Mixed connective tissue disease

Rheumatoid Arthritis
Juvenile Rheumatoid Arthritis

Hiba Mohammed Irfan

Group 2
Tbilisi State Medical University
Mixed Connective Tissue Disease (Sharp syn.)
• MCTD is characterized by overlapping symptoms of three
autoimmune diseases: systemic sclerosis (SSc), systemic lupus
erythematosus (SLE), and polymyositis

• Epidemiology
• Peak onset during the fourth decade of life
• Female: male (3:1)

• Etiology: unknown
Clinical features:
• Course is usually milder than that of other connective tissue
diseases (CTD) but may progress into another CTD.
• Initial presentation: usually nonspecific symptoms (e.g., fatigue,
arthralgia, low-grade fever)
• Characteristic symptoms, usually manifesting over the course of
several years, include:
Raynaud phenomenon (∼ 90% of patients)
Polyarthralgia, arthritis
Acrosclerosis, synovitis, and overlapping features such as myositis
Gastroesophageal reflux disease (GERD)
• Less common symptoms include aseptic meningitis, hepatomegaly,
and splenomegaly.
Diagnosis
• Involves clinical examination,
patient history, and serological tests
• Patients are positive for ANAs and
anti-U1 RNP
• ANA patterns help determine the
type of immune disease.
• Generally, all ANAs have a speckled
pattern on immunofluorescence.
• In addition to speckled,
immunofluorescence patterns of ANA
tests can also be:
o Diffuse and peripheral in SLE
o Nucleolar in SSc
Treatment
• Low to moderate doses of corticosteroids (e.g., prednisolone) to treat
disease flares
• Immunosuppressants to prevent pulmonary hypertension
• Disease-modifying antirheumatic drugs for rheumatoid arthritis-like
polyarthritis
• Proton pump inhibitors for GERD
• Calcium channel blockers (CCBs) for Raynaud phenomenon
• Antimalarials to modify lupus-like disease

Complications: increased risk of pulmonary hypertension and interstitial lung

disease
Rheumatoid Arthritis (RA)
• Rheumatoid arthritis (RA) is a symmetric, inflammatory polyarthritis
and chronic, progressive, autoimmune disorder.
Epidemiology:
• More prevalent in:
• Native Americans
• North America
• Northern Europe
• 2–3 times more common in women
• Peak age of presentation is 30–50-years-old.
Risk factors
The cause of rheumatoid arthritis (RA) is unknown, but several risk factors play a role.

