Musculoskeletal Flashcards
Valgus
knock-kneed (2-5 degrees at baseline in normal knees)
Varus
Bow-legged
Patella baja
Abnormally low-lying patella
Patella alta
Abnormally high patella
Infrapatellar bursitis
“Roofer’s knees”
- Seen in someone on knees repeatedly
- Often bilateral (vs suprapatellar)
Knee movement: extension
Quadriceps muscle
L4 (Femoral nerve)
To -5 degrees
Knee movement: flexion
Four flexors, including hamstrings
Sciatic nerve L5-S1
To 130 degrees
Baker’s cyst
Extra-articular swelling mass with transillumination
Popliteal artery aneurysm
Pulsatile mass, nontransilluminable on auscultation
- Bruit
5 Features of ACL tear and assessment
- Acute pain
- Severe swelling
- Audible pop
- Inability to walk
- Clenched fist upon manipulation of knee
- Severe tear may show anterior sag of tibia
Assess for:
- Effusion
- Foot pulses
- Great toe extension= Deep peroneal nerve
- Great toe flexion= Tibial nerve
- Sensation on top of foot= deep peroneal
- Sensation on bottom of foot= tibial nerve
Lachman’s maneuver
To assess for ACL tear
- 80-85% sensitive
Knee stabilized at 25 degrees flexion
Tibia subluxed > 5 mm anteriorly on femur
Anterior drawer maneuver
To assess for ACL tear
- 40% sensitive
Knee stabilized at 90 degrees
Knee subluxed > 5mm anteriorly on femur
Passive crank maneuver
Stabilize humerus, upper extremity in “handshake”
- Palpate head of humerus
- Note pain or limitation of movement
1. Passively internally rotate to 30 degrees
2. “” external
3. “” abduct humerus
Auenbrugger’s maneuver
Auscultatory percurssion
- Stethoscope over AC joint, tap on olecranon
- Diminished sound= discontinuous structures (fractured humerus or scapula)
Abduction of humerus
170 degrees
- Baseline to 100 degrees intrinsic
- 100 to 170 degrees extrinsic
Apley scratch test
Infraspinatus: brush hair
Subscapularis: unhook bra
Yergason’s maneuver
Patient in neutral handshake position
- Examiner inspects anterior shoulder
- Patient supinates forearm, flex elbow against resistance
- Pain at bicipetal groove= bicipetal tendonitis
Elbow passive ROM
Passively flex to 130
asdf
Elbow active ROM
Active flexion= biceps brachiii C5 musculocutaneous
Active extension= trceps C7and radial nerve
Active pronation: pronator teres
Active supination: musculocutaneous
Medial epicondylitis
Pain with active flexion, pronation
Pronator syndrome
Pain, tingling on palm of forearm to digits 1, 2, 3
Postive Tinel’s test
- Entrapment of proximal medial and branch of anterior interosseous nerve
Cubital tunnel syndrome
Pain and tingling of ulnar forearm, hand
- Positive Tinel’s test
Severe:
- Weakness to finger 2-5 abduction/adduciton
- Weakness in flexion of digits 4, 5 when making a fist
- Atrophy of intraosseous muscles
Olecranon bursitis
Serous= cool, non-erythematous, fluctuant mass
- Transilluminable
- “Student’s elbow
Infected olecranon bursitis
- Fluctant warm, red, tender, non-transilluminable mass
Tophi= 1+ firm, nontender, gritty nodules
- Yellow-colored papules
Rheumatoid nodules
- Subcutaneous, firm nodules
- Aponeurosis of triceps muscle`
Radial tunnel syndrome
Pain and tingling of dorsal side of forearm–> digits 1, 2, 3 + anatomic snuffbox
- Positive Tinel’s over radial tunnel
- No motor deficits
Vs Radial head fracture=
- pain in lateral elbow to snuffbox with a “Squeeze sign” (pain on lateral, antecubital elbow)
- decrease in passive/active supination and pronation
Rheumatology
Incorporates Inflammatory states: - Autoimmune (RA, SLE, Vasculitides) - Autoinflammatory (Gout, Juvenile RA, TRAPS, FMF) Non-inflammatory musculoskeletal states: - Degenerative disease (osteoarthritis)
Autoimmune disease
Inflammatory state
= Immune system response against “self” antigens
- Characterized by B and T lymphocyte activation and autoantibody production
- Selection in Thymus destroys “self” reactive T-cells (needs low affinity for thymus cells to survive)
Innate system:
1. Antigen-presenting cells:
- Phagocytes, NK-cells, dendritic cells, epithelial surfaces, non-antibody molecules (activated cells)
- B cells (adaptive) and T cells (adaptive)
Antigen-presenting cells
- Express Toll-like receptors (TLR) in their surface
- Internalizes and presents antigens
- Secrete co-stimulatory molecules (CD80, CD86)
- Secrete cytokines: regulate process
B cells
- B cells also recognize antigens via surface receptors
- Antigens are internalized and processed into peptide fragments
- Fragments bind to MHC molecules (B cells are also APC) and are
- Recognized by T cells
- T cells become activated
T cells
- T cells mature in the thymus
- T cell activation requires recognition of MHC+peptide (signal 1) and
- Co-stimulation (signal 2). Ex CD28 (APC) by CD80/86 (T cells) or CD40 (APC) by CD40L (T cells)
- In the absence of signal 2, T cells undergo apoptotic death
T-cell types and stimulating interleukins: 1. APC presents native T cell with: Th-1: IL-12, IL-18 Th-2: IL-4 Th-17: IL-6, TGF-beta Treg: Il-2, TGH beta 2. Nucelated cell presents native T-cell: Forms Cytotoxic T-cell
T-cell goes to Thymus:
- Positive selection= low affinity for “self”
- Negative selection= high affinity for “self”–> destroyed in Thymus
Autoreactive T cells in periphery
May escape negative selection Inactivated in periphery by: - Immune ignorance (hidden in body in eye, brain, testes--> won't react) - Anergy - Suppression by regulatory T cells
Autoreactive B cells
Produce antibodies that recognize self antigens
Autoantibodies are randomly generated during B cell development
Mechanisms to prevent self-reactive B cells from maturing:
- clonal deletion (delete autoreactive B cell clones)
- anergy
- editing (rearrangement of B-cell receptor–> no longer self-reactive)
- apoptosis
Mechanisms inducing defects in “self” tolerance
- Immunization with self-antigens in presence of adaptive immune system stimulants (adjuvants)
- Etiology: Genetics, sex/sex hormones, environmental triggers
See:
- self-antigen recognition by lymphocytes
- autoantibody production
- tissue damage
Genetic predisposition to autoimmune disease
Studies of familial concordance for SLE and RA:
- 25-40% identical twin concordance for SLE or RA
- Inherited deficiencies of HLA class III genes encoding for C1q, C2 and C4A and C4B (1-2% of patients with SLE )
- Spontaneous polymorphisms of HLA class II genes (HLA DR2 and HLA DR3 among others) in SLE or association of HLA-DR genes with RA
- Mutations in non-HLA genes ( ex FCGR2A, FCGR3A, IRF5 association with SLE, or PTPN22 association with SLE and RA)
Sex/sex hormone effects on autoimmunity
Strong female predominance in SLE (F:M 9:1 ratio) due to:
- Dose effect of X chromosome: 2 X chromosomes confer higher risk than 1 X, independently of sex hormones
- Hormone (estrogen and prolactin) effect on survival and activation of T and B lymphocytes antigen presentation and autoantibody production
Environmental effects on autoimmunity
Examples of environmental triggers:
- UV exposure can cause disease exacerbation
- Medications can cause SLE-like syndrome
- Silica can cause Scleroderma-like disease
- DNA or RNA viruses can activate the immune system, however there is no clear association with specific autoimmune disease
- Smoking, viral and bacterial (P gingivalis) effect in RA
Molecular mimcry
B-cells cross-react against foreign and self-antigens
- Escape tolerance (allowed to survive)
- Stimulated by foreign antigen, become hyperactive against self-antigen
Example: Rheumatic heart disease:
- Antibodies to M protein of Group A strep cross-react with cardiac myosin
Effector mechanisms of autoimmune disease
Antibody-mediated:
- Injury from anti-tissue antibody
- Leads to tissue injury - Injury from immune complex deposition
Cell-mediated tissue damage:
1. Central and peripheral T-cell tolerance defects
- Cytokines released by T cells:
- Th1–> IFN-gamma–> cell-mediated immune responses
- Th2–> IL-4–> B-cell class-switching, Ig produciton
- Th17–> IL-17–> recruit neutrophils, macrophages to infected tissues
- Treg–> IL-10, TGF-beta–> regulate autoreactive cells, inhibit Th1 responses - RNA (virus)–> activates TLR7 on dendritic cells:
- IFN-alpha released:
- Promotes autoreactive T-cell survival; promotes B cell differentiation, plasma cell production; activates more dendritic cells (increased responsiveness to nucleic acids)
Actinomyces in oral cavity
Saprophitic, gram positive anaerobic bacteria
- Part of normal flora
- Colonize tonsillar reypts, dental plaque, ginigval sulci
- Acute form= painful abscesses
- Chronic form= granulomatous inflammation, abscesses that drain by fistula formation
Ameloblastoma
Tumor arises from enamel organ or progenitor cell lines
- Develop soft tissue components of odontogenic epithelial
- Benign, slow-growing, locally inasive
- Arise in mandibular ramus, maxilla, floor of nasal cavity
Histo:
- Islands of proliferating odontogenic epithelium reminiscent of enamel organ
- Basophilic columnar cells at periphery with reverse polarization (nuclei away from basement tissue)
- Edematomous cells in nests or cords
Treatment:
- Wide surgical ressection
- Long-term follow up due to 25-55% recurrence rate
Salivary gland benign neoplasm: Pleomorphic adenoma (benign mixed tumor)
- MOST COMMON salivary glands neoplasm
- Most commonly in the PAROTID followed by minor salivary glands
- Wide age at presentation
- PAINLESS, slowly growing mass, mobile
- Paresthesia due to nerve compression - rare
Histo:
- Well-circumscribed, variably encapsulated mass
- Multinodular (esp. in recurrent disease)
- Composed of three cell types:
1. Epithelial glandular ductal structures
2. Myoepithelial cells
3. Mesenchymal stroma: myxoid, chondroid, hyalinized, osseous
Treatment:
- Surgical excision
- Recurrence rate: 45% after simple enucleation (due to lack of encapsulation or incomplete removal)
- Recurrence rate: 2.5 % with superficial or total parotidectomy
- Malignant transformation – in 2-7%
Warthin’s tumor
- Second most common benign salivary gland tumor
- Characteristically presents in the parotid
- Bilaterality or multifocality occurs more frequently than any other tumor, and it is synchronously identified with other tumors more than any other tumor type
Histo:
- Circumscribed, solid/cystic. Cysts may contain yellow-brown fluid.
- Papillary fronds and cystic spaces lined by double layered oncocytic epithelium
- Dense lymphoid node-like stroma intimately associated with the epithelial component
Treatment:
- Surgical excision
- 4-25% recurrence due to multifocality or incomplete excision
Mucocele (salivary gland)
The most common non-neoplastic lesion of salivary glands
- “Pooling of mucin in a cystic cavity”
Types:
- Retention type – mucin pooling confined within a dilated excretory duct
- Extravasation type – escape of mucin from the duct system into connective tissue – most common type
Seen in: lower lip, tongue, floor of mouth, palate
Presentation: soft, fluctuant semitranslucent painless swelling that may occur after a traumatic event
Treatment - complete excision, including minor salivary gland
Sialolithiasis (salivary gland)
Collection of concretions which form a stone within the salivary gland excretory duct system (stone in duct)
- Most common involves the submandibular gland (Wharton’s duct) and may cause a chronic sialadenitis distal to the stone.
