2. Rheumatoid arthritis.
De nition: Rheumatoid arthritis (RA) is an in ammatory autoimmune disorder characterized by
joint pain, swelling, and synovial destruction. RA predominantly a ects middle-aged women. The
condition can also cause various extra-articular manifestations such as rheumatoid nodules and
pulmonary brosis.
Etiology:
- chronic in ammatory autoimmune disorders or unknown origin
- hypotheses suggest the etiology is multifactorial, with the following factors playing a role
- genetic predisposition: RA appears to be associated with speci c HLA types
- environmental triggers ( e.g. infection, tobacco)
- hormonal factors
Pathophysiology:
- Initially, non-speci c in ammation a ects the synovial tissue, which is later ampli ed by
activation of T cells (autoimmune response).
- With time, it may lead to in ammatory joint e usion and synovial hypertrophy, as well as
progressive destruction and deterioration of cartilage and bone.
- Synovial lining hyperplasia
- Pannus formation along the synovial tissue → produce proteinases → destroy cartilage
extracellular matrix
- Patients with positive rheumatoid factor (RF) are more likely to develop extra-articular
manifestations of rheumatoid arthritis.
Clinical features:
Articular manifestations
- Polyarthralgia
- Symmetrical pain and swelling of a ected joints (also at rest).
- Frequently a ected joints
- Metacarpophalangeal joints (MCPJs)
- Proximal interphalangeal joints (PIPJs)
- Wrist joints
- Knee joints
- Joints of the axial skeleton are usually spared except for the cervical spine (see RA of the
cervical spine)
- Morning sti ness > 30 min; often improves with activity
- Joint deformities
- "Rheumatoid hand" is characteristic, and can include the following deformities:
- Deepening of the interosseous spaces of the dorsum of hand
- Swan neck deformity: PIP hyperextension and DIP exion
- Boutonniere deformity: PIP exion and DIP hyperextension.
- Hitchhiker thumb deformity (Z deformity of the thumb): hyperextension of the
interphalangeal joint with xed exion of the MCP joint
- Ulnar deviation of the ngers
- Hammer toe
- Atlanto-axial subluxation
Extra- articular manifestations
- Constitutional symptoms: low-grade fever, myalgia, malaise, night sweats
- Skin: rheumatoid nodules (common); non-tender, rm, subcutaneous swellings (2 mm–5 cm)
- Lungs: brosis, nodules, pleuritis, and pleural e usions
- Eye: keratoconjunctivitis sicca, scleritis, and episcleritis
- Endocrine and exocrine glands: secondary Sjögren syndrome
- Hematological: anemia of chronic disease
- Other musculoskeletal
- Tenosynovitis and bursitis
- Carpal tunnel syndrome (entrapment neuropathy)
- Typical nocturnal paresthesia of volar hand and ngers I–III
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, - Atrophy of thenar muscles → di culty making a st; inability to oppose the thumb
- Tarsal tunnel syndrome
- Heart: pericarditis and myocarditis; higher risk of myocardial infarction, stroke, and CHF
- Vascular: peripheral vasculitis manifesting as livedo reticularis, Raynaud phenomenon, purpura,
necrosing ngertips or peripheral neuropathy
Diagnosis:
- lab
- non speci c parameters
- ↑ In ammatory markers: CRP, ESR correlate with in ammatory activity.
