Rheumatoid Arthritis – Symptoms and Treatment

Rheumatoid Arthritis – Disease Definition and Causes:

Rheumatoid arthritis is a chronic inflammatory disease affecting connective tissues, leading to joint damage and systemic effects on internal organs. While primarily impacting joints, it can also affect other systems (such as the lungs, heart, and nervous system). Joint damage occurs due to chronic inflammation of the synovial membrane – the inner layer covering the joint capsule. As the disease progresses, bone erosion and joint deformity occur. The disease is characterized by an autoimmune nature, where antibodies are formed against self-tissues. Long-term tissue destruction and inflammation result from the effects of these antibodies.

The prevalence of the disease in adults ranges from approximately 0.5-2% (around 5% for women under 65 years old). The estimated incidence of rheumatoid arthritis is about 50-100 new cases per 100,000 people per year. The prevalence ratio between women and men ranges from 2-3:1. All age groups are affected, including children and the elderly. The disease is often diagnosed between the ages of 30 and 55.

The causes of developing rheumatoid arthritis are unknown.
Predisposing factors include:

• Infection (Epstein-Barr virus, Parvovirus B19, among others).
• Genetic factors, carrying the tissue compatibility antigen HLA-DR4.
• Smoking, excessive coffee consumption, high body mass index, and stress.
• Exposure to mineral oils (engine or hydraulic oils). Studies have shown that these oils possess properties that stimulate arthritis.
• Sex hormones and reproductive factors (pregnancy, childbirth, etc.).

Symptoms of Rheumatoid Arthritis

The onset of rheumatoid arthritis is characterized by an initial period that develops over several weeks and/or months before the typical symptoms of rheumatoid arthritis appear. This period manifests with general weakness, fatigue, muscle and joint pain, loss of appetite, and mild fever (between 37.1 to 38 degrees Celsius).

The onset of rheumatoid arthritis may present with various clinical forms:

• Non-specific symptoms with mild joint manifestations (moderate joint pain).
• Acute polyarticular arthritis (pain, swelling in the joints of the hands and feet, difficulty in movement) primarily affecting the joints of the hands, feet, and moderate morning stiffness.
• Acute arthritis with systemic manifestations: fever (from 38 to 39 degrees Celsius), lymph node swelling (enlargement of lymph nodes; may reach the size of a walnut), and hepatosplenomegaly (enlargement of the liver and spleen).

In the early stage of rheumatoid arthritis, the impact is notably positive on the second and third finger joints between the finger phalanges and metacarpophalangeal joints (sharp pain upon joint pressure). The characteristic formation of joint deformities (joint shape changes, such as swan neck or boutonniere deformity) in the joints between the finger phalanges is one of the typical symptoms of rheumatoid arthritis.

One of the earliest and most distinctive symptoms is morning stiffness (the patient unable to bend and extend the joints, as if their hands were in tight gloves). The severity of stiffness depends significantly on the activity of inflammation. In cases of high inflammatory activity, it persists for several hours but is particularly noticeable in the morning and gradually decreases after physical activity.

In the advanced and final stages of the disease, typical manifestations of rheumatoid arthritis such as destruction, deformities, and stiffness (joint stiffness and loss of movement) appear.

Types of joint deformities:
Hands:

• Ulnar deviation of the metacarpophalangeal joints (fingers deviate towards the ulnar side in a claw-like appearance), usually occurring 1-5 years after the onset of the disease.
• Boutonniere or swan-neck finger deformity.
• “Telescope” hand deformity.

Baker’s cyst:
Knees: Varus (bowleg) deformity, Baker’s cyst (cyst behind or under the knee).

Feet: Subluxation of the metatarsophalangeal joints, hallux valgus (lateral deviation of the big toe).

Cervical spine: Subluxations in the cervical spine region, sometimes with complications involving spinal cord compression or vertebral artery compression.

Carpometacarpal joint: Enlargement of the voice, shortness of breath, difficulty swallowing, recurrent airway inflammation.

Tendons and synovial sheaths: Tendonitis (inflammation of the tendon sheath) in the hand and wrist area; synovial sheath inflammation (inflammation in the synovial sheath), often in the elbow area; synovial cyst on the back side of the knee (Baker’s cyst).

Rheumatoid arthritis is characterized by the appearance of various non-articular and systemic manifestations.

General Symptoms:

General symptoms include overall weakness, fatigue, significant weight loss leading to cachexia (weight below 40 kg), and mild fever.