- Always visible on radiographic examination
- Nidus of cellular debris in the center of concentric laminated calcium deposits
Sjogren Syndrome of salivary gland
Describes a characteristic lymphocytic infiltrate in salivary glands; doesn’t commit to an etiologic cause but describes histologic findings
Most cases – women in the 4th and 5th decades
- Associated with or is a precursor of Sjogren’s syndrome
Two types:
- Systemic: collagen vascular disease
- Localized to salivary and lacrimal glands
Pathology:
- Uni or bilateral enlargment of parotid glands with preserved lobulation
Histo:
- Periductal chronic inflammation extending into acini
- Glands replaced by polyclonal lymphocytes, germinal centers, plasma cells
- Lesion= lymphoepithelial sialadenitis (epimyoepithelial islands)
- Similar changes present in minor salivary glands in Sjogren syndrome (biopsy smaller glands first)- need clinical diagnosis and serologic specimen to confirm dx
Sinusitis
- Acute:
- Haemophilus, Branchamella - Allergic:
- Hypersensitivity reaction to fungal antigens (atopic patients), aspergillus - Fungus ball (mycetoma, aspergilloma)
- Sinuses with poor drainage; fungi proliferate and form dense mass of hyphae
- DO NOT invade mucosa/vessels - Invasive fungal sinusitis
- Seen in immunosuppressed patients
- Fungi invade sinus mucosa, vessels
- Can spread to venous sinuses, meninges, brain
- High mortality
- Mucormycosis: common in diabetic patients; can involve skin, bone, orbit, brain
Schneiderian Papilloma
Benign sinus papilloma
- Schneiderian membrane: the ciliated columnar epithelium of ectodermal origin that lines the nasal cavity (except the nasal vestibule and the superior wall of the nasal cavity)
- Papillomas derived from the schneiderian membrane:
1. Inverted (endophytic)- most common
2. Exophytic
3. Columnar cell (oncocytic)
Inverted Papilloma
Location: lateral nasal wall, middle meatus, paranasal sinuses, rarely in the nasopharynx or middle ear
Clinical presentation: nasal obstruction, epistaxis, rhinorrhea, facial pressure
CT, MRI – unilateral polypoid mass filling the nasal cavity, +/- displacement of nasal septum and opacification of sinuses
Histo:
- Markedly thick , inverted neoplastic proliferation replacing mucoserous glands and ducts
- Transitional/squamoid epithelium with numerous intraepithelial microcysts containing cellular debris
- Stroma: edematous, myxomatous, fibrous. No seromucinous glands in the stroma
Prognosis:
- Recurrence: up to 60% of cases (depending on type of surgery)
- Malignant transformation (squamous cell carcinoma): in 10% of cases
Nasopharyngeal angiofibroma
- Benign, highly cellular and richly vascularized mesenchymal neoplasms that arise in the roof of the nasopharynx
- Exclusively in YOUNG MALES (mean age 15yo)
- There is an association with FAP
Presentation:
- Nasal obstruction, spontaneous epistaxis, nasal drainage
- Endoscopy – mass involving the posterior nasal wall
Treatment:
- Preop angiography – identifies the feeding vessel and allows for presurgical embolization (reduces risk of surgical hemorrhage
Histo:
- Round, nodular nonencapsulated masses with a sessile or pedunculated base
- Tumor surface – covered by intact mucosa (+/- focal ulceration)
- Microscopic: 3 elements:
1. abnormal vascular network (lack muscular wall- can’t constrict, can cause hemorrhage),
2. connective tissue stroma (fine and coarse collagen)
3. stromal cells (cytologically bland spindle cells)
Treatment:
- Selective angiographic embolization, surgical excision
- Local aggressive growth, recurrences in 20% of patients, usually within the first 2 years after diagnosis
- Mortality – up to 9%, due to hemorrhage
Cholesteatoma (ear)
Destructive squamous epithelial cyst of middle ear or mastoid region
- usually secondary to chronic otitis media, but occasionally congenital
- Origin in superior posterior middle ear, may demonstrate locally aggressive growth into adjacent structures
Presentation:
- May lead to progressive conductive hearing loss
- Intracranial extension may lead to lethal complications: meningitis, epidural abscess, lateral sinus thrombosis
- Otorrhea, otalgia, tinnitus, vertigo;
- Otoscopic appearance: white-gray to yellow irregular mass associated with otitis media or perforated tympanic membrane
Treatment: surgical extirpation of the squamous epithelial lining is essential
Malignant External “Otitis” (MEO)
Infection of the external auditory canal which progresses to a highly aggressive, invasive osteomyelitis of the temporal bone and skull base, most often in immunocompromissed patients
> 90% of cases: in DIABETICS, most over 60 yo
- Initiated by minor trauma (cleaning ear) to the external auditory canal mucosa that allows entry of an opportunistic agent (Pseudomonas aeruginosa)
- Can lead to invasive osteomyelitis of skull base
Clinical presentation:
- Erythema of the auricle and ear canal, otalgia
- Severe headache, purulent otorrhea
- Clinical exam: granulation tissue on the floor of the external auditory canal
Histo:
- necrotic material and granulation tissue
- Culture of debridement specimen is crucial in the management of MEO
Treatment:
strict diabetes control, careful debridement and IV multidrug antibiotic treatment
Tumors of the ear:
Jugulotympanic paraganglioma and Schwannoma
Jugulotympanic paraganglioma:
- The most common benign tumor of the middle ear
- Slow growth (years)
- Cells with lobular arrangement; rich, vascular stroma
Schwannoma:
- The most common tumor of the inner ear
- Nearly all arise from vestibular nerves
- Bilateral Schwannomas are common in NF2
Branchial cleft anomalies
Lateral cervical cyst that results from congenital/developmental defects arising from the primitive 2nd branchial apparatus
- 80-90% of branchial anomalies are associated with the second apparatus
- Lateral neck, near the mandibular angle
- Equal gender distribution, 75% of patients between 20-40 yo
Clinical presentation
- Mass along the anterior border of the sternocleidomastoid muscle
- Painless, long duration
- May become secondarily infected
Prognosis, treatment:
- Complete excision
- Recurrence rate 2.7%
Histo:
- Unilocular cysts, 2-6 cm
- Lining: stratified squamous epithelium (90%), respiratory epithelium, or both
- Keratinaceous debris inside the cyst
- Lymphoid aggregates with or without germinal centers beneath the epithelial lining
- Acute and chronic inflammation, foreign body giant cell reaction and fibrosis
Erythrocyte sedimentation Rate
Detects rate erythrocytes fall in column
- Should fall at ~ 10 mm/hour
- Faster rate of fall= erythrocytes stick together (aggregation)
- Inflammatory proteins increased erythrocyte stickiness
Elevation of ESR caused by:
- Acute-phase reactants (fibrinogen)
- Monoclonal Ig
- Anemia
- Polycythemia
- Malignancy
- Inflammation secondary to infection
Affected by:
- Age
- Gender
- Race
** ESR and CRP can predict radiographic progression of disease (but markers may not be present)
C-reactive protein (CRP)
Produced in response to inflammatory cytokines (IL-1, IL-6, TNFa)
Increases rapidly for 2-3 days
Half-life is ~19 hours (unless there is continuous infection, inflammation, malignancy)
- Abnormal elevation can rapidly correct in non-chronic conditions
Activates the classic complement pathway
Binds to Fc gamma receptor
Normal/minor elevation ( < 1mg/dL):
- Vigorous exercise
- Common cold
- Pregnancy
- Gingivitis
- Seizures
- Depression
- Insulin resistance and diabetes
- Obesity
Moderate Elevation (1-10mg/dL)
- Autoimmune diseases (Most connective tissue diseases, Rheumatoid arthritis)
- Myocardial infarction
- Malignancies
- Pancreatitis
- Mucosal infection (bronchitis, cystitis)
Marked Elevation (>10mg/dL)
- Acute bacterial infection (80%-85%)
- Major trauma
- Systemic vasculitis
Affected by:
- Gender
- Race
** ESR and CRP can predict radiographic progression of disease (but markers may not be present)
Complement levels and assessment of inflammatory disease
Ex: C3, C4, CH50 levels decrease when disease is active (using up complement!)
- CH50= marker of complement activity (not as useful as C3, C4)
- Initial diagnosis of Systemic Lupus Erythematosus
- Assessing SLE activity
- Assessing response to treatment
- Diagnosing or assessing activity of cryogobulinemia
- Rheumatoid vasculitis
- Sjogren’s syndrome: normal C3, low C4
Rheumatoid Factor
IgM or IgG antibody against Fc portion of IgG
RF in Rheumatic/autoimmune disease:
- Rheumatoid Arthritis
- SLE
- Sjogren’s Syndrome
- Mixed Connective Tissue Disease
- Mixed Cryoglobulinemia
- Juvenile Chronic Arthritis
- Psoriatic Arthritis
RF in non-Rheumatic diseases:
- Lymphoproliferative Syndromes
- Other Malignancies
- Viral or parasitic Infection
- Hepatitis C
- Usually IgM of lower affinity, polyspecific (reacts to two unrelated antigens such as ssDNA, thyroglobulin, histone and other antigens)
CCP antibodies
Recognize enzymatic post-translational modification of Arg to Citrulline
- Citrullination (deimination) catalyzed by Peptidyl Arinine Deiminase (PAD1)
- Binds to citrullinated peptides (NOT similar peptides containing Arg)
Similar sensitivity (53-68%) but higher specificity (95-96%) than RF for diagnosis of Rheumatoid Arthritis
Associated with erosive and deforming potential.
Detectable early in the disease course (vs other autoantibodies which may not be detectable until well after symptoms start)
Protein products targeted by CCP autoantibodies:
- Collagen Type II
- Fibrinogen/fibrin
- Wimentin
- IgG (Fc)
ANA= Anti-nuclear antibodies
Antibodies that bind nuclear factors, including double stranded DNA, histone proteins, RNA/Protein nuclear complexes
Method:
- HEp-2 Cells in dish
- Add patient’s serum in serial dilutions
- Add fluorescent anti-human Antibodies
- Will fluoresce if patient’s Ab are targeting nuclear antibodies (fluoresces over nucleus)
ANA type= highest dilution (high titer) of serum where immunofluorescence visible
- Indicates high concentration of autoantibody if reaction occurs even with lots of dilutions
- Titer does not necessarily correlate with disease activity or prognosis
SLE: ANA is 95% sensitive, but lacks specificity. Could also be:
- Scleroderma
- Mixed connective tissue disease
- Polymyositis/dermatomyositis
- Rheumatoid arthritis
- Sjögren’s syndrome
- Hepatitis C (15%)
- HIV (15%)
- Subacute bacterial endocarditis
- Tuberculosis
- Malaria
- Multiple sclerosis (23-30%)
- Liver disease: Primary biliary cirrosis
- Graft Versus Host Disease
- General population ( 3-5%) with no autoimmune disease (autoreactive B cells present without disease)
** May be able to detect ANA years before SLE diagnosis (50% had positive test 5 years before diagnosis)
Subtypes of ANA
- Anti-Smith (SLE- 95% specific, 30% sensitive), Anti-RNP (SLE, mixed connective tissue disease): Antibodies to extractable nuclear antigens (ENA)
- Antibodies to nuclear, non-coding RNA-containing protein complexes
- Specific but not sensitive - Anti-SSA (40% SLE, Sjogren’s), Anti-SSB (40% SLE, 15% Primary Sjogren’s)
- Antibodies to nuclear, non-coding RNA-containing protein complexes
- Specific but not sensitive
* * Anti-SSA/Anti-Ro antibodies can cross placenta, can cause neonatal lupus (RARE). Can vary from facial rash, transient liver enzyme abnormalities to fetal cardiac disease (heart block) - Anti-dsDNA:
- Antibodies to nuclear, dsDNA
- 60-70% specific to SLE - Anti-centromere antibodies: limited to scleroderma (CREST)
- Anti-Scl-70 antibodies (topoisomerase I): 90% specific, not sensitive for scleroderma
- Anti-histone antibodies: 95% specific for drug-induced lupus
Antiphospholipid antibodies
Target cellular membranes
Confer increased risk for Antiphospholipid antibody syndromes (APS):
- Thrombosis
- Pregnancy morbidity
- Thrombocytopenia
** Can detect similar antibodies after infections like Lyme, Malaria
Types:
- Anti-cariolipin antibodies (IgG, IgM, IgA)
- Detected by ELISA - Beta 2 glycoprotein I (B2GPI) antibodies:
- Directed against phospholipid-binding plasma protein
- Detected by immunoassays - Lupus anticoagulant
- Tests for Inhibitor of phospholipid-dependent clotting
Anti-nuclear cytoplasmic antibodies (ANCA)
c-ANCA= target proteinase 3 (PR-3)
Associated with:
- Granulomatous polyangitis (GPA) also known as Wegener’s disease
- Churg Strauss (eosinophilicGPA?)
- Microscopic polyangiitis (MPA)
- Renal-limited vasculitis (ANCA-associated kidney disease)
p-ANCA= target myeloperoxidase (MPO) and elastase, cathepsin, lysosyme, lactoferrin
Associated with:
- Churg Strauss (eosinophilicGPA?)
