disease. Nausea or poor absorption may limit its effectiveness.

It can be given by subcutaneous injection alone. You should give folic acid with methotrexate to limit side effects, although this may reduce effectiveness. You should monitor the complete blood count for liver function tests. Methotrexate usually works within 1-2 months. Most patients remain on methotrexate, indicating that this is an effective therapy with relatively few side effects.

Leflunomide

Leflunomide is a DMARD that achieves its immunomodulatory effects by preventing pyrimidine production in proliferating lymphocytes by blocking the enzyme dihydroorotate dehydrogenase. Most cells can bypass this blockade, but T cells cannot – therefore, it has a specific effect on blocking T cells’ clonal expansion by slowing the progression through phases G and S1. It is well absorbed when taken orally. It has a long half-life, 4-28 days. A bolus dose of 100 mg is usually used for 1-3 days, followed by 20 mg (10 mg if diarrhea is a problem).

The main side effects are diarrhea, nausea, alopecia, and rash. Diarrhea decreases over time. Monitoring of the complete blood count is mandatory. The onset of leflunomide onset is 4 weeks, in contrast to methotrexate which has 6 weeks. The initial response is similar to that of sulfasalazine, but progression continues and is better maintained after 2 years.

Leflunomide works in some patients who do not respond to methotrexate or may be given methotrexate to improve the response. As far as planning a pregnancy is concerned, one should wait 2 years after taking leflunomide for conception in women, 3 months in men, so it is best to avoid it in women planning a family.

Biological therapy

The availability of drugs that block TNF-α has significantly changed DMARDs’ traditional use. They are used because of their cost when at least two DMARDs (usually sulfasalazine and methotrexate) have been tested. 

Infliximab

Infliximab is a chimeric monoclonal antibody against TNF-α, administered intravenously and prescribed with methotrexate to prevent loss of efficacy due to antibody production.  Adalimumab is a fully-humanized monoclonal antibody against TNF-α and is also co-administered with methotrexate.

These drugs slow or stop the formation of erosions in up to 70% of patients. Patients often report that their fatigue and tiredness improve in a way not seen with other DMARDs. There is a 50% incidence of secondary failure with infliximab in the first year, less with adalimumab and another TNF-α blocker, etanercept. The change to another anti-TNF drug is justified, and disease control is achieved again. 

A small proportion of patients taking biologic therapy may become ANA positive and develop a reversible lupus-like syndrome, leukocytoclastic vasculitis, or interstitial lung disease. Reactivation of old tuberculosis may also occur (therefore, a chest X-ray or quantifier test is required before treatment), and you should treat tuberculosis before starting therapy. There is an increased risk of infection that requires closer monitoring.

Biologic therapy is costly compared to classic DMARDs but can reduce the cost of treatment in the long run by reducing disability and the need for hospitalization.

Rituximab

Rituximab is a chimeric monoclonal antibody that causes lysis of CD-20 positive B cells. CD-20 is a surface phosphoprotein antigen. Its expression is limited to pre-B and mature B cells but is not present on stem cells and is lost before differentiation into plasma cells. Rituximab produces a significant improvement in rheumatoid factor-positive rheumatoid arthritis at 8 months to several years when used alone or in combination with corticosteroids and/or methotrexate.

This is associated with six to nine months of B cell lymphopenia with small circulating immunoglobulins changes. Reactivation of the disease is associated with a return of peripheral lymphocyte counts and elevated CRP levels. Rituximab can be re-used if the disease is activated. Repeated therapies over 5 years are acceptable and well-tolerated, and about 80% of RF-positive patients respond, and 50-60% show long-term disease control. Therefore, you should try this drug in patients who have not responded to anti-TNF therapy. 

Less commonly used medications

Hydroxychloroquine is an antimalarial used in mild diseases as an adjunct to other DMARDs. The most serious side effect is retinopathy, but it is rare at least 6 years before treatment.

Azathioprine at a maximum dose of 2.5 mg/kg body weight and cyclophosphamide 1-2 mg0 kg body weight were usually used when other DMARDs were not effective. They are often used with severe extra-articular manifestations, especially with vasculitis. There is a high risk of neutropenia and possible liver toxicity in genetically deficient patients in the enzyme thiopurine methyltransferase.

Cyclosporine 2.5-4 mg/kg is used for active rheumatoid arthritis when conventional therapy has been ineffective. Side effects include elevated creatinine levels and hypertension.

Prognosis

Rheumatoid arthritis reduces life expectancy by 3 to 7 years, where the main culprits for death are heart disease, infections, gastrointestinal bleeding; treatment, malignant diseases, and underlying diseases may also be responsible.