In the multifaceted presentation of rheumatoid arthritis, cardiac involvement is rare. Cardiac symptoms may result from the direct inflammatory process in the heart or as a complication of rheumatoid arthritis with arteriosclerosis. In this disease, harmful effects can include damage to the myocardium (the heart’s largest muscle), the outer membrane of the heart (pericardium), the inner membrane of the heart, the aorta, and the coronary arteries. These conditions may include pericarditis (inflammation of the outer membrane of the heart), valvular damage (very rare), early development of arteriosclerosis, and inflammation of the coronary arteries.

Lung damage often occurs in cases of rheumatoid arthritis. This can manifest as:

• Pleuritis (inflammation of the pleura).
• Involvement of the lung parenchyma (inflammation and destruction of the alveolar walls and pulmonary capillaries).
• Diffuse alveolar damage (progressive and constant blockage of small airways).
• Rheumatoid nodules in the lungs (Caplan’s syndrome).

The most serious manifestation of lung involvement is pulmonary fibrosis, which is attributed to the autoimmune nature of the disease and the use of certain anti-inflammatory medications, including methotrexate, gold drugs, and D-penicillamine. Pulmonary fibrosis presents with non-productive cough (dry, without mucus), difficulty breathing during exertion (shortness of breath), and a grayish-blue discoloration. It leads to pulmonary hypertension and the development of pulmonary heart disease (enlargement of the right heart chambers). Pulmonary graph consolidation and the “honeycomb” phenomenon (structural changes in the lungs characterized by numerous thick-walled air spaces) are identified.

Dermatological Syndrome:
Dermatological manifestations of rheumatoid arthritis are varied. Common extrajoint signs include rheumatoid nodules (bony formations on joints the size of peas or walnuts), usually located subcutaneously most commonly on the extensor surfaces of the elbow joints, and when placed in an atypical location, they may appear on the Achilles tendons, cornea, and in tendons.

The development of various skin diseases in rheumatoid arthritis is possible:

• Cutaneous vasculitis (inflammation of blood vessels in the skin) ranging from ulcerative necrotic changes to swelling and loss of richness in the skin.
• Palpable purpura (inflammation and destruction of subcutaneous blood vessels), rarely accompanied by finger necrosis.
• Small ulcers in the butterfly area (circulatory disorders, vessel occlusion with thrombosis and appearance of black spots on the fingers).
• Livedo reticularis (constriction of the network, or Livedo reticularis) – a pattern of thin blue discoloration in a reticular shape.

Damage to the Peripheral Nervous System:
Damage to the peripheral nervous system is often explained by compression or vascular problems affecting nerve roots. Complementary neurological symptoms of rheumatoid arthritis include carpal tunnel syndrome (long-lasting pain and numbness in the fingers), tarsal tunnel syndrome (pain in the ankle joint area, and a sensation of crawling or tingling in the hand), and so forth. Compression of nerve roots manifests as pain, tingling, numbness, and localized muscle atrophy. Peripheral nerve damage can also occur, resulting in sensory or sensorimotor disturbances.

Muscle Damage:
Muscle damage is significant in rheumatoid arthritis: muscle wasting between bones in the hand, tenar wasting (thumb elevation), and hypotenar wasting (little finger elevation). Muscle wasting is characterized by atrophy in muscles close to the affected joints, such as hand muscle wasting between bones and lower thigh muscle wasting in prominent knee joint inflammation. Muscle wasting can result from rheumatoid vasculitis, neuropathy, for example, in carpal tunnel syndrome or cubital tunnel syndrome, long-term corticosteroid use, or restrictions in muscle activity.

Eye Diseases:
Ocular deformities are one of the distinctive features of rheumatoid arthritis. Oftentimes, there is inflammation of the ocular membranes (inflammation of tissues surrounding the eye), rarely accompanied by serious complications or fibrosis (tissue infiltration) with corneal perforations and eye removal. Scleritis (inflammation of the sclera) and scleritis and keratitis (inflammation of the sclera and cornea) usually manifest as severe pain and redness in the sclera. Dry eyes are also considered part of this disease, resulting from lymphocytic cell accumulation in the lacrimal glands and are usually part of Sjögren’s syndrome.

Renal Diseases:
Renal diseases manifest as clinical features of rheumatoid arthritis through glomerular nephritis (renal inflammation), diffuse amyloidosis (amyloid protein accumulation) with primary effects on the kidneys, or drug-induced nephropathy (tissue damage and renal tubular system) due to the use of nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac or combined analgesics with phenacetin, leading to pelvic inflammation (interstitial tissue inflammation of the kidney).