- ↑ Ferritin as an acute phase protein
- Possibly leukocytosis, thrombocytosis
- anemia of chronic disease
- serology ( speci c parameters)
- ACPA
- rheumatoid factor
- IgM autoantibodies against the Fc region of IgG
- low speci city
- ANA ( elevated in 30%)
- synovial uid analysis
- collected by joint aspiration
- Cloudy yellow appearance
- Sterile specimen with leukocytosis (WBC: 5,000–50,000/μL)
- ↑ Neutrophils, granulocytes, and ragocytes
- ↑ Proteins, ↓ viscosity
- Possibly rheumatoid factor
- imaging: can be normal
- conventional x- ray
- Dorso-palmar x-ray of both hands
- Radiological ndings
- Early: soft tissue swelling, demineralization (juxta‑articular)
- Late: joint space narrowing, erosions of cartilage and bone, demineralization
(generalized)
- MRI: with or without contrast), especially if cervical spine involvement is suspected or in
early stages
- US: joint e usion; formation of panes
- Further: contrast- enhanced US; scintigraphy
DD:
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, Treatment:
General measures
- For acute episodes of in ammation: cryotherapy
- Physical and occupational therapy
- Physical activity
Acute anti-in ammatory therapy
- Indication: acute attack
- Glucocorticoids: given until DMARD's onset of action or as long-term therapy for highly active
RA.
- Systemic
- Intra-articular injections of PRN
- Prevention of osteoporosis: optimization of su cient calcium and vitamin D intake
- NSAIDs and COX-2 inhibitors: symptomatic relief without improving prognosis
- PPIs are recommended because combining glucocorticoids with NSAIDs substantially
increases the risk of GI ulcers.
Long-term anti-in ammatory therapy with disease-modifying antirheumatic drugs (DMARDs)
- Induce immunosuppression, leading to potential remission of RA
- Reduce mortality and morbidity by up to 30%
- Slow progression of disease
- Preserve joint function
- Limit complications
- Slow onset of action (≥ 6 weeks), so symptomatic treatment with glucocorticoids and NSAIDs
is often required
- Non-biologic agents
- Drug of choice: methotrexate (MTX)
- First-line treatment for moderate to severe RA
- Bene ts: highly e ective, relatively well-tolerated, low cost, possibly life-prolonging
- Gastrointestinal side e ects , rash, hepatotoxicity (abnormal liver chemistry), interstitial
pneumonitis and pulmonary brosis, bone marrow suppression , nephrotoxicity, increased
risk of lymphoproliferative disorders, teratogenicity, alopecia [34]
- To minimize side e ects, folic acid is recommended 24–48 hours after taking MTX.
- Do not give NSAIDs on the same day as MTX, as they can worsen the side e ects of MTX
by inhibiting its renal excretion .
- Alternative drugs
- Le unomide
- Hydroxychloroquine
- Sulfasalazine: for use in pregnancy
- Biologic therapy
- Indication: moderate or severe disease activity remaining after three months of DMARD
therapy
- Should be combined with non-biologic DMARDs
- Tumor necrosis factor (TNF) α inhibitors: e.g., adalimumab, in iximab, etanercept
- See contraindications to anti-TNF-α treatment.
- Others: rituximab (anti-CD20) and anakinra (interleukin-1 receptor antagonist, particularly for
Still disease)
Complications:
- upper limb: deformities
- lower: baker cyst; foot impairment
- other: muscle weakness, lung disease, CV disease, vasculitis, amyloidosis, septic arthirits,
osteopenia, osteoporosis, fractures, sjörgen syndrome ( 2ndary form)
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, 3. Ankylosing spondylitis.
De nition/ etiology: Ankylosing spondylitis (spondyloarthritis) is a chronic in ammatory disease of
the axial skeleton that leads to partial or even complete fusion and rigidity of the spine. Males are
disproportionately a ected and upwards of 90% of patients are positive for the HLA-B27
genotype, which predisposes to the disease.