• Genetic predisposition:
• 2–3 times more likely in those with a 1st-degree relative with RA
• Associated with:
 HLA-DR1
 HLA-DR4
• Environmental factors:
• Lifestyle:
 Cigarette smoking
 Obesity
• Hormonal
• Infectious:
 Epstein-Barr virus (EBV)
 Parvovirus B19
 Hepatitis B and C
 Rubella
 Mycoplasma
Pathophysiology
• Not completely understood
• An external trigger sets off the autoimmune response and ↑ expression of enzymes that convert
arginine to citrulline → creation of antigens
• B cells produce antibodies to citrullinated proteins → bind to fibrinogen and collagen → complement
activation
• Synovium is infiltrated by immune cells (e.g., macrophages, mast cells, B cells, CD4 T cells) → cytokine
and chemokine production → synovial membrane thickening and villus formation
• Hyperplastic synovial tissue (pannus) releases:
o Collagenase
o Stromelysin
o Interleukins (IL)
o Tumor necrosis factor (TNF)-alpha
• Leads to:
o Continued synovial inflammation
o Cartilage destruction
o Osteoclasts-mediated bone destruction
Clinical Presentation
Articular manifestations o Hips
o Knees
• Symptoms: o Ankles
o Joint pain
o Joint swelling • Atlantoaxial subluxation can occur in 20%–
o Early morning stiffness ( > 1 hour) 50% of patients:
• Characteristics: o Neck and shoulder stiffness and pain
o Gradual onset o Radiculopathy
o Polyarticular
• Note: Distal interphalangeal (DIP) and
o Symmetric carpometacarpal (CMC) joints are typically
• Commonly affected joints: spared
o Wrists
o 2nd and 3rd metacarpophalangeal (MCP) joints
o Proximal interphalangeal (PIP) joints
o Metatarsophalangeal (MTP) joints
o Shoulders
Physical exam
• General:
o Synovitis:
 Joint tenderness
 Swelling
 Effusions may be noted in larger joints.
o Interosseous muscle atrophy
• Common lower extremity findings:
o Joint deformities o Restricted hip movement
o ↓ Range of motion o Baker's cyst:
 Caused by large knee effusions
 Cyst caused by entrapment of the synovium
• Common hand findings:
between articular structures.
o ↓ Grip strength  Swelling or fullness will be noted behind the
o Ulnar deviation of MCP joints knee.
o Boutonniere deformity:  Also seen in osteoarthritis, trauma, gout, and
 PIP flexion meniscal tears
 DIP hyperextension o Hammertoe: MTP joint hyperextension
o Swan neck deformity:
 PIP hyperextension
 DIP flexion
o Hitchhiker thumb ("Z" deformity):
 MCP flexion
 Interphalangeal joint (IP) hyperextension
Swan-neck deformity of the 5th finger in an Synovitis in RA:
individual with RA Presentation includes symmetric swelling and tenderness of
MCP joints, PIP joints, and wrists.
Physical exam findings in rheumatoid arthritis (RA):
An individual with RA with several classic deformities: ulnar
deviation (left hand) and boutonnière deformity (3rd, 4th, and
5th fingers of the right hand)
Extraarticular manifestations
• General:
o Fatigue
o Fever
o Weight loss
o Myalgias
• Cutaneous:
o Rheumatoid nodules:
Not painful
Seen on extensor surface of the elbow, heel, ischial tuberosities, and fingers
Can also occur in the viscera
o Skin ulcers
o Neutrophilic dermatosis:
Sterile neutrophil infiltration
Symmetric, erythematous papules
• Ocular:
o Sjögren syndrome (keratoconjunctivitis sicca)
o Episcleritis
o Uveitis
• Neurologic:
o Myelopathy and radiculopathy
o Mononeuritis multiplex or polyneuropathy
o Carpal tunnel syndrome
o Depression
• Respiratory:
o Interstitial lung disease
o Upper airway obstruction due to:
 Cricoarytenoid arthritis
 Rheumatoid nodules of the vocal cords
o Pleuritis
o Pleural effusion
o Pulmonary nodules
• Cardiac:
o Myocardial infarction
o Pericarditis
o Myocarditis
o Pericardial effusion
o Valvular insufficiency (from rheumatoid nodules)
o Conduction abnormalities (from rheumatoid nodules)
• Vascular:
o Vasculitis
o Peripheral vascular disease
o Deep vein thrombosis
• Hematologic:
o Felty syndrome:
 RA
 Neutropenia
 Splenomegaly
o Anemia of chronic disease
Rheumatoid nodules in RA:
Firm, non-tender, subcutaneous swelling on the extensor
surface of the elbow in a RA patient
Diagnosis
Rheumatoid arthritis (RA) diagnosis is based on high clinical suspicion and confirmed by serology and imaging.
 Laboratory testing
• General:
o Complete blood count (CBC):
 ↓ Hemoglobin → anemia of chronic disease
 ↑ Platelets
 Neutropenia → Felty syndrome
 Mild leukocytosis may be present.
o Inflammatory markers:
 ↑ Erythrocyte sedimentation rate (ESR)
 ↑ C-reactive protein (CRP)
 ↑ Ferritin
• Serology:
o Rheumatoid factor (RF):
 Present in 70%–80% of patients
 RF is present in 15% of patients without RA.
o Anti-cyclic citrullinated peptide (anti-CCP) antibodies: highly specific
o Antinuclear antibody (ANA):
 Nonspecific
 Positive in 30% of patients
• Synovial fluid analysis:
o Leukocytosis (5,000–50,000 cells/microliter) with neutrophil predominance
o ↓ Glucose
o
 Imaging