- Microscopic polyangiitis (MPA)
- Renal-limited vasculitis (ANCA-associated kidney disease)
- Inflammatory bowel disease
c-ANCA OR p-ANCA seen in:
- Drug-induced
- CTDs (SLE, RA, Sjogren’s)
- Bacterial Endocarditis caused by S. Aureus or S. viridans (cANCA more common than pANCA)
- Paraneoplastic syndromes (lung, esophageal cancer, leukemia, lymphoma)
Inflammatory Myopathy Antibodies
Detected in 30-40% of inflammatory myopathies
Anti-synthetase (Jo-1): associated with interstitial lung disease (ILD), Raynaud’s, mechanics’ hands, in polymyositis or dermatomyositis and with moderate response to treatment.
Anti-Mi2: associated with dermatomyositis and may be indicators of good therapeutic response and prognosis
Anti-SRP: may be associated with cardiac disease and severe weakness.
Epidemiology of RA
Relatively common disorder
- Affects >1% of the population of North America
- Female:male 2.5:1
- Incidence increases with age (Peak: 4th-6th decade)
Pathogenesis of RA
Familial aggregation
Environmental or infectious factors
Chronic, systemic autoimmune disease
Primarily mediated by T lymphocytes
Primary target tissue: synovium
Synovial tissue is infiltrated by T lymphocytes
- Identified T-lymphocytes as culprit based on RA HIV patients who went into remission when CD4 lymphocyte count low
Imbalance in cytokines between:
- anti-inflammatory (IL-10, TGF-beta, IL-4, sTNFR, sIL-1R, IL-1Ra) and
- Inflammatory (TNF, IL-1, IL-6, LIF, LT-alpha, chemokines)
Genetic predisposition: MHC class II, non-MHC genes (HLA-DRB 0401,0404 in whites)
Shared epitope on the hypervariable region–> AG binding & presentation –> CD4+T cell activation –> non-T effector cells –> cytokine production
–> T-cell recruitment
–> chronic inflammation
—> Bone, cartilage, ligament, tendon damage
–> erosions, joint deformity
Synovial inflammation:
- Fluid filled with neutrophils
- Pannus infiltrated by T lymph, macrophages, fibroblasts, plasma cells, endothelial dendritic cells
Clinical presentation of RA
Bilateral, symmetrical Large and small joints Inflammation of the synovium Fluid accumulation in the joint Joint swelling and pain If not diagnosed and treated vigorously--> destruction, deformity, disability
Associated with shortened life expectancy
Constitutional symptoms: low grade fever, wt loss, anorexia, fatigue
Extra-articular involvement:
- Lungs, skin, heart, hematologic, eye, vessels
- Rarely: CNS (rheumatoid nodules), kidneys
- Differentiate from drug side effect!
Diagnosis of RA
Joint involvement at time of onset:
- Polyarticular (75%)
- Small joints of hands and feet (DIP joints)
- Large joints - Monarticular (25%)
- Knee, shoulder, wrist, hip, ankle, elbow
Need to examine joints:
- Should be soft, elicit tenderness
1. Psoriatic arthritis= inflammation of joint
2. Osteoarthritis= swelling of bone at joint
Bone scan: demonstrates inflammation of bone
X-ray: Protrusio acetabulum (hip protrudes into pelvis
Late RA:
- Atrophy, ulnar deviation of joints in hands
- Rheumatoid nodules (not inflammatory, mainly fibrotic)- seen outside joint space
- Loss of cartilage
- Pannus eats away at bone on edges of joints
Autoantibodies in RA
Two most important:
- Fc region of IgG= Rheumatoid factor (IgM- most common, or IgG)
- Citrullinated proteins (don’t bind arginine-containing peptides, do bind same proteins once converted to citrulline)
Diseases associated with Rheumatoid factor
RA (80%) Juvenile inflammatory arthritis (20%) Sjogren’s Syndrome (90%) Lupus (40%) Scleroderma Sarcoidosis Cryoglobulinemia Cirrhosis Post-vaccination Aging
Chronic Infections:
- Subacute bacterial endocarditis
- Hepatitis C
- TB
Overlap Syndromes:
- Ankylosing Spondylitis (< 15%)
- Cryoglobulinemia (> 90%)
- Psoriatic arthritis (negative)
- Reactive arthritis (negative)
APCA (anti-CCP)
- detectable already years before the first clinical symptoms
- also predictive for the level of erosiveness
APCA detection in clinical practice:
- Effect of Smoking
- Earlier, worse arthritis in ACPA+ smokers - Differentiate RA from arthritis in HCV infection
- positive RF 12/14pt, negative aCCP–> probably arthritis, not RA - Predict erosive and progressive disease
- Combination of anti-CCP and IgM RF
Testing for RA
- Object is to confirm the presence of a systemic inflammatory process
- Evaluate for serious major organ involvement
- Check for pertinent but unusual causes of systemic polyarthritis
Labs:
- CBC: anemia, nL or slightly elevated WBC, and/or platelet
- ESR elevation
- CRP elevation
- BUN, creatinine
- Liver enzymes
- ANA (not usually positive)
- Hepatitis C
Imaging:
- X-rays (only helpful with later damage)
- U/S: synovial swelling, hypertrophy; doppler to show increased blood flow in inflammatory state
- MRI
- Bone scan
- Arthrocentesis, synovial fluid analysis
Classification criteria for RA
DO NOT NEED TO MEMORIZE: Score of 6+ needed for classification of RA: A. Joint involvement: 1 large joint= 0 2-10 large joints= 1 1-3 small joints= 2 4-10 small joints= 3 > 10 joints (at least one small)= 5
B. Serology
Negative RF, negative CCP= 0
Low-positive RF, low-positive CCP= 2
High-positive RF, high positive CCP= 3
C. Acute-phase reactants:
Normal CRP and normal ESR= 0
Abnormal CRP, abnormal ESR= 1
D. Duration of symptoms
< 6 weeks= 0
6+ weeks= 1
Articular manifestations of RA
Hands:
- Ulnar deviation
- Swan-neck deformity
- Boutonnière deformity
- Tenosynovitis
- Extensor tendon rupture
- Carpal tunnel
Knee
- Synovitis causing Baker’s cyst (rupture-DVT)
Feet
- MTP joints cock-up deformity
- talonavicular joint-pronation
- eversion of the foot
- ankle joint-tarsal tunnel syndrome (burning paresthesia of the sole)
Spine
- Tenosynovitis of the C1 transverse ligament–> C1-C2 instability
- Erosion of odontoid process
- myelopathy
Extra-articular manifestations of RA
Subcutaneous Nodules Vasculitis - Arterioles, capillaries, venules - Mostly leukocytoclastic vasculitis - Skin ulcerations (necrotizing)
Nervous system:
- Myelopathy
- Mononeuritis multiplex:
- disorder characterized by simultaneous or sequential damage to more than one nerve group
- isolated damage to at least 2 separate nerve areas
- involves destruction of the axon
- interferes with nerve conduction at the location of the damage (see wrist, foot drop)
- causes include a lack of oxygen caused by decreased blood flow or inflammation of blood vessels. No cause is identified for about one-third of cases - Entrapment syndromes:
- Carpal Tunnel, Tarsal Tunnel etc.
Ocular
- Keratoconjunctivitis sicca (also seen in Sjogren’s)
- Episcleritis (more superficial than scleritis)
- Scleritis
- Scleromalacia perforans (rheumatoid nodule)
Cardiac
- Pericardial effusion
- Paricarditis
- Valve nodules
Pulmonary
- Pleural disease
- Interstitial lung disease
- Pulmonary nodules
Renal
- Amyloidosis (more common with early age of onset–> longer time to develop)
- Drug toxicity
- Papillary necrosis
RA treatment
Goal is complete remission
- Start with anti-inflammatory medications
- NSAIDs
- Corticosteroids - Add immunomodulators (DMARDs) early
- If no significant improvement in first few months add “biologics”
- Antibodies against inflammatory cytokines
Acute monoarthritis: Diagnostic possibilities
Rheumatologic emergency:
- Urgent- investigate thoroughly
Diagnostic possibilities:
- Infections
- Bacterial (most destructive)
- Viral
- Fungal - Crystals
- Monosodium urate (MSU) (Gout)
- Calcium pyrophosphate (CPPD)
- Apatite - Hemorrhagic
- Tumors
- Villonodular synovitis
- Malignancy - Vascular
- Sickle cell disease
- Osteonecrosis - Other
- Hemarthrosis
- Systemic inflammatory arthritis
Diagnostic techniques:
- Aspirate Joint
- Synovial fluid examination:
- Cell count
- Gram Stain
- Culture and sensitivity
- Light microscopy
- Polarized microscopy
Synovial fluid cell count
Normal: Clear, colorless, viscous
- < 200 leukocytes, < 25% PMNs
Non-inflammatory: clear, yellow, viscous
- 200-2000 leukocytes, < 25% PMNs
Inflammatory: cloudy, yellow, watery, low glucose
- 2000-100,000 leukocytes, > 50% PMNs
Septic: Purulent, very low glucose
- > 80,000 leukocytes, > 75% PMNs
Bacterial arthritis: causes
Non-gonococcal bacterial infection: Most serious
- S. aureus: most common
- Streptococcus species
- Gr- and fungi: increasing in frequency; seen in Immunocompromised or debilitated host
Pathomechanism:
- Hematogenous spread (most common)
- Contiguous spread
- Soft tissue-skin infection
- Penetrating trauma
- Surgery
- Adjacent osteomyelitis
- Intraarticular injection (1:500-1:5,000)
Predisposing factors:
- Systemic connective tissue disorders
- OA of the joint
- Diabetes mellitus
- Immunocompromised patients
- Advanced age
- Alcoholism
- Prosthesis or foreign body in the joint
Bacterial arthritis: presentation
Acute severe pain Swelling Increase in joint temperature Fever (+/-) Systemic toxicity (chills etc +/-)
Site:
- Knee > large diarthrodial joints
- In children: knee and hip
- IV drug users: axial (sternoclavicular, SIJ)
- Methicillin resistant S. aureus
- Serratia
- Ps. aeruginosa
Bacterial arthritis: diagnosis and treatment
- Joint aspiration (needle or open)
- WBC: >10,000/mm2 (>50,000/mm2 in 70%)
- Neutrophils: >80%
- Gram stain (+ in 50%, + in 75% for gram+ cocci)
- Culture (+ in >90%) - Blood culture: 50% + in non-GC arthritis
- Increased WBC with left shift
- X-ray findings
- Get a baseline and also to Dx osteomyelitis
- No initial changes, except for effusion
- Osteomyelitis findings (10-20 days to develop)
- Radionucleide imaging, gallium scanning
- CT scan
Tx: start empiric antibiotic!
