• Rheumatoid arthritis (RA) is the most common cause of chronic inflammatory arthritis (frequency 0.5-1%).
• The female/male ratio is approximately 3/l.
• It most commonly begins between the ages of 25-55.
• The main site of involvement is synovium (synovitis).
• Rheumatoid arthritis is an inflammatory arthritis.
RISK FACTORS
• HLA-related genes (HLA DR-1, HLA DR-4, common epitope)
• Smoking
• Periodontitis (Porphyromonas gingivalis)
• To the hormonel Factors (However, during pregnancy, RA clinical findings improve. In addition, oral contraceptive use reduces the risk of RA)
in pregnancy
Rheumatoid arthritis ---- Soothes
Systemic lupus erythematosus ------ Exacerbated
pathogenesis
• Pannus develops as a result of synovitis. Pannus causes bone and cartilage destruction (erosion).
• In the following process, destruction and deformities develop in the joint.
joint findings
• Involves the joints in a symmetrical, polyarticular fashion that attaches one after the other and predominantly involves the peripheral skeleton.
• It usually starts in the small joints of the hand (PIF and MCF) and foot (MTF).
• Large joints (hand and ankle, knee, elbow, hip, shoulder ...) are involved later.
• In the axial skeleton, it may involve the atlantoaxial joint (C1-C2). With atlantoaxial dislocation, it can cause spinal cord compression and death.
• Joints least expected to be involved in RA:
- Distal interphalangeal joints
- Intervertebral joints except atlantoaxial (Cl-C2)
- Sacroiliac joints
• Pain, swelling and temperature increase are seen in the involved joint.
• Morning stiffness in the joint > 30 minutes is characteristic. Morning stiffness decreases with working
• The disease may cause deformities (Swan neck deformity, Boutonniere deformity, ulnar / radial deviations, etc.) in untreated cases.
• Inflammation in the wrist can lead to carpal tunnel syndrome.
• Also in the course of RA; There may be involvement of tendon sheaths and bursae (popliteal Baker's cyst).
• Baker's cyst rupture can be confused with thrombophlebitis.
Extra-articular findings
Rheumatoid nodules:
• It is the most common extra-articular finding of RA.
• It is often located subcutaneously (most often in the elbow), but it can also be found in many organs or tissues (lung, heart, etc.).
• Usually hard and painless.
• Sometimes they may develop due to methotrexate treatment.
cardiac involvement
• Pericardium is most commonly involved (pericarditis, pericardial effusion).
• The most common valve disease is mitral insufficiency.
• Increased risk of coronary artery disease. Cardiovascular diseases are the most common cause of death in RA.
Most common heart valve diseases
Rheumatoid arthritis ------------ Mitral regurgitation
Ankylosing spondylitis ----------Aortic regurgitation
Pulmonary involvement
• The pleura is most commonly involved (pleuritis, pleural effusion).
• The pleural fluid is exudate; glucose is very low, pH is low, LDH and protein are high.
• Rheumatoid nodules may be seen in the lungs.
• Coexistence of RA, pulmonary nodules and pneumoconiosis (silica, coal worker) is called Caplan syndrome.
• Interstitial lung disease may develop.
• Interstitial pneumonia and pulmonary fibrosis may be associated with methotrexate use.
Hematological involvement
• The most common finding is normochromic normocytic anemia (Anemia of chronic disease).
• The platelet count has increased. Immune thrombocytopenia, different from other connective tissue diseases, is rare.
• Felty's syndrome; It is the combination of RA + splenomegaly + neutropenia.
• Increased risk of Non-Hodgkin lymphoma (most commonly Diffuse large B-cell lymphoma).
• Large granular lymphocytic leukemia (LGL) may develop (T-cell leukemia).
Eye involvement
• The most common ocular manifestation is keratoconjunctivitis sicca (secondary Sjögren's syndrome).
• Other ocular findings include episcleritis, scleritis, and scleral nodules.
• Steroid-related posterior subcapsular cataract, antimalarial drug-related retinal toxicity may develop.
Neurological involvement
• The most common neurological finding is entrapment neuropathies (most often carpal tunnel syndrome).
• Spinal cord compression due to atlantoaxial subluxation may be seen.
Other findings
• Periarticular and/or diffuse osteoporosis may be seen.
• Hypogonadism can be detected in the course of RA
• Kidney involvement; membranous glomerulonephritis may be in the form of AA type amyloidosis.
Laboratory findings
• Rheumatoid factor (RF);
o RF are autoantibodies that recognize the Fc portion of immunoglobulin G as antigen (most often in IgM structure).
o It is positive in 70-80% of patients. However, its specificity is low.
Situations where RF can be positive
Sjogren's syndrome 90%
Essential mixed cryoglobulinemia 90%
Rheumatoid arthritis 70-80%
Other collagen tissue diseases (SLE, Scleroderma, Myositis etc.)
Chronic infections {Subacute bacterial endocarditis, HBV, HCV etc.)
Elderly individuals 15%.
• Anti-CCP (cyclic citrullinated peptide) antibodies;
o Positive in approximately 70%-SO of RA patients.
o Specificity (95%) for rheumatoid arthritis is higher than RF.
• RF and anti-CCP positivity; is associated with more severe joint disease, extra-articular involvement, and poor prognosis. These two tests used in diagnosis have no place in follow-up.