Clinical features:
1) Articular symptoms
- Most common presenting symptoms: back and neck pain
- Gradual onset of dull pain that progresses slowly
- Morning sti ness that improves with activity
- Pain is independent of positioning, also appears at night
- Tenderness over the sacroiliac joints
- Limited mobility of the spine (especially reduced forward lumbar exion)
- In ammatory enthesitis (e.g., of the Achilles tendon, iliac crests, tibial tuberosities): painful on
palpation
- Dactylitis
- Arthritis outside the spine: hip, shoulder, and knee joint
2) Extra- articular manifestations
- Most common: acute, unilateral anterior uveitis (∼ 25% of cases)
- Gastrointestinal symptoms: associated with chronic in ammatory bowel disease (∼ 5–10% of
cases, see also: colitis ulcerosa or Crohn's disease)
- Prostatitis
- Fatigue, weakness, fever, weight loss
- Restrictive pulmonary disease due to decreased mobility of the spine and thorax
- Rare
- Cardiac: aortic valve insu ciency, atrioventricular blocks
- Kidney: IgA-nephropathy
Diagnostics:
- diagnostic approach
- Physical examination, patient history, and pelvic x-ray: If results are conclusive, no additional
testing is required!
- If inconclusive → HLA-B27 testing
- If still inconclusive → pelvic MRI
- clinical tests
- Chest expansion measurement: in full expiration and inspiration
- Pathological di erence: < 2 cm
- Physiological di erence: > 5 cm
- Spine mobility tests
- Examination of the hip[3]
- Mennell sign: tenderness to percussion and pain on displacement of the sacroiliac joints
- FABER test: FABER (Flexion, ABduction, and External Rotation) provokes pain in the
ipsilateral hip
- imaging
- x- ray
- Can help con rm a diagnosis or evaluate the severity of disease, but is not required for the
diagnosis
- Changes are generally more evident in later disease
- Sacroiliac joints: signs of sacroiliitis, including ankylosis of sacroiliac joints
- Spine
- Loss of lordosis with increasing abnormal straightening of the spine
- Sclerosis of the vertebral ligamentous apparatus
- Syndesmophytes resulting in a so-called 'bamboo spine' in anteroposterior radiograph
in the later stages (see the table in “Di erential diagnosis” below)
- Signs of spondyloarthritis, including ankylosis of intervertebral joints
- MRI: more sensitive than CT scan for detecting sacroiliitis; best methods for early detection
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ff fi ffff ff ffi ff fl fl fl
De nition: Rheumatoid arthritis (RA) is an in ammatory autoimmune disorder characterized by
joint pain, swelling, and synovial destruction. RA predominantly a ects middle-aged women. The
condition can also cause various extra-articular manifestations such as rheumatoid nodules and
pulmonary brosis.
Etiology:
- chronic in ammatory autoimmune disorders or unknown origin
- hypotheses suggest the etiology is multifactorial, with the following factors playing a role
- genetic predisposition: RA appears to be associated with speci c HLA types
- environmental triggers ( e.g. infection, tobacco)
- hormonal factors
Pathophysiology:
- Initially, non-speci c in ammation a ects the synovial tissue, which is later ampli ed by
activation of T cells (autoimmune response).
- With time, it may lead to in ammatory joint e usion and synovial hypertrophy, as well as
progressive destruction and deterioration of cartilage and bone.
- Synovial lining hyperplasia
- Pannus formation along the synovial tissue → produce proteinases → destroy cartilage
extracellular matrix
- Patients with positive rheumatoid factor (RF) are more likely to develop extra-articular
manifestations of rheumatoid arthritis.
Clinical features:
Articular manifestations
- Polyarthralgia
- Symmetrical pain and swelling of a ected joints (also at rest).
- Frequently a ected joints
- Metacarpophalangeal joints (MCPJs)
- Proximal interphalangeal joints (PIPJs)
- Wrist joints
- Knee joints
- Joints of the axial skeleton are usually spared except for the cervical spine (see RA of the
cervical spine)
- Morning sti ness > 30 min; often improves with activity
- Joint deformities
- "Rheumatoid hand" is characteristic, and can include the following deformities:
- Deepening of the interosseous spaces of the dorsum of hand
- Swan neck deformity: PIP hyperextension and DIP exion
- Boutonniere deformity: PIP exion and DIP hyperextension.