Gonococcal arthritis
Cause: disseminated GC infection in immunocompetent 60,000/mm2
- Outcome: favorable
Crystalline arthritis
Very common type of arthritis
- Starts monoarticular (Gout, pseudo-gout)
Associated findings:
- Gout:
- HTN,
- hyperuricemia,
- EtOH,
- male (post-menopausal females) - CPPD (pseudo-gout)= Calcium pyrophosphate dihydrate disease
- Older age,
- DJD (degenerative joint disease),
- chondrocaclinosis (calcium in cartilage) on x-ray
Gout: pathophys
Acute arthritis; inflammatory response to MSU (urate) crystals in joints
- Generally starts in 1st MTP joint (big toe)
- Peripheral joints, tendons, any tissue
- Recurent
- Chronic, deforming
- Males/post-menopausal women
- Associated with Lesch-Nyhan syndrome: mutations in the HPRT gene located on X chromosome–> HGPRT enzyme defect–> uric acid buildup
Pathophys:
- Sodium urate triggers immediate immune response (potent trigger)
- Leads to production of IL-1–> inflammatory cascade
- Cells move to site of urate deposition
- Cannot remove urate
- Eventually immune response tapers
Gout: clinical features
Acute attack
- Abrupt, monoarticular
- Involves MTP –> ankle, tarsal joint, knee, wrist, elbow
- Exquisite tenderness, swelling, warmth
- Fever, leukocytosis may occur
- Overlying skin desquamates
- Lasts 3-10 days w/o treatment
Precipitating event of acute attack:
- Trauma, surgery, stress, infection, food (red meat, shellfish), alcohol (beer)
- Diuretics, low dose aspirin
Interval gout:
- Asymptomatic periods shorten
- Attacks increase in frequency
- 10-20 years until chronic phase
Chronic gout (tophaceous gout): Result of: - Years of persistent hyperuricemia - Frequent attacks - Inadequate therapy
Features of chronic gout:
- Joint destruction
- Tophi: subcutaneous tissue, tendons, IP-MCP joints, pinna of ear
- Extra-articular: myocardium, pericardium, aortic valves, extra-dural spinal, kidneys
- May mimic RA but less symmetrical
Gout: diagnosis
Diagnosis
- Crystal in the aspirate:
- Monosodium urate monohydrate= needle shaped
- Differentiate from calcium pyrophosphate dihydrate (pseudo-gout)- NOT needle shaped
- Crystal aligned with polarizer= yellow
- Perpendicular to polarizer= blue
- Negative birefringence (vs CPP= positive birefringence)
- Crystal inside neutrophils= acute gout attack
SF WBC 2,000-100,000/mm3
Other clinical features:
- Serum uric acid may be normal during acute attack
- Urine excretion over 1,000 mg/d is suggestive
X-ray:
- Acute phase
- Soft tissue swelling - Chronic
- Oval, round periarticular or intraarticular erosion (bite-out)
- Sclerotic margin
- Joint space is preserved until late
Chondrocalcinosis
Pseudo-Gout= Degenerative Joint Disease (DJD)
- calcium pyrophosphate crystals in articular, peri-articular tissue
- Idiopathic or associated with certain metabolic diseases
Five types of clinical features:
- chondrocalcinosis: Calcium deposition in cartilage (may be asymptomatic)
- Pseudo-gout (symptomatic)
- Pseudo-osteoarthritis
- Pseudo-rheumatoid arthritis
- Pseudo-Charcot (neuropathic bone destruction
Laboratory Findings
- rod shaped, often intracellular crystals
- positively birefringent (blue, when parallel to the axis of a polarizing microscope compensator)
Evaluation:
serum Ca, Mg, phosphorus, PTH, alkaline phosphatase, ferritin, iron, iron binding capacity, glucose, (TSH), uric acid
Radiologic findings:
- punctate and linear densities in articular cartilage
- Site: knee, acetabular labrum, symphysis pubis, articular disk of the wrist, and annulus fibrosus of the intervertebral discs
X-ray screening:
- AP views of both knees, pelvis, hips, symphysis pubis,
PA view of both hands.
Pseudo-gout
- Acute inflammatory process
- 1 or more joints
- Lasts for several days
- Similar to gout, not as severe
- Smaller, less painful attacks between flares
- Any joints, but knee most often
- Crystal deposition in tendon, ligaments, synovium, cartilage
- More common in elderly, women
Systemic Sclerosis
Systemic autoimmune disease of unknown etiology.
- Autoimmune activation, activation of fibroblasts and deposition of collagen
The third most common systemic autoimmune disease.
More common in females (4-8:1 female to male) and affects all racial groups and all ages.
Peak of disease onset in the fourth and fifth decades.
Familial SSc is rare. There is no evidence of genetic inheritance.
Organ system involvement: Skin 100% Raynaud's phenomena 89 GI tract 87 Lungs 64 Bones/joints 45 Muscles 35 Heart 24 Kidneys 15
Systemic sclerosis: cutaneous involvement
Skin sclerosis in 95% of patients. In 5% there is typical visceral involvement in the absence of skin sclerosis (Scleroderma sine Scleroderma).
Thickened and hidebound skin first appears distally (Sclerodactyly) and progresses proximally.
- Flexion contractures at joints
- Shiny, taut skin
1. Limited cutaneous involvement: - hands, feet, face, forearms and legs.
2. Diffuse cutaneous involvement: - upper arms, thighs, chest, abdomen and back in addition to above.
The face is expressionless with loss of wrinkles, beaked nose, thin lips with radial furrowing, and microstomia.
Diffuse hyperpigmentation or hyperpigmented hair follicles surrounded by depigmented areas (“salt-and-pepper” pattern).
Telangiectasia on the hands, face, lips and tongue.
- Mucosal telangiectasia (gastric, small intestinal or colonic, implicated as a source of gastrointestinal bleeding).
Painful ulcerations at the fingertips and other areas where the skin is tightly stretched.
Cutaneous calcifications at the fingertips, along the extensor surface of the forearms, and periarticular areas.
Raynaud’s phenomenon
Raynaud’s phenomenon is the initial symptom of systemic sclerosis in a majority of patients.
- Often precedes the onset of other SSc features.
- Ultimately develops in virtually all SSc patients.
Is common among premenopausal women, only a minority of whom develop a connective tissue disease, most commonly SSc.
Characterized by abrupt, temporary occlusion of peripheral arteries.
- Triggered by cold exposure, tobacco smoke or emotional stress.
- Typical findings are the waxy blanching of fingers followed by numbness, tingling and paresthesias.
- Restoration of blood flow causes cyanotic discoloration followed by erythema of affected regions.
Irregular capillary beds in Systemic sclerosis exacerbate phenomenon
Systemic Sclerosis: skeletal involvement
X-rays show resorption and often complete dissolution of the distal end of the phalanx (acro-osteolysis).
Indolent myopathy with minimal elevation in serum muscle enzymes (focal muscle fibrosis and fiber atrophy).
Some patients develop typical inflammatory myopathy (polymyositis) with elevation in muscle enzymes and EMG changes.
Systemic sclerosis: GI tract involvement
- Esophageal abnormalities in up to 90% of patients:
- Incompetence of the lower esophageal sphincter and decreased or absent peristalsis in the lower two-thirds (smooth muscle involvement- NOT striated) cause dysphagia and odynophagia.
- Chronic reflux and esophageal stasis cause esophagitis, Barrett`s esophagus and lower esophageal stricture.
- Increased frequency of esophageal cancer in SSc.
- Reflux of gastric contents causes hoarseness, cough and aspiration pneumonitis. - Gastric/esophageal dilation
- Watermelon stomach= Gastric Antral Vascular Ectasia (GAVE) with painless severe GI bleeding
- Disordered motility:
- Gastric distension
- Bacterial overgrowth, diarrhea, malabsorption, pseudo-obstruction
- Colonic disease with wide-mouth sacculation (pseudodiverticula)
Systemic Sclerosis: Respiratory system involvement
Lung involvement is the leading cause of morbidity and mortality in SSc.
Lung involvement results in pulmonary fibrosis (ILD) or pulmonary hypertension.
Pulmonary fibrosis in SSc is insidious at onset and progressive.
Physical exam discloses fine inspiratory crackles at the lung bases.
Pulmonary hypertension and cor pulmonale may develop in patients with limited SSc, even in the absence of pulmonary parenchymal involvement.
Diagnosis:
- Chest roentgenograms are insensitive for detection of early lesions.
- Pulmonary function studies are more sensitive (decreased DLCO, decreased TLC).
- Isolated reduction of DLCO (TLC/DLCO ratio > 1.5) suggests pulmonary hypertension.
- High resolution CAT scan is highly sensitivity and allows the detection of alveolitis (ground glass appearance) in early stages.
- Late CAT scan changes include severe fibrosis and traction bronchiectasis.
Systemic sclerosis: renal involvement
Renal involvement is considered to be the most deadly complication of SSc.
Renal crisis= develops in 15-20 percent of patients and usually occurs with an abrupt onset (within hours)
Malignant hypertension, acute cardiac failure, myocardial infarction, stroke, and rapidly progressive renal insufficiency characterize scleroderma renal crisis.
Progression to renal failure and death occurs rapidly unless the diagnosis of renal crisis is established and aggressive treatment instituted promptly.
Patients with diffuse and rapidly progressive skin involvement are at the highest risk.
Systemic sclerosis: Cardiac involvement
Heart involvement: 80% of patients
- clinically significant primary cardiac dysfunction is less common.
- Tachyarrythmias and cardiac conduction disturbances are frequent.
- Pericardial effusion is found by echocardiography in many patients, but symptomatic pericarditis is rare.
- Right heart strain in cases of pulmonary hypertension.
Systemic sclerosis: other visceral involvement
Peripheral neuropathy (trigeminal neuralgia and carpal tunnel syndrome) can occur but the CNS is spared. - Can cause some pain
Erectile dysfunction develops in many male patients, and can precede other SSc manifestations.
The sicca syndrome is frequently found (Secondary Sjögren’s Syndrome).
- Replacement of exocrine glands by fibrotic tissue
Hypothyroidism is detected in a third of the patients.
Primary biliary cirrhosis has been documented in a number of cases.
Laboratory findings in Systemic Sclerosis
The diagnosis is generally made on clinical grounds.
Laboratory data help in defining the type and extent of visceral involvement:
- ESR is usually normal.
- ANA test is positive in greater than 90% of patients and most characteristically speckled or nucleolar in diffuse form and anticentromere in limited form.
- No antibodies to native DNA, Sm and RNP
SSc-specific antibodies:
1. Anti-centromere antibodies > 80%
- Anti-Scl-70 antibody (anti-topoisomerase 1)= specific for SSc, present in 30-40% of patients
- Seen more commonly in severe interstitial lung disease
** Both anti-centromere and anti-Scl-70 antibodies helpful in classification of SSc subset (anti-centromere= limited disease, Anti-Scl-70= diffuse)
- Anti-RNA polymerase III antibodies: less common
- Seen in severe, diffuse disease, renal crisis
Diffuse vs Limited Cutaneous Systemic Sclerosis
Diffuse:
- Higher mortality
- Raynaud’s= earlier onset
- Truncal, acral skin sclerosis
- Early lung invovlement
- Renal crisis
- Cardiac fibrosis
- Anti-topoisomerase antibodies (Speckled/nucleolar (anti-Scl-70) antibodies)
- RARE to see anti-centromere antibodies
Limited Cutaneous Raynauds:
- Lower mortality,
- > 1 year to Raynaud’s onset
- Acral skin sclerosis
- Late lung involvement (pulmonary hypertension)
- Rare renal crisis
- Rare cardiac fibrosis
- Pattern of antibodies= anti-centromere (90%)
Course and prognosis of Systemic Sclerosis
The course of SSc is often characterized by progression.
- The highest mortality is seen in the first two-five years of the disease.
- The prognosis of SSc is related to the extent of visceral involvement:
- Limited SSc has low overall mortality.
- Diffuse SSc has a 50-60% mortality at 5 years.
A grave prognosis is closely correlated with the presence of renal, pulmonary and cardiac involvement.
Systemic Sclerosis: Pathogenesis
Three outstanding features responsible for the clinical and pathologic manifestations of SSc:
- Excessive deposition of collagen and other connective tissue macromolecules in skin and internal organs.
- The most prominent clinical manifestations and high mortality of SSc are caused by tissue fibrosis of the affected organs.
- The excessive collagen deposition in SSc is due to overproduction of this protein by fibroblasts.
- Alterations in the regulation of collagen gene expression may be induced by cytokines and growth factors released from the tissue-infiltrating inflammatory cells.
- Prominent role of TGF-b and SMAD pathway. - Vascular lesions of capillaries and small arteries.
- Endothelial cell dysfunction may be the initial event in SSc pathogenesis.
- The vascular abnormalities become apparent prior to the onset of tissue fibrosis.
- Severe fibroproliferative vasculopathy.
- Perivascular cellular infiltration with activated T-cells and macrophages. - Alterations of humoral and cellular immunity.
- Almost universal occurrence of anti-nuclear antibodies.
- Mononuclear cell infiltrates in affected tissues.
- Activation of innate immune response and Interferon signature.
- The mononuclear infiltrates are predominantly activated lymphocytes (helper T-cells) and macrophages.
- There is no evidence of autoantibody - mediated tissue injury in SSc.