At least 10% of patients eventually have a permanent disability despite full treatment. Caucasians and women have a worse prognosis, as do patients with subcutaneous nodules, older age at onset, inflammation of more than 20 joints, early erosions, smoking, higher erythrocyte sedimentation rate, and higher levels of rheumatoid factor or anti-CCP.

Pain relievers

IN winterize glucosamine and chondroitin sulfate supplements to reduce pain and slow cartilage loss. Evidence suggests that this combination may be effective for people with mild to moderate arthritis. Follow the proofing instructions on the label and persevere: it may take a month or more before you start to feel the beneficial effects.

Take half a teaspoon of powdered ginger or up to 35 g (about 6 teaspoons) of fresh ginger a day. Research shows that ginger root helps relieve pain in arthritis, probably because of its ability to increase blood circulation, removing inflammatory compounds from painful joints.

Take two doses of 400 mg SAM_a (S-adenosylmethionine) per day. It has been shown that the addition of SAM_a, a chemical found in all cells of the body, helps relieve arthritis pain by increasing levels of proteoglycans in the blood – molecules that appear to play a key role in preserving cartilage by helping it stay “inflated” and well oxygenated.

If you get good results from 800 mg per day, reduce the dose after two weeks to 400 mg per day. SAM has several side effects, although it can cause indigestion and nausea. It is safe to take with most prescription and over-the-counter medications. Still, if you are taking medications prescribed for bipolar disorder (manic depression) or Parkinson’s disease, you should consult your doctor before taking SAM_a supplements.

Look for warm relief and cool comfort

Applying heat to a sore joint can provide significant relief. You can use electric blankets and hand warmers, heating pads, or warm pads as heat sources. Heat a sore joint for 20 minutes. Simply bathing in warm water can also be soothing.

Cold treatments can work well when the joints are inflamed. Wrap ice cubes in a larger face towel and hold over the sore wrist. You can use a bag of frozen peas instead.

A natural way to reduce disease symptoms

Recipe 1. Bone pain

Take three tablespoons of finely chopped onion, horseradish root (grated), and fresh cabbage (grated). Mix everything and pour over with 100ml of oil. Lightly fry over high heat. Cool and get the obtained, mash, put the obtained porridge on a linen cloth, and attach it to the diseased bone. The dressing lasts all night. After removing the dressing, wash the place where you kept the dressing (the affected area) with lukewarm water, and then rub it with wine vinegar for 10 minutes. Bone pain should pass after 3-4 treatments (nights).

Recipe 2. Tea against rheumatism

Mix two tablespoons of finely chopped willow bark, walnut leaves, juniper berries, and buckthorn grass. Pour 1400 ml of boiling water over the resulting mixture of herbs. Cover and let stand for two hours. Strain and drink 200 ml during the day before breakfast, lunch, and dinner.

Recipe 3. Massage solution for patients with rheumatism

Mix 50 g of finely chopped rosemary and St. John’s wort. Pour the resulting mixture of herbs into a one-liter glass bottle. Fill the bottle with homemade lump brandy, or 70% ethanol. Keep the bottle in a warm (warm room or sunny window) for 20 days. Shake the bottle several times during the day. After 20 days of extraction, strain the bottle and use the obtained liquid to massage the body’s diseased parts. The affected areas are massaged for a maximum of 30 minutes until the skin absorbs fluid or until a tingling sensation is felt.

Sources:

1. Aletaha D, Neogi T, Silman A, Funovits J, Felson D, et al. 2010 Rheumatoid Arthritis Classification Criteria: An American College of Rheumatology / European League Against Rheumatism Collaborative Initiative. Arthritis Rheum 2010; 62: 2569-81
2. Davidson’s Principles and Practice of Medicine, 21st. edition with student consult online access; Nicki R. Colledge, BSc, FRCP (Ed), Brian R.Walker, BSc, MD, FRCP (Ed) and Stuart H. Ralston, MD, FRCP, FMedSci, FRSE
3. Vrhovac B. et al. (ed.): Internal Medicine, IV amended edition, Naklada Ljevak doo, Zagreb 2008
4. Gibofsky A. Overview of epidemiology, pathophysiology, and diagnosis of rheumatoid arthritis.Am J Manag Care. 2012 Dec; 18 (13 Suppl): S295-302.
5. Izabela Korczowska. Rheumatoid arthritis susceptibility genes: An overview. World J Orthop. Sep 18, 2014; 5 (4): 544–549.
6. Song Li, Yangsheng Yu, Yinshi Yue, Zhixin Zhang, and Kaihong Su. Microbial Infection and Rheumatoid Arthritis. J Clin Cell Immunol. Dec 2013; 4 (6): 174