• Radiographs:
o May be normal in early disease
o Soft tissue swelling
o Periarticular osteopenia
o Bony erosion
o Joint-space narrowing
o Joint subluxation

• Ultrasonography:
o Erosion
o Joint-space narrowing
"Z" deformity shown in both thumbs and joint-space
o Synovitis narrowing/bony erosion noted in CMC, MCP, and PIP joints

• Magnetic resonance imaging (MRI):

o More sensitive than radiographs
o Detects erosion earlier
Management
• The goal is to prevent deformity and permanent damage. Patients should be referred to a rheumatologist.
Nonpharmacological therapies:
o Physical and occupational therapy
o Smoking cessation
Acute exacerbation management:
• Nonsteroidal antiinflammatory drugs (NSAIDs)
• Glucocorticoids:
o Can be used as a bridge to disease-modifying antirheumatic drug (DMARD) therapy or for acute flares
o Options: systemic or intraarticular injection
Long-term pharmacological therapy:
• DMARDs:
o Should be initiated in all patients upon diagnosis
o Methotrexate is usually the 1st choice.
o Additional options: sulfasalazine, hydroxychloroquine, azathioprine, leflunomide
• TNF-alpha inhibitors:
o May be added if DMARD therapy is not effective
o Options: etanercept, adalimumab, infliximab, golimumab, certolizumab
• Other biologic therapy options:
o IL-6 inhibitors (tocilizumab)
o CD20 monoclonal antibody (rituximab)
Surgery:
• Indicated for severe damage and limited function
• Can be considered if pharmacologic therapy is unsuccessful
• Options:
o Joint replacement
o Joint fusion
o Synovectomy
Additional considerations:
• While on glucocorticoid treatment, patients should be monitored for:
o Osteoporosis
o Diabetes
o Hypertension
• Appropriate vaccinations should be given to prevent infectious complications of immunosuppressive
medications.
• All patients should be screened for tuberculosis and hepatitis.
• Patients require ongoing laboratory monitoring for drug toxicity:
o CBC
o Liver function
o Creatinine
• Cervical spine imaging prior to surgical procedures:
o Evaluate for cervical subluxation (most often at the atlantoaxial joint).
o Intubation can be fatal in those with cervical instability.
Prognosis
• RA is a chronic, progressive disease:
o The majority of patients relapse.
o 10% will be severely disabled despite adequate management.
• Associated with an increased risk of:
o Cardiovascular disease
o Infection
o Respiratory disease
o Gastrointestinal bleeding
o Lymphoma (especially with Felty syndrome)
• 2–3 times higher risk of death than the general population
• Risk factors for a poor prognosis:
o Extraarticular manifestations Differential Diagnosis
o Advanced age • Osteoarthritis (OA)
o Women • Gout
o Caucasians • Pseudogout
o Early erosion on imaging • Psoriatic arthritis
o Cigarette smoking • Reactive arthritis
o High inflammatory markers and/or antibody titers
o ≥ 20 affected joints
Juvenile Idiopathic Arthritis (JIA)
• Juvenile idiopathic arthritis, formerly known as juvenile rheumatoid
arthritis, is a term used to describe a group of inflammatory
conditions of the joints affecting children younger than 16 and lasting
6 weeks or longer.
• Classification according to symptomatology (as per the International League of
Associations for Rheumatology):
Epidemiology
• Most common rheumatic disease in children
• Frequencies of different subtypes:
o Oligoarthritis: 50%–60%
o RF-negative polyarthritis: 11%–28%
o RF-positive polyarthritis: 2%–7%
o Systemic arthritis: 10%–20%
o Psoriatic arthritis: 2%–15%
o Enthesitis-related arthritis: 1%–7%

Prevalence varies secondary to disease and patient variables:

• Gender:
o Mostly predominant in girls (girl-to-boy ratio = 2:1–3:1)
o Systemic JIA girl-to-boy ratio = 1:1
o Enthesitis-related arthritis is predominant in boys.
• Geographical location:
o RF-negative polyarthritis is more common in North America.
o Oligoarthritis is more common in southern Europe.
o Systemic arthritis and enthesitis-related arthritis are more common in Southeast Asia.
• Age (note: by definition, onset must be before 16 years of age):
o 1–3 years of age: peak incidence of JIA (predominantly girls)
o 8–10 years of age: 2nd peak (smaller, and more boys with oligoarticular JIA)
o Mean age of onset for both systemic and polyarticular disease: approximately 6 years old
o Mean age of onset for oligoarticular disease: 4 years in girls and 10 years in boys
Etiology
• Idiopathic
• Immunological predisposition: different HLA associations
o Oligoarticular JIA: HLA-DR8, HLA-DR5
o Polyarticular JIA: HLA-DR4
o Enthesis associated and psoriatic JIA: HLA-B27
• Possibly triggered by a viral or bacterial infection
• Exposure to antibiotics during childhood may increase the risk of JIA.

Pathophysiology
Autoimmune and/or autoinflammatory disease → chronic synovial inflammation
with infiltration of plasma cells, B lymphocytes, and T lymphocytes → joint
capsule hyperplasia → growth of fibrovascular connective tissue (pannus) →
invasion of the articular surface → loss of joint function
Clinical features
• Arthritic symptoms
o Swollen joints, rarely erythema
o Early morning stiffness
o Limited or painful joint movement
• Extra-articular manifestations
o Fever (for ≥ 2 weeks)
o Uveitis
o Rash
o Nail changes
o Lymphadenopathy
o Hepatosplenomegaly
• Nonspecific features
o Excessive crying
o Lethargy
o Decreased scholastic performance
o Growing pains
Widespread joint involvement in polyarticular juvenile
idiopathic arthritis

Typical rash in systemic juvenile idiopathic arthritis

Diagnostics
 Laboratory tests
Blood tests are used to classify JIA, assess the prognosis, and rule out other similar conditions.
Autoantibodies levels
• Rheumatoid factor (RF)
o Absent in most cases of JIA (except seropositive polyarticular JIA)
o Associated with poor prognosis
• ↑ ANA
o Most commonly associated with oligoarticular JIA ( ∼ 70%)
o Incidence of anterior uveitis increases when antinuclear antibodies (ANA) are present.
• Anti-CCP antibodies: indicate a poor prognosis
Acute phase reactants
• ↑ ESR: usually seen with all forms of JIA
• ↑ CRP, ferritin: usually associated with systemic JIA
CBC
• Anemia
• Leukocytosis
• Thrombocytosis: denotes a more severe inflammatory response in polyarticular and systemic
JIA
 Imaging tests
Ultrasound
• Used to detect synovial hypertrophy and intraarticular fluid collections
• Best imagistic tool for the detection of early bone erosions
X-ray
• May be used for the identification of JIA complications
• Should not be performed routinely

 Other diagnostic tests

Synovial biopsy
• Can provide a definitive diagnosis of JIA
• Shows infiltration of plasma cells, B lymphocytes, and T lymphocytes
• Slit lamp examination: should be performed for regular ophthalmological screening in patients with anterior
uveitis
• Slit lamp examination
o Patients with a high risk of developing anterior uveitis (ANA positive, age of onset ≤ 7 years, and disease duration ≤ 4 years)
should undergo ophthalmic screening every 3 months.
o All other patients should undergo ophthalmic screening every 12 months.
o Patients with anterior uveitis should be monitored every 1–3 months, depending on the choice of therapy and response to
The differential diagnosis of JIA includes other causes of
nonsuppurative arthritis in children:
• Acute lymphocytic leukemia
• Reactive arthritis
• Acute rheumatic fever
• Juvenile ankylosing spondylitis
• Connective tissue disease (e.g., SLE, Sjögren syndrome)
• Trauma
• Hemophilia
Treatment
References
• https://en.wikipedia.org/wiki/Mixed_connective_tissue_disease
• https://app.lecturio.com/#/article/2736
• https://next.amboss.com/us/article/-f0DK2?q=rheumatoid+arthritis#
Z0bdeffd118af8bb1971e0d4ae4d7881e
• https://next.amboss.com/us/article/w40hlT