Achondroplasia
Growth plate disorder
- Most common disease of growth plate
- Failure of norrmal epiphyseal plate cartilage
- Autosomal dominant; MOST are new mutations in: FGFR-3, CHR 4
Scurvy
Growth plate disorder
- Vitamin C deficiency affecting collagen synthesis
- Woven bone not formed
- Prominent calcified cartilage
Osteochondroma
Developmental defect (hamartoma) at epiphyseal plate
- “Ring of Ranvier”
- Cartilage capped growth growing away from joint
Hereditary multiple osteochondromatosis:
- Extra genes on Chromosomes 8, 11, 19–> chondrocyte proliferation and differentiation
Bone Fracture
Most common bone lesion. Types: 1. Spiral 2. Transverse 3. Compression Primary vs Secondary (due to tumor)
Complications:
- Soft tissue and nerve damage
- non-union
Fracture healing
- Inflammatory phase:
- 1-2 days: hemorrhage
- 2-5 days: neovascularization at periphery
- 7 days: early callus - Fracture healing:
- After 1st week: Reparative phase (repair from periphery to center of fracture)
- Weeks later: remodeling phase (cortex restore, callus ingrowth seals ends)–> can take years
Osteoarthritis
Most common form of joint disease
- Slow, progressive
- Seen in articular cartilage of weight bearing joints, fingers
- Older patients (or young following trauma)
- Primary osteoarthritis:
Unknown etiology; several postulated factors:
- increases with age
- 85% of patients age 75-79
- < 45 years= male predominant; > 55 years= females
- Hereditary factors? - Secondary osteoarthritis:
Known etiology
Clinical: See joint space narrowing, subchondral bone thickening, painful joint - Pain follows activity - Restriction of motion - Lab findings unhelpful - Supportive therapy
Pathology:
- Seen at DIP, PIP of upper extremity; knees, hips, cervical and lumbar spin
- Narrowing of joint space on x-ray
- Increased subcondral bone, bone cysts
- Osteophyte formation
Histology:
- Earliest= death of articular cartilage
- Cracking, fibrillation
- Reactive bone/cartilage–> fibrocartilage plug
- Eburnation (loss of articular cartilage), subchondral bone cyst (decreased density on x-ray), osteophyte (dense bone formation with cartilage cap, continuous marrow)
Degenerative disc disease
Pathophys:
- Loss of ratio of short to long chains in aggrecan molecules
- Short chain= Keratin sulfate
- Long chain= chondroitin sulfate
Aging= Increased keratin (short chain), decreased chondroitin (long chain)
- Cellular changes: chondrocyte loss (apoptosis, necrosis)–> decrease in T2 cartilage
- Develop osteophytes (outgrowth of edge of vertebrae), herniation of discs
High risk populations:
- Smoking
- Obesity
- Heavy laborers: repetitive axial loading, prolonged driving (vibration), repetitive bending, twisting
Arthritis of spine
Presentation:
- Axial or radicular pain
- Neurologic impairment
- Radiographic instability: scoliosis, spondylolisthesis
Red flags in Spinal pain assessment
Constitutional symptoms
- Progressive, unrelenting pain (non-mechanical)
- Worse at night, at rest
- Fever, chills, sweats
- Anorexia with weight loss, fatigue
Neurological symptoms:
- Progressive weakness
- Acute dexterity / balance changes
- Bladder dysfunction
- Cervical myelopathy: loss of dexterity, coordination; impaired balance/gait
May indicate:
- infection
- Cancer
- Myelopathy
- Severe nerve compression
Cauda equina syndrome
Clinical presentation:
- Severe leg pain
- Saddle anesthesia (perineum, perianal)
- Altered bladder function (retention)
Radiculopathy symptoms
Exert tension on nerve roots to see where pain radiates
Cervical radiculopathy:
- Frozen shoulder
- Carpal tunnel
- Cubital tunnel
- Subacromial bursitis
- TOS
Lumbar radiculopathy:
- radiating pain; leg > back
- motor / sensory - compressed nerve
- depressed reflex - compressed nerve
- no pathological reflexes
UMN findings
Pathological reflexes:
- Babinski’s sign
- Hoffman’s sign
- Ankle clonus
- Hyperreflexia
Diagnostic imaging
Confirms clinical impression
- After failure of non-operative treatment
- Setting of “red flags”
- Plain radiographs (orthogonal views)
- looking for issues with bones - MRI or CT scan/myelogram
T2 MRI
Spinal fluid= white
Dark= Low intensity
- Spinal disc= dark, impinges on white spinal fluid
- Should have some white in discs (fluid-filled)- degenerative disc disease may see loss of lightness
Treatment of arthritis of spine
“Clinical Diagnosis” Most improve < 6 weeks Stepwise treatment algorithm Surgical treatment - rarely necessary - “last resort” when indicated
Natural history:
90% better < 6 weeks
“other 10%” = 90% of costs
Time dependent likelihood of improvement
>6 weeks symptoms–> 20% improvement
>12 weeks symptoms–>10% improvement
Compensation > 6 months –>never return to work
Medical managment:
- Short course rest
- Nonsteroidals and acetaminophen
- Physical therapy
- Oral steroids (prednisone taper)?
- Muscle relaxants??
- AVOID NARCOTICS!
Physical therapy, education, strengthening, conditioning
- AVOID BEDREST!
Treatment for radiculopathy
- Initial:
- Collar/Brace
- NSAIDS
- Traction
- Physical Therapy
- Injections - Surgery:
- For recalcitrant symptoms (4-6 weeks)
- Neurologic deficit, correlative imaging
- Signs of spinal cord compression
Lumbar stenosis
“shopping cart sign”
- Pain relieved by leaning forward while walking
Commonly seen in patients > 60 years
- Bilateral
- Structurally abnormal spine
- “Claudication”- not enough room for nerves
Spondylolisthesis
“Slip of the vertebra” Isthmic (crack in ring) - 5% of population - not prognostic Degenerative - F > M, over 40 yrs - with spinal stenosis
Myelopathy
Clinical syndrome
Spinal cord problem with NO PAIN
- 70% worsen with time
- IF they have functional problem, get imaging ASAP
See recurrent falls, ataxia
Treatment: progressive worsening–> early surgery referral
- Success of Surgical Decompression:
- Length of symptoms
- Age
- Medical status
Overview of Cervical treatments:
Neck Pain–> Degenerative Disk Disease
1. Try Exercise, Therapy, Chiro, Medications
Arm Pain –> Pinched Nerve
- Try Exercise, Therapy, Chiro, Medications
- Surgeon If Not Improved, Worsening, Weakness
Fine Finger Movement, Balance, Bladder –> Spinal Cord Compression
1. Speak With Surgeon Early
Overview of Lumbar treatments
Back Pain –> Disk Degeneration
1. Try Nonsurgical Treatment
Leg Pain –> Pinched Nerve
- Try Exercise, Therapy, Chiro, Medications
- Surgeon If Not Improved, Worsening, Weakness
Bowel/Bladder Problem –> Cauda Equina Syndrome
1. Surgeon
Risk factors for fracture
Female with age > 65 (vertebral fracture 8:1 F:M ratio; hip 2:1) - 15% hip fractured by 80, 25% by 90 years Previous fracture Family history of hip fracture Low body weight (less than 125 lbs) Cigarette smoking Excess alcohol intake Non-Hispanic white women and Asian women
Patient characteristics in osteoporosis
Prolonged immobilization Low dietary intake of calcium, phosphorus, and Vitamin D Late menarche Early menopause High levels of caffeine ingestion Obesity Low level of physical activity
Secondary causes of osteoporosis
Endocrine disorders:
- Acromegaly, Cushing’s syndrome, Eating disorders, Hyperparathyroidism, Hyperthyroidism, Hypogonadism, Hyperprolactinemia
Gastrointestinal disease
- Celiac disease, Gastrectomy, Inflammatory bowel disease, Jejunoileal bypass, Gastric bypass surgery, malabsorption, pancreatic insufficiency, TPN
Marrow related disorders
Organ transplantation
Idiopathic hypercalciuria, hypophosphatasia…
Renal dysfunction
Medications associated with osteoporosis
Anti-convulsants (Dilantin) Certain cancer chemotherapy medications Glucocorticoids Lithium Cyclosporine Heparin Thyroxine
Recommendations for osteoporosis treatment
National Osteoporosis Foundation:
- History of hip or vertebral fracture
- T score less than -2.5 w/o secondary cause
- T score between -1 and -2.5 at femoral neck, hip, and spine with a high risk factor
FRAX assessment tool (WHO)
- Integrates clinical risk factors and BMD
Calcium and Vitamin D supplementation for osteoporosis prevention
Diet replete with calcium and vitamin D:
- Premenopausal women should consume ~1000 mg of calcium daily (total diet plus supplement)
- Postmenopausal women should consume ~1200 mg of calcium daily (total diet plus supplement)
- 800 international units of Vitamin D per day
Calcium and Vitamin D supplementation for osteoporosis prevention
Diet replete with calcium and vitamin D:
- Premenopausal women should consume ~1000 mg of calcium daily (total diet plus supplement)
- Postmenopausal women should consume ~1200 mg of calcium daily (total diet plus supplement)
- 800 international units of Vitamin D per day
Inflammatory myopathies: Polymyositis, Dermatomyositis
Bohan and Peter classification (4/5 criteria)
- Symmetric proximal muscle weakness
- Elevated serum levels of muscle enzymes
- Myopathic changes on electromyography
- Characteristic muscle biopsy findings
- Appearance of a distinct rash
- Can also have myositis as part of other connective tissue disease/overlap syndrome
Demographics:
- Can be found in children and adults
- Incidence is higher in African-Americans (3:1) and females (2:1)
- Is rare with 2 to 10 new cases per million per year
- Patients report a symmetric proximal limb weakness that is often painless and has a subacute onset
- Patients may have trouble combing hair, rising from a chair
- May be associated with malignancy (DM>PM)
- Dermatomyositis has pathognomic skin rashes
Diagnosis:
- Elevated muscle enzyme levels such as: Creatinine Kinase (CPK), Aldolase, Lactate Dehydrogenase (LDH), Aspartate Aminotransferase (AST) and/or Alanine Aminotransferase (ALT)
Autoantibodies are detected in ~50% of patients
- Myositis specific antibodies directed against amino-acyl tRNA synthetases (Jo-1, EJ, OJ…) often associated with Anti-synthetase syndrome
- Myositis specific antibodies such as SRP, Mi-2
- Myositis associated antibodies (PM-scl, SSA)
Treatment:
- Corticosteroids
- Methotrexate, azathioprine, IVIG, mycophenylate mofetil
Polymyositis histopath
Infiltrate of CD8+ cells around normal myofiber
- Inflammation localized to endomysium
- Anti-Ro Jo-1, PMScl
Dermatomyositis histopath
Infiltrate of CD4+ cells in myofiber
- Inflammation in perivascular areas of perimysium
- Atrophy of fascicles
Inclusion body myositis
Is classified under inflammatory myopathies but it is unknown if it is auto-immune
Demographics:
Patients > 50 years, M > F
Symptoms:
Weakness is distal and can be assymetric
Labs:
CPK is usually less than PM/DM
Treatment:
It responds poorly to corticosteroids
Hisopath:
- Vacuolated muscle fibers, muscle fiber inclusions, paired helical fibers by EM
Benign Bone tumors: Epiphyseal
Chrondroblastoma
Giant cell tumor
Benign bone tumors: Metaphyseal
Osteoblastoma Osteochondroma Non-ossifying fibroma Osteoid carcinoma Chrondromyoid fibroma Giant cell tumor
Benign bone tumors: diaphyseal
Enchondroma
Fibrous dysplasia
Malignant bone tumors: diaphyseal
Ewing sarcoma
Chondrosarcoma
Malignant bone tumors: metaphyseal
Osteosarcoma
Jusxtacortical osteosarcoma
Fibrous dysplasia
Developmental abnormality
Path: activating mutation in alpha subunit of guanine nucleotide binding protein–> increased cAMP
X-ray: lucent ground glass quality, well-marginated borders
Histo: disorganized fibrous and osseous elements
- Irregular trabecular bone within fibrous stroma, no osteoblastic component
- Monostotic:
- Most common (75-80%)
- 2nd to 3rd decade, M=F
- Sites: proximal femur, tibia, ribs, facial bones
- Asymptomatic or pathologic fractures - Polyostotic:
- 25%, 1/2 skeleton
- Childhood, F > M
- Pathologic fractures
- Pregnancy may stimulate growth - McCune Albright:
- FD + endocrine, skin, sarcoma (< 1%)
Treatment: curettage, fracture repair
Non-ossifying fibroma
AKA: Fibrous cortical defect
- Common (25-40%, 4-10 years old)
- Sites: tibia, femur
- Neoplastic vs developmental
- May see fratures
X-ray: cortical, scalloped, eccentric
Histo: spindle cells with multinucleated giant cells, macrophages
Solitary bone cyst
Unilocular, fluid-filled, non neoplastic cyst
- Disturbance of bone growth with trauma
- Kids/adolescents, M > F (3:1)
- 2/3 upper humerus, femur
- Metaphyseal, adjacent to growth plate
X-ray: demacated
Histo: thin, fibrous cyst wall
Clinical: fracture, usually asymptomatic
Aneurysmal bone cyst
Expansive, hyperemic (blood filled sponge)
- Kids, adolescents
- Periosteum around lesion thin but intact
Histo: granulation tissue, mononucleated giant cells and osteoid trabeculae
May represent cystic degeneration of underlying lesion
Treatment: curettage (remove entire segment due to risk of osteosarcoma underlying hemorrhage
Osteoid Osteoma
Small, painful benign lesion
- M > F (3:1), 5-25 years
- Cortical, usually metaphysis; diaphysis of lower extremity long bones
Clinical: pain, worse at night, relieved by ASA
X-ray: sclerotic cortical lesion
Histo: nidus composed of thin trabecular bone, granulation tissue background
- Numerous osteoclasts, osteoblasts
Treatment: curettage, radiofrequency, electrocautery, mini bloc excision
Osteoblastoma
Histo: similar to osteoid osteoma but larger
- M=F, 10-25 years
- NOT accompanied by sharp pain
Sites: mainly spine, long bones
Imaging shows benign process: encapsulated, no inflammatory reaction