- Hitchhiker thumb deformity (Z deformity of the thumb): hyperextension of the
interphalangeal joint with xed exion of the MCP joint
- Ulnar deviation of the ngers
- Hammer toe
- Atlanto-axial subluxation
Extra- articular manifestations
- Constitutional symptoms: low-grade fever, myalgia, malaise, night sweats
- Skin: rheumatoid nodules (common); non-tender, rm, subcutaneous swellings (2 mm–5 cm)
- Lungs: brosis, nodules, pleuritis, and pleural e usions
- Eye: keratoconjunctivitis sicca, scleritis, and episcleritis
- Endocrine and exocrine glands: secondary Sjögren syndrome
- Hematological: anemia of chronic disease
- Other musculoskeletal
- Tenosynovitis and bursitis
- Carpal tunnel syndrome (entrapment neuropathy)
- Typical nocturnal paresthesia of volar hand and ngers I–III
fi fi fl fiffff fi fifl fiflfl fl ffff flff fffi fi fl fi ff fi
, - Atrophy of thenar muscles → di culty making a st; inability to oppose the thumb
- Tarsal tunnel syndrome
- Heart: pericarditis and myocarditis; higher risk of myocardial infarction, stroke, and CHF
- Vascular: peripheral vasculitis manifesting as livedo reticularis, Raynaud phenomenon, purpura,
necrosing ngertips or peripheral neuropathy
Diagnosis:
- lab
- non speci c parameters
- ↑ In ammatory markers: CRP, ESR correlate with in ammatory activity.
- ↑ Ferritin as an acute phase protein
- Possibly leukocytosis, thrombocytosis
- anemia of chronic disease
- serology ( speci c parameters)
- ACPA
- rheumatoid factor
- IgM autoantibodies against the Fc region of IgG
- low speci city
- ANA ( elevated in 30%)
- synovial uid analysis
- collected by joint aspiration
- Cloudy yellow appearance
- Sterile specimen with leukocytosis (WBC: 5,000–50,000/μL)
- ↑ Neutrophils, granulocytes, and ragocytes
- ↑ Proteins, ↓ viscosity
- Possibly rheumatoid factor
- imaging: can be normal
- conventional x- ray
- Dorso-palmar x-ray of both hands
- Radiological ndings
- Early: soft tissue swelling, demineralization (juxta‑articular)
- Late: joint space narrowing, erosions of cartilage and bone, demineralization
(generalized)
- MRI: with or without contrast), especially if cervical spine involvement is suspected or in
early stages
- US: joint e usion; formation of panes
- Further: contrast- enhanced US; scintigraphy
DD:
fl flfififf
fi fi fi ffi fi fl
, Treatment:
General measures
- For acute episodes of in ammation: cryotherapy
- Physical and occupational therapy
- Physical activity
Acute anti-in ammatory therapy
- Indication: acute attack
- Glucocorticoids: given until DMARD's onset of action or as long-term therapy for highly active
RA.
- Systemic
- Intra-articular injections of PRN
- Prevention of osteoporosis: optimization of su cient calcium and vitamin D intake
- NSAIDs and COX-2 inhibitors: symptomatic relief without improving prognosis
- PPIs are recommended because combining glucocorticoids with NSAIDs substantially
increases the risk of GI ulcers.
Long-term anti-in ammatory therapy with disease-modifying antirheumatic drugs (DMARDs)
- Induce immunosuppression, leading to potential remission of RA
- Reduce mortality and morbidity by up to 30%
- Slow progression of disease
- Preserve joint function
- Limit complications
- Slow onset of action (≥ 6 weeks), so symptomatic treatment with glucocorticoids and NSAIDs
is often required
- Non-biologic agents
- Drug of choice: methotrexate (MTX)
- First-line treatment for moderate to severe RA
- Bene ts: highly e ective, relatively well-tolerated, low cost, possibly life-prolonging
- Gastrointestinal side e ects , rash, hepatotoxicity (abnormal liver chemistry), interstitial
pneumonitis and pulmonary brosis, bone marrow suppression , nephrotoxicity, increased
risk of lymphoproliferative disorders, teratogenicity, alopecia [34]
- To minimize side e ects, folic acid is recommended 24–48 hours after taking MTX.