Hematologic System:
The hematologic system responds to the autoimmune inflammation process by presenting anemia, an increase in platelet count (thrombocytosis), and neutrophil decrease (reduction in white blood cell count). Secondary complications associated with medications can also occur.

• The hematopoietic system responds to the anti-tumor drugs with a decrease in the level of all types of blood cells (pancytopenia).
• In the context of high doses of corticosteroids, a leukemoid reaction (increase in the total number of white blood cells) may occur.
• The large cell system often responds to active inflammatory processes by developing lymph node enlargement and splenomegaly, leading to the formation of a specific type of rheumatoid arthritis known as Felty’s syndrome.

Gastrointestinal Impact:
The impact on the gastrointestinal tract can lead to the development of secondary diseases such as pancreatic enlargement, and the effect on the stomach and intestines may result from the use of nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids.

Vasculitis:
Vasculitis can develop in patients with high activity of rheumatoid arthritis and includes:

• Digital artery inflammation (digital).
• Sensitivity-susceptible skin rash (purpura) that can be palpated.
• Molds and signs of suffocation, which appear as a purple mesh pattern on the skin.
• Peripheral nerve paralysis.
• Atherosclerotic artery inflammation: inflammation of the blood vessel walls that supply the heart muscle (coronary), arterial thrombosis (blockage of blood vessels in the abdomen), acute pulmonary inflammation, and airway inflammation.
• Raynaud’s syndrome (tingling and pain in the fingers).

Endocrine Gland Manifestations:
Hormonal results – Diseases such as autoimmune thyroiditis (chronic inflammation of the thyroid gland leading to gradual cell destruction) and Sjogren’s syndrome can develop in the context of the disease’s immune nature.

Rare Clinical Forms of Rheumatoid Arthritis:
Felty’s syndrome is characterized by a set of symptoms: neutrophil deficiency, splenomegaly, liver enlargement, severe joint involvement, extrajoint effects (vascular, neurological, pulmonary fibrosis, Sjogren’s syndrome), darkening of the skin at the bottom of the extremities, and increased risk of infection complications. This syndrome develops in patients with continuous exacerbation of arthritis.

Adult-onset Still’s Disease:
Adult-onset Still’s disease – recurrent fever, arthritis, skin rash, high laboratory activity. It occurs equally in men and women. This syndrome is characterized by draining fever, often reaching temperatures above 41 degrees Celsius. The fever is constant and responds unexpectedly to treatment. Joint involvement is benign. In Still’s syndrome, there is an increase in the number of white blood cells and a shift in the formula to the left, an increase in liver enzyme activity, anemia, a disturbance in plasma protein balance, an increase in erythrocyte sedimentation rate, an increase in C-reactive protein reflecting acute inflammatory processes in the body, and an increase in ferritin levels (elevated ferritin in the blood).

Mechanism of Rheumatoid Arthritis Inflammation:
In the normal state, the synovial membrane of the joint is thin and secretes synovial fluid that lubricates and nourishes the joint. The mechanism of rheumatoid arthritis inflammation can be conceptualized as follows:

1. Rheumatoid arthritis leads to the immune cells attacking the healthy synovial membrane. Swelling occurs under the synovial membrane, where lymphocytes, multinucleated white blood cells, monocytes, and plasmatic cells accumulate.
2. In this context, immune cells secrete defensive proteins – cytokines, stimulating the growth of blood vessels in the synovial membrane. Increased blood flow leads to tissue enlargement. Synovial membrane cells proliferate rapidly, leading to synovial tissue enlargement. This abnormally enlarged tissue is called “pannus.” Pannus cells secrete protein-degrading enzymes that destroy cartilage.
3. At the same time, under the influence of excessive production of painful cytokines (TNF-alpha and others), bone cells (cells in the bones that destroy the old structure) are activated, leading to bone damage. Subsequently, bone tissue destruction occurs with erosion formation.
4. The erosive changes in bones also occur as a result of fibroblasts activation (the main cells in soft connective tissues), which begin to secrete enzymes capable of destroying articular cartilage. The disease progresses to transform pannus into mature fibrous tissue, leading to joint surface fusion.