Enchondroma
Intraosseous tumor
- Well-differentiated cartilage
- Any age, asymptomatic
- Removal only due to concern of well-differentiated osteosarcoma
Site: metacarpals, phalanges
- Hands/ feet
X-ray: well delineated, lytic
Histo: increased cellularity, atypia
Treatment: curettage if painful or causing fractures
Chrondroblastoma
Uncommon epiphyseal tumor
- 2nd-3rd decade, M > F
Sites: femur, tibia, humerus
X-ray: lytic, eccentric
Histo: chondroblasts, mineralized matrix, multinucleated giant cells; “Chicken wire” matrix
Osteosarcoma
Most common PRIMARY malignant bone-forming tumor (most common bone tumor= metastatic)
- 2nd decade, M > F
- Rb gene mutation in 2/3; p53
Sites: metaphysis of femur, tibia > humerus
X-ray: lytic, sunburst pattern, codman’s triangle
Clinical: Pain, increased alk phos
Histo: woven bone (osteoid) with malignant osteoblasts
Variants:
- Parosteal
- Periosteal
- Telangiectatic
Chondrosarcoma
2nd most common primary malignant bone tumor
- M > F, 4th-6th decade
- Some from cartilage enchondromas
- Variants classified by location
- Can see molecular trisomy 7, rearrangement of chrom 17
- extracellular sarcoma mixoid type: (9;22)(q31;q12)
Sites:
- Axial, proximal femur, humerus
X-ray: lucent or ring-like
Histo: grading based on cellularity, degree of atypia
Ewing sarcoma
Uncommon
- 2/3 < 20 years, M > F (2:1)
- Reciprocal translocation t(11;22)(p13;q12), PNET family
Clinical: pain, swelling
X-ray: midshaft/diaphysis of long bones; “onion skin pattern”
Histo: small round blue cell tumor
- PAS, CD99
- t(11;22) or t(21;22)
Treatment:
- Chemo/radiation
- surgery
- 60-75% 5-year recurrence rate
Giant cell tumor
Locally aggressive
- 3-4th decard; F > M, Asians
- Site: epiphysis, metaphysis of long bones
Clinical: pain, path fractures
X-ray: lytic, multilobulated “soap bubble”
Gross: Blood-filled sponge
Histo: mononuclear and mononucleated giant cell tumors
Treatment: curettage, recur (50%), 10-15% lung mets
Multiple Myeloma
Malignant plasma cells
- M > F, 65 years
- Sites: skull, spine, ribs, pelvis, femur
X-ray: lytic
Plasmacytoma=
Multiple myeloma=
Histo: sheets of plasma cells
Diagnosis:
- Protein electrophoresis
Treatment: radiation, chemo
- MM: Poor prognosis (32 months)
- Plasmacytoma: 65% 5-year survival
Metastatic bone tumors
Most common malignant tumor of bone
Most are carcinomas
Sites: vertebrae
x-ray: lytic, blastic
Origin: Prostate, breast, kidney, thyroid, lung
Treatment: surgery, chemo, radiation
- Prognosis: represents advanced cancer stage
Nodular fasciitis
Benign, fast-growing tumor
- adults
- Site: extensor surfaces
Etiology: trauma-induced reactive proliferation
Histo: active fibroblastic lesion
Treatment: excision
Fibromatosis
Slow-growing, locally aggressive
- Increased incidence in diabetics, alcoholics, epileptics
- May recur after excision
- Palmar (1-2%), plantar
Histo: bland spindle cells
Fibrosarcoma
Malignant fibroblastic tumor
- Adults: seen in thigh, knee
- Congenital form= t(12;15)
- Firm mass
Histo: cellular fibroblastic proliferation with varying atypia
- Pleomorphic, hypercellular
- “herringbone pattern”
Treatment: surgical
Prognosis: 40% 5-year, directly related to differentiation
Undifferentiated high grade pleomorphic sarcoma
Malignant fibrous histiocytoma
- Most COMMON soft tissue tumor
- seen in older adults
Sites: deep fascia, skeletal muscle
Histo: pleomorphic, storioform
Prognosis: dependent on cytologic atypia
- 50% recur
- Lung metastases
Lipoma
Most common benign soft tissue mass
- Sites: subcutaneous tissue, upper half of body
Gross: yellow, soft, lobulated
Histo: mature adipocytes
Treatment: simple excision
* Deeper: harder to differentiated from liposarcoma
Liposarcoma
2nd most common sarcoma
- Adults, > 50 years
- Slow-growing, may be large (thigh, retroperitoneum)
Histologic subtypes:
- Myxoid variant: t(12;16)(q13,p11)
Prognosis: dependent on subtype (round cell type- < 20% 5 year survival)
Leiomyoma
Benign smooth muscle tumor
- Extrauterine: subcutaneous tissue
- May be painful
Histo: bland spindle cells, low mitotic rate
Treatment: simple excision
Leiomyosarcoma
Seen in extremities, BV wall
- Larger with necrosis, cystic degeneration
Histo: fascicles of spindle cells with varying atypia, mitotic rates
Prognosis: majority eventually metastasize
Rhabdomyosarcoma
Striated muscle differentiation
- Most common soft tissue sarcoma in children
HIsto: 5 types: prognosis best–> worst
- Botryoid embryonal: best prognosis
- Spindle
- Embryonal
- Alveolar
- Undifferentiated
Treatment: combined therapy
Prognosis: 80% 5-year
Synovial sarcoma
Arises in joint; highly malignant
- 10% soft tissue sarcomas
- Seen in adolescents, young adults
- Painful, tender mass
Histo: bi- or mono-phasic
60% recur; lung metastases
Prognosis: 50% at 5 years
Osteopetrosis: Pathogenesis
Marble bone disease: Albers-Schonberg disease
- Group of rare, heritable disorders; increased skeletal mass due to abnormally dense bone
Autosomal recessive= severe, fatal to infants
- Marked anemia, cranial nerve entrapment, hydrocephalus, infection
Autosomal dominant= mild anemia/ asymptomatic
Pathogenesis:
- Failed osteoclastic bone resorption
- Mutation in osteoclast formation/function genes
- Defect in acidification of bone
- Mutations: TCIRG1 (AD- proton pump); CLCN7 (AR- Chloride channel), Carbonic anhydrase II (AR); transciption factors, cytokines causing osteoclast differentiation
- Primary spongiosum remains–> cartilage cores, thickened cortex, lack of funnelization of metaphysis
Ostopetrosis: clinical
Short, block-like radiodense bones on x-ray/CT
- Radiopaque, 2-3 times normal weight
- WEAK bone due to disorganized structure (can’t remodel with stress)
- Calcified cartilage= weak, friable
Anemia due to replacement of marrow by sheets of osteoclasts, marrow fibrosis
- Extramedullary hematopoeisis
- Pancytopenia
Blindness, deafness (foramen entraps nerves)
Treatment: bone marrow transplant, human IFN-gamma
Osteogenesis imperfecta
AD mutation in Type 1 collagen gene (Chr 17,7)–> delayed maturation of bone, joints, ears, ligaments, teeth, skin (7 types)
OI1= mildest form, blue sclerae
- Fractures after birth
- Exuberant callus formation (tumor-like)
- Ossicles fuse–> deafness (age 20-30)
- Normal stature
OI2= lethal prenatal form
- Marked short stature, limb deformities
- Crushed in utero
OI3= progressive, most severe type
- multiple fractures present at brith
- AD (rare AR)
- Severely short stature
OI4= similar to OI1 with normal sclera
- Cortical bone woven–> eventually matures
- Aggressively treated to prevent dwarfism
Osteogenesis: pathogenesis
Mutations of Col1A1 (all OI), Col1A2 (OI 2, 3, 4) on chrom 17, 7
- Point mutation of glycine residue most common in OI
- Col1A2 mutation seen in 1/2 synthesized collagen molecules- variable phenotypes
Osteonecrosis
Bone, marrow death; more common in children
Multiple causes:
- Trauma
- Emboli
- Systemic disease
- Steroids
- Bisphosphonates
Necrotic bone: stress fracture and compaction over time–> fracture of rigid articular cartilage and subchondral bone
Legg-Calve-Perthes
Avascular necrosis of femoral head in children
- Necrosis and remodeling–> collapse of subchondral bone, incongruous articular surface
- May cause severe arthritis
Femoral head in kids depends in lateral epiphyseal vessels susceptible to trauma, intrarticular pressure
Osteomyelitis
Infection of bone (usually bacterial: staph, strep, haemophilus, salmonella) and marrow
- Direct penetration (trauma) or hematogenous
- Can also cross cartilage, infect joint spaces
Hematogenous: kids 5-15 years- may see fever, localized pain, etc
- Can also be seen in drug addicts
X-ray to diagnose aggressive process
Pathogenesis:
- Unique blood supply at metaphyseal area–> slowing of blood
- Bacterua penetrate wall–> infection
- Increased pressure–> compromised blood supply–> necrosis–> more bacteria
- Access to cortex, periosteum, joint, skin (claoca)
- Sequestrum= dead cortical bone
- Involucrum= new bone formation around dead bone
- Brodie abscess= sequestrum within pus
In vertebral bodes: disc are NOT barrier for spread
- Enterics, staph–> attract inflammatory cells–> collagenase–> move to other cells
- Complications: vertebral body collapse, spinal epidural abscess, cord compression
- Vertebral body collapse, neurologic defects
Complications:
- Septicemia
- Acute bacterial arthritis (joint space)
- Pathologic fracture
- Squamous cell carcinoma (chronic infection)
- Amyloidosis (chronic infection)
- Chronic osteomyelitis
Chronic osteomyelitis
Changes from acute inflammatory process–> chronic
- See plasma cells, lymphocytes
- Due to failure to resolve acute osteomyelitis
** Differentiate from myeloma, cytoma (plasma cell)- run immunohistochemical stains for light chains (polyclonal vs monoclonal)
Marrow fibrosis–> fibrosseous lesion
Treatment:
- Surgical debridement; long term antibiotics
Tuberculosis
From focus elsewhere
- Affects vertebral bodies; spares lamina, spines (Pott’s disease)
- Thoracic vertebrae (t-11> cervical or lumbar)
- Leads to collapse of vertebral body
- Can track down anterior soft tissue, spinal ligaments–> moves into pelvis, inguinal region (Cold abscess= psoas abscess)
Path: Caseating granulomatous inflammation - Slow resorption of bone - Little or no woven bone--> collapse - Special stains (AFB- organisms visible), look for sarcoid, fungi
Osteoporosis types
Primary= more common
- Type 1= post-menopausal; absolute increase in osteoclast activity due to estrogen withdrawal
- Type 2= > 70 years, attenuated osteoblast function (no increase in osteoclast activity)
Secondary osteoporosis: Associated with other conditions:
- Endocrine (Cushing’s, hyperthyroidism, hypogonadism, iatrogenic steroids–> inhibited osteoblasts)
- Hematologic malignancies (Multiple myeloma–> activates osteoclasts
- Malabsorption (decreased Ca, Ph, Vit D)
- Alcoholism–> directly inhibits osteoblasts
Primary hyperparathyroidism and bone disease
Increased PTH–> bone resorption
- Early= line of osteoclasts–> flare lesions 1. osteitis fibrosa (osteoclast stimulation–> marrow fibrosis)
2. osteitis fibrosa cystica - -> brown tumor (hemosiderin deposition) : late stage
- Subperiosteal bone resorption
Osteomalacia
Inadequate bone mineralization of newly formed bone, cartilage matrix
- Adults and kids–> osteopenia
Causes:
- abnormal Vit D metabolism
- Intestinal malabsorption
- Renal disorders
- Phosphate deficiency
- mineralization defects
Path:
- pseudofractures
- Exaggerated osteoid seams (osteoclast activity can’t occur, delayed calcification)
Paget’s disease: path
Chronic condition: bone enlargement and lytic lesions (disordered remodeling)
- uncoupling osteoblast/osteoclast activity
- See clast only activity, or blastic activity with patchy clast activity–> mosaic bone
- Seen in M & F > 60 years (3-4% in certain populations)
- Solitary or multiple sites
Pathogenesis: hereditary AD (chr 18)
- Sequestosome 1–> p62 protein in RANK pathway (more aggressive form)
- Viral nuclear inclusions similar to SSE (subacute sclerosing encephalitis)- giant cell tumor of bone
Path:
- “Hot” osteoclastic stage= lytic
- Mixed stage
- “cold” burnout stage: little activity
Histo:
- Prominent cement lines (“mosaic”)
- Osteoclast= pathologic cell; “killer clasts” with 50+ nuclei (vs normal 8)
- Can see sarcomatous change in < 1% (adult type of osteosarcoma)
Paget’s disease: clinical
Pain (focal feature)
- Skull involvement (frontal/parietal)
- Pagetic steal–> light headedness (calvareal bone is stealing blood supply)
- Fractures/ arthritis
- High output cardiac failure (significant part of skeleton involved–> increased cardiac demands)
- Sarcomatous change, osteosarcoma in older patients (< 1%)
Osteoarthritis
NOT inflammatory process
“Wear and tear” loss of cartilage
Cartilage breaks down, retains water–> thinning, cracking–> narrow joint space
- Versus just aging–> decreased cartilage water content
Osteophytes (cysts), subchondral cysts, sclerosis
Joint: synovitis, inflammation, stiffness/grinding–> pain
Joint reactive forces
One cause of osteoarthritis- cumulative stress of weight and muscle force on joints. Examples (on knees): - Walking= 2.5 times body weight - Jogging= 4.5x body weight - Running= 5.5 x body weight - Stairs = 7x body weight
Causes of osteoarthritis
Risk factors:
- Female
- Obese
- Prior joint injury
- Family history
Physical exam for osteoarthritis
Appearance ROM (limited, may have contractures) Tenderness Stability Crepitus (grinding) Maneuvers (Patricks: abduct hip) Neurovascular status (maybe claudication is causing pain) - Examine above and below site: hip may be causing knee pain Varus vs valgus alignment Should have no erythema, may be warm
Osteoarthritis testing
- Radiographs (weight-bearing X-ray)
- Joint space narrowing
- Subchondral cysts
- Bony sclerosis
- Osteophyte formation
** Severity of x-rays and clinical symptoms do NOT always correlate
- NO lab tests
- MRI can show arthritis, but x-ray best
Osteoarthritis treatment: non-operative
Alleviate pain, restore function
Non-operative treatment:
- Patient controlled (weight loss, activities)
- Physician controlled (meds- NSAIDs, supplements- glucosamine, chondroitin, PT/braces, injections- next step!)