• Synovial fluid analysis:
o Typically, inflammatory synovial fluid is detected.
o The number of white blood cells varies between 5,000 and 50,000/mm3.
o The predominant cell type (>50%) is neutrophils.
joint imaging
• Direct radiography findings can rarely be detected in the early period.
radiological findings in rheumatoid arthritis
Early period
Periarticular osteopenia (first finding)
soft tissue swelling
Marginal erosions
Symmetrical narrowing of joint space
late period
Subluxations
Generalized osteoporosis
joint deformities
Ankyloses
• Soft tissue changes such as (teno) synovitis can be detected more sensitively and earlier with MRI and USG.
• MRI also shows bone marrow edema, one of the early indicators of inflammatory arthritis.
Rheumatoid arthritis classification criteria 2010 ACR and EULAR
joint involvement
1 large joint (shoulder, elbow, hip, knee, ankle) ---score = 0
2-10 large joints ----Score = 1
1-3 small joints (MCP, PIP, thumb interphalangeal,wrist) -- score = 2
4-10 small joints -----score = 3
> 10 joints (at least 1 small joint) ---- score = 5
Serology
Negative RF and negative Anti CCP --score = 0
Low titer of positive RF or Anti CCP antibodies --score = 2
High titer of positive RF or Anti CCP antibodies --- score = 3
Acute phase reactants
Normal CRP and normal ESR --score = 0
Abnormal CRP or abnormal ESR ---score = 1
Symptom duration
< 6 weeks ---score = 0
>= 6 weeks ----score = 1
>= 6 points, significant for Rheumatoid arthritis.
Treatment
Non-steroidal anti-inflammatory drugs (NSAIDs)
• They provide analgesic and anti-inflammatory effects.
• However, long-term use should be avoided due to its lack of disease-modifying effects and toxicity. (Caution: NSAIDs modify the disease in ankylosing spondylitis.)
corticosteroids
• They can be used for the control of pain and inflammation in the acute phase of the disease until the effect of other long-acting drugs appears (bridge therapy).
• Although it slows down the disease clinically and radiographically, they should be given in the lowest possible dose and as soon as possible due to their side effects.
DMARD ( disease-modifying anti-rheumatic drugs)
Conventional DMARDs
• Drugs that have the potential to change the course of the disease are called DMARDs.
• These drugs should be started as soon as the diagnosis of RA is made, because they show their effects late (2-6 months for maximum effect) and should be used in combination.
• Methotrexate
o Inhibits dihydrofolate reductase enzyme.
o It is the first choice in RA and almost always found in combination therapies.
o May cause toxicity on rapidly dividing cells (Hair loss, stomatitis, bone marrow suppression, GIS irritation and hepatoxicity). These side effects are dose dependent and can be prevented with folic acid replacement.
o Rarely, interstitial pneumonia may develop with the use of methotrexate. Unlike other toxicities, it is not dose related and cannot be prevented by folic acid replacement.
It is teratogenic.
• Leflunomide
o Inhibits dihydro-oratate dehydrogenase enzyme and suppresses activated T lymphocytes.
It is teratogenic.
o Excretion from the body can be accelerated with cholestyramine.
o The most common side effect is diarrhea.
• Antimalarial drugs (chloroquine, hydroxychloroquine)
o These drugs have not been shown to delay radiographic progression in RA (not a true DMARD).
o They are very safe drugs (least toxic DMARDs). They can be used during pregnancy.
o Annual retinal examination is recommended after 5 years of treatment due to the risk of long-term retinal toxicity.
o They reduce cholesterol levels and reduce the incidence of newly diagnosed diabetes.
• Sulfasalazine
o It can cause hemolysis in glucose-6-phosphate dehydrogenase deficiency.
Biological DMARDs
• Although highly effective, they are used in patients who are resistant to conventional DMARDs or in whom conventional DMARDs cannot be used due to the risk of infection and high treatment costs.
Anti-TNF non-alpha biological DMARDs
Anakinra: IL-1 receptor antagonist
Rituximab: Anti CD20 monoclonal antibody
Abatacept: Added CTLA4 to the Fc part of IgG (co-stimulation inhibitor)
Tocilizumab: monoclonal antibody against IL6 receptor
Tofacitinib: J AK1 and J AK3 inhibitor
• Except for Tofacitinib (oral), it is used parenterally.
• Before all biological DMARDs, latent tuberculosis screening should be performed (PPD test) and INH prophylaxis should be given to risky patients (Tuberculosis risk is more pronounced in TNF alpha inhibitors and anakinra.)
• Side effects of TNF alpha inhibitors;
o Increased risk of infection
o TB reactivation
o Infusion reactions (hypersensitivity)
o Psoriasis
o SLE
o Pancytopenia
o Demyelination
o Worsening of heart failure
o Serious liver disease
o Increased risk of hematological malignancy (though the risk of developing solid malignancy was not increased).
• Conditions where TNF alpha inhibitors are contraindicated;
o Presence of active infection or high risk of infection
o Malignancy or premalignant condition
o history of SLE
o History of multiple sclerosis
• Pregnancy and breastfeeding are no longer contraindications for anti-TNF drugs. Babies should not receive live vaccines for the first 6 months.
• Rituximab increases the risk of hepatitis B reactivation and progressive multifocal leukoencephalopathy (JC virus).
• Tofacitinib and tocilizumab can cause hyperlipidemia.
• Tofacitinib can cause upper respiratory tract infection and nasopharyngitis.