Rheumatoid Arthritis Classification and Stages:

1. International Classification of Diseases 10th Revision (ICD-10):

• M05: Seropositive rheumatoid arthritis.
• M06: Other rheumatoid arthritis.
• M05.0: Felty’s syndrome.
• M06.1: Adult-onset Still’s disease.
• M06.9: Rheumatoid arthritis, unspecified.

1. Clinical Classification of Rheumatoid Arthritis (2002 project):

• Seropositive rheumatoid arthritis (M05).
• Polyarthritis (M05). Rheumatoid vasculitis (M05.2) (digital artery swelling, chronic skin ulcers, Raynaud’s phenomenon, etc.).
• Rheumatoid nodules (M05.3). Polyneuropathy (M05.3).
• Rheumatoid lung disease (M05.1) (pulmonary inflammation, rheumatoid lung).
• Felty’s syndrome (M05.1). Seronegative rheumatoid arthritis (M06.0).
• Polyarthritis (M06.0). Adult-onset Still’s syndrome (M06.1).

1. Revised American College of Rheumatology Diagnostic Criteria (1987):

• Morning stiffness (lasting at least one hour).
• Arthritis in three or more joint areas.
• Arthritis of hand joints.
• Symmetric arthritis.
• Rheumatoid nodules.
• Rheumatoid factor.
• Radiographic changes.
• A definitive diagnosis of rheumatoid arthritis is made when four of the seven criteria above are present, and the first four criteria persist for at least six weeks.

Primary Diagnosis:

• Seropositive Rheumatoid Arthritis (M05.8).
• Seronegative Rheumatoid Arthritis (M06.0).

Special Forms of Rheumatoid Arthritis:

• Felty’s Syndrome (M05.0).
• Adult-Onset Still’s Disease (M06.1).
• Probable Rheumatoid Arthritis (M05.9, M06.4, M06.9).

Clinical Stages:

• Very early stage: lasts less than 6 months.
• Early stage: lasts from 6 months to a year.
• Advanced stage: lasts more than a year with typical symptoms of rheumatoid arthritis.
• Late stage: lasts 2 years or more, characterized by extensive damage to small joints (radiographic stage III-IV) and presence of complications.

Disease Activity:

• 0 = Remission: DAS28 < 2.6 (DAS28 – Disease Activity Score).
• 1 = Low: 2.6 < DAS28 < 3.2.
• 2 = Moderate: DAS28 = 3.2-5.1.
• 3 = High (DAS28 > 5.1).

Extra-Articular Manifestations (Systemic):

• Rheumatoid nodules.
• Cutaneous vasculitis (digital artery inflammation, purpuric skin ulcers, vasculitic neuropathy).
• Vasculitis in other organs.
• Neuropathy (mononeuropathy, polyneuropathy).
• Crystalline vasculitis (dry, necrotizing granulomatous inflammation).
• Sjogren’s syndrome.
• Eye involvement (scleritis, episcleritis, retinitis).

Additional Descriptors:

• Presence of erosion (using X-rays, possibly MRI, and ultrasound):
  • Non-erosive.
  • Erosive.
• Radiographic stage (according to Steinbrocker, modified):
  • Stage I – Periarticular soft tissue swelling.
  • Stage II – Soft tissue swelling + joint space narrowing, some erosions may appear.
  • Stage III – Features of the previous stage + multiple erosions + joint subluxation.
  • Stage IV – Features of the previous stage + bone fusion.

Functional Class:

• Class I – Patient performs all three vital functions: self-care, professional, and non-professional responsibilities.
• Class II – Patient is limited only in non-professional activities (all elements of recreation, leisure, and ordinary life practice).

Complications of Rheumatoid Arthritis include:

1. Renal Amyloidosis: May occur due to long-standing rheumatoid arthritis. Manifests with edema, high blood pressure, and increased protein levels in urine tests.
2. Bone Necrosis (Osteonecrosis): Death of a portion of bone due to disrupted blood flow. Presents with sharp pain in the affected joint and reduced range of motion. Diagnosis is confirmed by X-rays and joint CT imaging.
3. Secondary Osteoarthritis: Appearance of joint pain, crepitus, and swelling. Diagnosis is confirmed by joint X-rays.
4. Neurological Tunnel Syndromes: Nerve disorders manifesting with long-term pain and tingling in the hand fingers. Occurs due to nerve compression between bones and ligaments.
5. Cardiovascular and Vascular Manifestations: Rheumatoid arthritis patients have an early development of arteriosclerosis, increasing the risk of stroke and angina.
6. Drug-Related Effects (Therapeutic and Allergic): Abnormal medical conditions resulting from drug interactions, where medical interaction can lead to the emergence of new diseases, complications, or exacerbation of existing conditions.
7. Other Complications: Including gastrointestinal cancers, osteoporosis, Sjogren’s syndrome, Felty’s syndrome, lymphoma, and others.