- injections:
1. Corisone (should last up to 6 months)
2. hyaluronic acid (synvisc) supplementation (after cortisone not effective)
Osteoarthritis treatment: operative
Surgery:
- Failed conservative management
- Severe, intolerable pain
- Unable to perform activities of daily living
- Diminished quality of life
- Age limitations: not many, usually health
Surgical options:
- Debridement (only effective in elbow)
- Osteotomy (younger pts with one-sided degeneration)
- Arthrodesis (fusion- rare except in low back)
- Resection (may be seen after series of infection- seen at base of thumb= 2nd most common arthritis site after knee)
- Replacement:
1. Hemiarthroplasty
2. Unicondylar
3. Patellofemoral
Or TOTAL
Total joint replacement complications:
- Infection
- Bleeding
- DVT, PE
- Hip dislocation
- Periprosthetic fracture
- Neurovascular
Cytokines involved in RA
Proinflammatory:
- TNF-alpha
- IL-1
- IL-6
Anti-inflammatory
- IL-6 receptor antagonists
- IL-1 receptor antagonists
- IL-10
- Soluble TNF-receptor
History of RA treatment
1930s:
- Gold
1950s:
- Cortisone
- Antimalarials
- Immunosuppressants
1960s:
- Sulfasalazine (also used in IBD)
- Penicillamine (narrow therapy window)
1980s:
- Methotrexate
1990s: age of biologics (change in approach to treatment)
- Leflunomide
- Etanercept
- Infliximab
- Anakinra
1990s: emphasis on treatment of symptoms, limiting joint destruction; use of DMARDs in higher doses, earlier use
2004 on: use biologic monotherapy earlier, biologic with methotrexate
- When patient fails targeted therapy, switch therapy (monitor every three months)
Recommendations for use of biologic DMARDSs in RA patients
Low disease acitivity: Non-biologics for 6-24 months
Moderate:
- Features of good prognosis: non-biologics
- Poor prognostic features (high RA factore, bone erosions, etc.): Anti-TNF
High disease features:
- Anti-TNF
Renal elimination of uric acid
100% filtered at glomerulus
- 98% reabsorbed in PCT
- 40-50% secreted and reabsorbed
- 8-12% excreted
Overproduction of uric acid:
- Inherited enzyme disorders
- Myeloproliferative disorders (P. vera, hemolytic anemia, lymphoproliferative disorders, malignancies, psoriasis, obesity)
- Drugs (ethanol= beer, cytotoxic drugs)
- Diet (Shellfish)
- alcohol decreases uric acid excretion, increases uric acid production
Underexcretion of uric acid:
- Chronic renal failure
- Lead nephropathy
- Dehydration
- Starvation
- Drugs (diuretics, alcohol, low dose aspirin, cyclsporine, tacrolimus, niacin, ethambutol, pyrazinamide
Stages of hyperuricemia
Stage 1= asymptomatic
- Serum urate > 6.8 mg/dL
- Not indication for treatment
- Look for cause, associated conditions
Stage 2= acute gouty arthritis, intercritical gout
- Frequent attacks: prophylax to keep uric acid low
- Infrequent attacks: treat symptoms
- Tx for acute gout:
1. NSAIDs
2. Oral cochicine
3. Systemic glucocorticoids (hospital use)
4. Intra-articular glucocorticosteroids
5. Off-label: synthetic ACTH, IL-1 antagonism (anakinra)
Stage 3= chronic gouty arthritis:
- Tophi on physical exam
- Chronic degenerative arthritis
- Indications for drugs:
1. Frequent attacks ( > 2/year
2. Visible/radiographyically detected tophi
3. Defined uric acid overproduction
4. History of urolithiasis
5. Difficult to treat attacks due to polyarticular gout, CKD, CHF, major organ transplant
Spondylarthropathies (SpA)
Chronic inflammatory disease either axial symptoms of spine and sacroiliac joints or predominantly peripheral SpA
- Rheumatoid Factor negative (seronegative)
- Associated with human leukocyte antigen HLA-B27
- Characterized by inflammation around enthesis (site of ligament insertion into bone)
- Affect young M:F 4:1 adults with peak age of onset between 15 and 45 years
- Multisystem chronic inflammatory diseases
Can be associated with:
- Uveitis
- Psoriatic arthritis
- Psoriasis
- Reactive arthritis
- IBD
- Arthritis associated with UC/Crohn
Can see SpA on MRI (non-radiographic) or x-ray
Types of Spondyloarthritides
Predominantly axial:
- Non-radiographic axial SpA
- Ankylosing spondylitis
Predominantly peripheral:
- Reactive arthritis
- Psoriatic arthritis
- Arthritis with IBD
- Undifferentiated SpA
Assessment of SpondyloArthritis
Inflammatory back pain: 4/5 parameters fulfilled:
- Age at onset < 40 years
- Insidious onset
- Improvement with exercise
- No improvement with rest
- Pain at night (with improvement upon getting up)
In patients with >= 3 months back pain (w/ or w/o peripheral manifestations), onset < 45:
- Sacroillitis on imaging + 1+ SpA feature
- HLA-B27 + 2+ SpA features
In patients with peripheral manifestations ONLY:
- Arthritis, enthesitis (swelling at insertion of tendon into bone- commonly mistaken for achille’s tendon tear) or dactiylitis (swollen toes) plus SpA features
Seen in 16 common sites of joints
Extraarticular manifestations of Spondyloarthritis
- Uveitis: photophobia in one eye
- Aortic involvement
- Pericarditis
- Pulmonary fibrosis
- Amyloidosis
Pathophys of Ankylosing Spondylitis
- Joint space inflammation
- Erosive damage and repair
- NEW BONE formation (versus RA)
HLA-B27 and Spondyloarthropathies
Class II MHC (interaction between cells and environment)
- Seen in 90% of Caucasian Ankylosing spondylitis patients
- ONLY 1-2% HLA-B27 patients develop AS
- Male to female 4:1 + women have milder disease (underdiagnosed)
- Family history: 10-20% of patients with HLA-B27 will develop AS
Strong association with GI inflammation
- Reactive arthritis following shigella, salmonella, campylobacter
- HLA-B27-positive patients with IBD have higher risk of developing reactive arthritis
Diagnostic testing for Ankylosing spondylitis
MRI:
- Lumbar spine
- PA of pelvis
Spinal mobility: chest expansion
Schober test: spine should stretch by ~ 10 cm when bending forward
Reactive arthritis
Acute inflammatory arthritis 1-4 weeks after infection
- Asymmetric oligoarthritis
- 75% Caucasian, 50% AA with reactive arthritis= HLA-B27+
- Triggered by: shigella, salmonella, yersinia, campylobacter, chlamydia, ureaplasma, HIV
Seronegative asymmetric arthritis following:
- Urethritis, cervicitis, infectious diarrhea
Associated features:
- Inflammatory eye disease, balanitis, oral ulceration, keratoderma, enthesopathy, sacroiliitis
Psoriatic arthritis
Polygenic autoimmune disease characterized by:
- Arthritis
- Enthesitis
- Spondylitis
M=F
Psoriasis in 2-3% population;
- PsA in 6-48% of psoriasis patients depending on case series (probably ~25%)
Risk factor= obesity; severity of psoraisis (not predictive of severity of arthritis; predictive of occurence)
Subsets:
- Asymmetric oligoarthritis (dactylitis)= sausage fingers
- DIP arthritis
- Rheumatoid arthritis-like polyarthritis
- Psoriatic spondylitis
- Arthritis mutilans
- HIV associated psoriatic arthritis
* * (50% of patients with axial scoriatic arthritis will be HLA-B27 positive,not in peripheral involvement)
Enteropathic arthritis
IBD-associated Inflammatory arthritis (Crohn or UC)
- NO association between HLA-B27 and peripheral arthritis
- 50% association with HLA-B27 in axial involvement
M=F, seen in younger patients with no age preference
Peripheral joint enteropathic arthritis (5-20% cases):
- Onset coincides with IBD symptons (abdominal pain, diarrhea) in 80% of cases but may also precede or follow the intestinal disease.
- Attacks are typically acute, episodic, recurrent and parallel bowel disease activity.
- Monoarthritis or asymmetric oligoarthritis (frequently migratory) involves the knee. Sausage fingers
- The arthritis of IBD is rarely destructive unlike rheumatoid arthritis
Spondylitis and Sacroiliitis:
- Occur in up to 7% of Crohn’s and 25% of ulcerative colitis patients and are often asymptomatic.
- Most often found in patients who are HLA-B27 positive.
- Radiographic findings resemble those seen in AS.
- Symptoms do not usually parallel activity of bowel disease.