- Do not give NSAIDs on the same day as MTX, as they can worsen the side e ects of MTX
by inhibiting its renal excretion .
- Alternative drugs
- Le unomide
- Hydroxychloroquine
- Sulfasalazine: for use in pregnancy
- Biologic therapy
- Indication: moderate or severe disease activity remaining after three months of DMARD
therapy
- Should be combined with non-biologic DMARDs
- Tumor necrosis factor (TNF) α inhibitors: e.g., adalimumab, in iximab, etanercept
- See contraindications to anti-TNF-α treatment.
- Others: rituximab (anti-CD20) and anakinra (interleukin-1 receptor antagonist, particularly for
Still disease)
Complications:
- upper limb: deformities
- lower: baker cyst; foot impairment
- other: muscle weakness, lung disease, CV disease, vasculitis, amyloidosis, septic arthirits,
osteopenia, osteoporosis, fractures, sjörgen syndrome ( 2ndary form)
fl fi fl ffflff ff fl fi ffi fl ff
, 3. Ankylosing spondylitis.
De nition/ etiology: Ankylosing spondylitis (spondyloarthritis) is a chronic in ammatory disease of
the axial skeleton that leads to partial or even complete fusion and rigidity of the spine. Males are
disproportionately a ected and upwards of 90% of patients are positive for the HLA-B27
genotype, which predisposes to the disease.
Clinical features:
1) Articular symptoms
- Most common presenting symptoms: back and neck pain
- Gradual onset of dull pain that progresses slowly
- Morning sti ness that improves with activity
- Pain is independent of positioning, also appears at night
- Tenderness over the sacroiliac joints
- Limited mobility of the spine (especially reduced forward lumbar exion)
- In ammatory enthesitis (e.g., of the Achilles tendon, iliac crests, tibial tuberosities): painful on
palpation
- Dactylitis
- Arthritis outside the spine: hip, shoulder, and knee joint
2) Extra- articular manifestations
- Most common: acute, unilateral anterior uveitis (∼ 25% of cases)
- Gastrointestinal symptoms: associated with chronic in ammatory bowel disease (∼ 5–10% of
cases, see also: colitis ulcerosa or Crohn's disease)
- Prostatitis
- Fatigue, weakness, fever, weight loss
- Restrictive pulmonary disease due to decreased mobility of the spine and thorax
- Rare
- Cardiac: aortic valve insu ciency, atrioventricular blocks
- Kidney: IgA-nephropathy
Diagnostics:
- diagnostic approach
- Physical examination, patient history, and pelvic x-ray: If results are conclusive, no additional
testing is required!
- If inconclusive → HLA-B27 testing
- If still inconclusive → pelvic MRI
- clinical tests
- Chest expansion measurement: in full expiration and inspiration
- Pathological di erence: < 2 cm
- Physiological di erence: > 5 cm
- Spine mobility tests
- Examination of the hip[3]
- Mennell sign: tenderness to percussion and pain on displacement of the sacroiliac joints
- FABER test: FABER (Flexion, ABduction, and External Rotation) provokes pain in the
ipsilateral hip
- imaging
- x- ray
- Can help con rm a diagnosis or evaluate the severity of disease, but is not required for the
diagnosis
- Changes are generally more evident in later disease
- Sacroiliac joints: signs of sacroiliitis, including ankylosis of sacroiliac joints
- Spine
- Loss of lordosis with increasing abnormal straightening of the spine
- Sclerosis of the vertebral ligamentous apparatus
- Syndesmophytes resulting in a so-called 'bamboo spine' in anteroposterior radiograph
in the later stages (see the table in “Di erential diagnosis” below)
- Signs of spondyloarthritis, including ankylosis of intervertebral joints
- MRI: more sensitive than CT scan for detecting sacroiliitis; best methods for early detection
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