Laboratory Tests:

• Complete blood count with platelet count.
• Chemical blood tests (total protein, albumin, globulin fractions, total bilirubin, urea, creatinine, uric acid, calcium, cholesterol, lipid spectrum, C-reactive protein, serum C-reactive protein).
• Anti-cyclic citrullinated peptide (ACCP) antibodies assay.
• Comprehensive urine analysis with proteinuria determination.
• Serum immunoglobulin assay.

It is preferable to perform ACCP testing for early detection of rheumatoid arthritis, as it is considered more sensitive and specific than rheumatoid factor (RF). ACCP appears in 40-50% of rheumatoid arthritis patients who test negative for RF.

Recommended Diagnostic Imaging Tests include X-rays of the joints, ultrasound, magnetic resonance imaging (MRI), joint arthroscopy, and diagnostic joint arthroscopy. Detailed diagnoses are necessary to differentiate between rheumatoid arthritis and similar conditions.

Treatment of rheumatoid arthritis includes:

1. General recommendations:

• Avoiding stress.
• Minimizing excessive sun exposure, as strong sunlight can exacerbate rheumatic diseases.
• Actively treating accompanying infections and considering vaccination when necessary.
• Preventing arterial sclerosis by maintaining a low-fat, low-cholesterol diet rich in unsaturated fatty acids, quitting smoking, controlling weight, engaging in physical activity, and taking folic acid.
• Preventing osteoporosis by consuming a calcium-rich diet, taking vitamin D supplements, and using bisphosphonates if necessary.

1. Medication:

• Disease-modifying anti-rheumatic drugs (DMARDs) are key in treating rheumatoid arthritis and should be prescribed for every patient with this diagnosis.
• Methotrexate is a primary medication in rheumatoid arthritis treatment, particularly in active stages of the disease, with doses ranging from 15 to 30 mg per week.
• Leflunomide, another DMARD, is used specifically for rheumatoid arthritis treatment.
• Biologic agents, including TNF-α inhibitors, IL-1 and IL-6 inhibitors, T cell activation inhibitors, and B cell blockers, have revolutionized the treatment of rheumatic diseases.

1. Biological treatments:

• Biological agents, particularly TNF-α inhibitors, have significantly improved long-term health outcomes for rheumatoid arthritis patients but come with potential side effects.
• Adverse effects may include increased susceptibility to infections, development of autoimmune diseases, and elevation in harmful cholesterol levels.

It’s important to carefully monitor patients for side effects and adjust treatment plans accordingly.

Small molecule group:

1. Tofacitinib (Jaquinus): A new class of medication for treating lupus erythematosus, can be used alone or in combination with methotrexate or other nonsteroidal anti-inflammatory drugs (NSAIDs) regardless of food intake.

Sequential therapy:

• Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Provide rapid therapeutic effects and effectively suppress pain and inflammation (such as diclofenac, nimesulide, Nimesil, etc.).
• Glucocorticoids (GCS): Used in cases where inflammation is at its peak, severe unrelieved pain by NSAIDs, generalized rheumatoid inflammation with oxidative manifestations, systemic lupus erythematosus, and local corticosteroid therapy inside and around the joint.

Non-pharmacological therapy:

• Although medication plays a primary role in treating lupus erythematosus, non-pharmacological methods are essential for achieving complete therapeutic effects. The aim of these measures is to restore lost or impaired patient capabilities and adapt to chronic illness.
• Physical therapy and occupational therapy (special exercises simulating movements during self-service, aimed at restoring mobility) are beneficial for lupus erythematosus patients.
• Nature therapy and hydrotherapy are useful for patients with low-inflammatory activity, significantly reducing symptoms and improving mobility.

Article Author:
Dr. Ibrahim Mansour
A general practitioner and orthopedic specialist with 9 years of experience in the emergency department. Specializes in treating infectious diseases and gastrointestinal diseases, with a focus on skeletal aspects using therapeutic, surgical, and conservative methods for injuries, including sports-related ones, and major joint diseases in the extremities. His area of interest includes joint-preserving procedures in the knee and hip joints.

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