Management of Ankylosing spondylitis
Education, exercise, activity
Peripheral disease:
NSAIDs
Sulfasalazine, local corticosteroids
TNF blockers
Axial disease:
NSAIDs
TNF blockers
Hard to tell what the progression of disease will be
- Monitor with MRI
- Conservative use of TNF-alpha inhibitors
- Systemic illness:
Giant Cell Arteritis (GCA)
Large Vessel Vasculitis
Used to be called temporal arteritis – but it can involve more than just the temporal artery
- Primarily affects the cranial branches of the arteries originating from the aortic arch
- May affect the aorta
- Most common primary form of vasculitis
- Seen primarily in Caucasians of N. European descent (not in AA), F > M, increases with age
Clinical presentation:
- Severe unilateral headache with scalp tenderness
- Jaw claudication and constitutional symptoms (fatigue, anorexia, weight loss)
- Impaired blood flow to affected area causes symptoms: Vertebral (stroke), retinal (blindness)
- Vision loss is most feared symptom, usually irreversible (anterior ischemic optic neuritis or retinal artery occlusion)
Evaluation:
- Physical exam: normal or show decreased pulse, thickened nodular artery
- NO LAB testing: high ESR may be found
- Biopsy can be helpful, not sensitive: biopsy every 1-2 cm to rule out “skip lesions”; biopsy both sides
- Looking for granulomas around large vessels
- No radiologic technique as specific as biopsy
Treatment:
- High dose steroids given severity of manifestations such as blindness
Polymyalgia rheumatica (PMR)
Patients report pain, stiffness in muscles of neck, shoulder, pelvic girdle
- Associated with signs of systemic inflammation such as elevated ESR, CRP
- Dramatically Responsive to low dose prednisone (vs arthritis, which is mildly responsive)
40-60% patients with GCA have PMR symptoms
- 15% of PMR patients will develop GCA; can be first symptom of GCA
- Low dose prednisone will not control GCA
Takayasu’s arteritis
Large vessel vasculitis
VERY uncommon
Primarily affects young Asian women < 40 years old
- Affects large vessels: aorta, coronary, pulmonary arterties
“Pulseless disease”
Systemic signs and neurologic /cardiac symptoms
- May have claudication of extremities
Diagnosis: made with imaging but physical exam may show bruit
- Imaging of vessels: any evidence of claudication
Treatment: Steroids
Polyarteritis nodosa
Slight male predominence, broad age range
- Constitutional symptoms
- Strongly associated with Hep B infection
Symptoms depend on organ affected by commonly affects GI tract: may also see:
- HTN, neuropathy, testicular pain, cutaneous disease
- Spares lung and glomeruli (can involve renal artery with aneurysms)
Mononeuritis multiplex= Blood vessels that supply nerves attacked–> nerve death–> wrist/foot drop (most common cause of foot/wrist drop is diabetes)
Evaluation:
- No specific diagnostic tests
- May see elevated inflammatory markers
- Mesenteric/renal angiography- aneurysms, irregular constrictions
- NOT ANCA-associated vasculitis
Treatment:
Immunosuppression required due to 2-5 year mortality
- Degree of treatment guided by disease severity
Kawasaki Disease
Acute, self-limiting illness affecting young children, infants (85% < 5 years)
- More common in Japan
Symptoms:
- Fever, congestions, conjunctival infection, oral cavity dryness/redness with blistering, lymph node swelling, rash on palms and soles
** May have later complications from cardiac disease (coronary arteries)
Pathology: PAN-like vasculitis with necrosis and inflammation affecting the entire thickness of the vessel wall but with less prominent fibrinoid necrosis. Pathologic changes outside the cardiovascular system are rarely significant!
** Treated with intravenous immunoglobulin (IVIG) early (less than 10 days) decreases aneurysm formation by up to five-fold
ANCA-associated vasculitis
ANCA= anti-neutrophil cytoplasmic antibody
- C-ANCA: cytoplasmic antigens (PR3)= ELISA
- P-ANCA: perinuclear antigens (MPO, many other antigens- less specific)
3 types; overlap in clinical features:
- Wegener’s granulomatosis= granulomatosis with polyangiitis (GPA)
- C-ANCA or PR3 (proteinase 3) in 80-90% patients - Microscopic polyangiitis (MPA)
- P-ANCA or MPO in 70% patients
- Like GPA with no granulomas - Churg-Strauss= eosinophillic granulomatosis with polyangiitis (EGPA)
- P-ANCA or MPO in ~50% patients
Diseases treated similarly: immuno-suppressants chosen based on degree of organ involvement
Granulomatosis with polyangiits
M=F, peak in middle age
- Patients usually have constitutional symptoms
- Limited form: only involves upper respiratory tract and/or lower respiratory tract
- Upper respiratory symptoms: chronic sinusitis, epistaxis, “infections”
- Can see nasal perforations, “saddle nose” deformity
Lower respiriatory symptoms: range from pulmonary infiltrates to alveolar hemorrhage
- Cavitary nodules
- Glomerulonephritis
Likely to see increased inflammatory markers: ESR, CRP, ANCA
- C-ANCA or PR3 in 80-90% patients
Treatment: immunosupression
Eosinophilic granulomatosis with polyangiitis (EGPA)
M=F, mean age= 40
- Majority of patients have asthma, atopy, allergy (ex: asthma that patient can’t control with meds)
- Can affect MULTIPLE organ systems (not just lung)
- Symptoms depend on affected organ, can also include recalcitrant asthma
Found with eosinophilia:
- Biopsy shows eosinophilic inflammation, necrotizing vasculitis
- Associated with P-ANCA, MPO
Cryoglobulinemic vasculitis
Ig precipitate in cold:
- Type 1= monclonal antibody (IgG)
- Type 2= Polyclonal IgG and monoclonal IgM RF
- Often due to Hep C (treat Hep C, cure vasculitis), HIV - Type 3= polyclonal immunoglobulins
Thought to induce disease through immune complex activation, deposition in vessels
Clinical features:
- Related to organ involvement
- May see digital ulceration/cyanosis, Raynaud’s phenomenon
- Neuropathy, renal failure, rash
IgA vasculitis
AKA Henoch-Schonlein purpura
- Primarily affects children ~ 5 years
- Most commonly diagnosed vasculitis in children
- Common Upper respiratory tract infection followed by purpuric rash, arthralgias, abdominal pain
- May also have glomerulonephritis
Treatment: supportive (self-limiting in children)
Hypocomplementic urticarial vasculitis
Patients have urticarial lesions that lasts > 24 hours and SCAR
- May also have arthritis, arthralgias, glomerulonephritis, uveitis, episcleritis, pulmonary involvement, abdominal pain
Labs:
- Low complements with low C1q level, anti-C1q antibodies
May be from primary autoimmune disease- associated with other etiologies
Behcet’s disease
Severe aphthous ulcers, genital ulcers, skin lesions, ocular involvement, all size blood vessels
- More common in Middle Eastern male patients
Pathergy: pustule forms where IV inserted into arm (unique to Behcet’s)
Cogan’s syndrome
Inflammatory disorder affecting eyes and ears, no direct test
Cutaneous leukocytoclastic angiitis
Characterized by immune complex deposition in arterioles, venules, capillaries
Systemic or primarily cutaneous: palpable purpura, maculopapular rash
Biopsy: cutaneous leukocytoclastic angiitis- not confirmatory for autoimmune disease
Therapy: remove inciting agent, immuno-suppression
Primary CNS vasculitis
Affects small and medium blood vessels in brain parenchyma, spinal cord, leptomeninges–> CNS dysfunction
Male predominant, may occur at any age
Rare disorder, poorly defined characteristics, incredibly difficult to diagnose
- Can have normal CSR
- See abnormal MRI/MRA (most likely due to HTN, other causes)
- Need brain biopsy to confirm: should see vasculitis
Treatment: high dose steroids, immune suppression
Isolated aortitis
Inflammation of just the aorta
- Numerous condition can cause it: Giant cell, Takayasu’s, peri-aortitis (majority)
- May be associated with retroperitoneal fibrosis
- May see “soft rind” around aorta
Treatment: immunosuppression
Rheumatoid vasculitis
Not seen often following improved treatments for RA
Sarcoid vasculitis
See vascular and pulmonary involvement
Drug-associated ANCA-associated vasculitis
Cocaine cut with antifungal powders causing immune response–> formation of C-ANCA and P-ANCA antibodies
- Can lead to vasculitis, necrosis of nose, ears
Skeletal muscle fiber types
Type I – Red, Slow Twitch, Oxidative
- Antigravity muscles, sustained contraction
- Red= Increased myoglobin, increased oxidative enzymes, more mitochondria
- Conditioning increases mitochondria
Type II- White, Fast Twitch, Glycolytic,
- Increased glycogen, decreased myoglobin,
- Hypertrophied with “aerobic exercise”
- Hypertrophied with anabolic steroids
- Atrophy with disuse
Atrophy with corticosteroids
Duchenne Muscular Dystrophy
- X-linked – most common non-inflammatory myopathy of children
- Particularly affects pelvic and shoulder girdles
- Women are carriers, however 30% of cases are spontaneous. (Dystrophin gene is HUGE)
- Mutation of dystrophin localized to Xp21
- Dystrophin links the cytoskeleton of the muscle cell to the sarcolemmal membrane.
- DMD= complete or almost complete loss of dystrophin due to deletions of the gene.
Path:
- Dystrophin deficient fibers display osmotic fragility and undergo spontaneous necrosis.
- Diagnosis: Immunohistochemical staining for dystrophin Western Blotting, PCR
Disease characteristics:
- necrosis of muscle fibers and regeneration
- Regeneration is insufficient to keep pace and there is progressive loss of fibers and fibroadipose replacement.
- Becker’s muscular dystrophy: dystrophin protein present but it is usually truncated. As a result, the disease is milder.
Clinical DMD:
- Weakness evident by age 3 or 4
- Pseudohypertrophy of the calf muscles
- Wheelchair bound by age 10 years
- Bedridden by 15 years
- Death due to respiratory insufficiency and/or cardiac arrhythmias
- brain is also affected (mild mental retardation)
Limb-girdle muscle dystrophy
Patients with LGMD show similar clinical features- weakness of the pelvic and shoulder girdles.
- Onset may be in childhood or adulthood with variable muscle weakness.
- Patients may have difficulty walking, running or rising from a sitting position.
- Cardiac involvement is common.
Histology:
- Variants show unusual features including inflammation (LGMD2B, Miyoshi myopathy), rimmed vacuoles (LGMD1A) similar to those seen in inclusion body myositis
Proper diagnosis requires:
- detailed clinical history
- battery of immunohistochemical, immunoblotting and genetic tests.
- LGMD (2C through 2F) are also known as the sarcoglycanopathies.
Congenital muscular dystrophy
Characterized by hypotonia, weakness and contractures (floppy kid)
- Some variants associated with leukoencephalopathy, brain malformations and eye involvement.
Path: resemble other muscular dystrophies, with variable fibrosis and fatty
infiltration of the muscle.
Some may also cause limb-girdle dystrophies, with different manifestations
Myotonic dystrophy
Most common form of adult muscular dystrophy
- Characterized by Myotonia (difficulty in relaxation) and progressive muscle weakness
Two forms with autosomal dominant inheritance:
- DM1= CTG trinucleotide repeat syndrome
- Repeats in the DM protein kinase (DMPK) gene (Serine-threonine protein kinase)
- Normal - 30 copies of the CTG repeat
- Affected > 50 copies
- Congenital forms in children of affected DM1 mothers
- slowly progressive muscle weakness and stiffness are seen, principally in the distal limbs
- Facial and neck weakness as well as ptosis - DM2= CCTG repeats in the first intron of the ZNF9 gene
- Zinc Finger Protein (binds RNA)
- Proximal weakness more common than in DM1
Extra skeletal muscular manifestations:
- Cataracts, testicular atrophy, personality deterioration.
- Smooth muscle disorders of the GI tract and uterus.
- Cardiac arrhythmias
** Congenital myotonic dystrophy is seen in children of affected mothers.
Myotonic dystrophy: path
Type I fiber atrophy (peculiar) Type II fiber hypertrophy Internal nuclei Ring fibers Mild necrosis and regeneration
Congenital myopathies
Congenital Hypotonia
- Decreased deep tendon reflexes, decreased muscle bulk, delayed motor milestones
Changes usually limited to Type I fibers
- No active muscle fiber necrosis and relatively mild increases (if any) of serum creatine kinase
Central core disease
Type of congenital myopathy:
Autosomal Dominant
Ryanodine receptor mutation
- Calcium-release channel of sarcoplasmic reticulum.
- May be associated with malignant hyperthermia.
Muscle biopsy:
- Type I fiber predominance with a central pale zone on oxidative stains (NADPH-Tr)
- Ultrastructure shows loss of membranous organelles in the center of the fiber
Central Nuclear myopathy
Type of congenital myopathy:
Previously synonymous with Myotubular Myopathy
- Now considered two separate entities
Central Nuclear Myopathy
- Heterogeneous group characterized by the presence of centrally placed nuclei.
1. Recessive form
2. Autosomal dominant, adolescent onset - Clinically resembles limb-girdle muscular dystrophy forms
Fibers resemble the myotubular stage in the embryogenesis of skeletal muscle
- Dynamin 2 - gene involved in membrane trafficking, centrosome and actin assembly.
Myotubular myopathy
X-linked Myotubularin mutation
- Phosphatase involved in Phosphatidyl Inositol signaling cascades
Features:
- Marked neonatal hypotonia
- Respiratory failure at birth
Path:
- Centrally placed nuclei in both fiber types
Inflammatory Myopathies
Acquired disorders characterized by nonsuppurative inflammation with muscle fiber necrosis and elevated serum muscle enzymes
- Insidious symmetrical proximal weakness except in inclusion body myositis where distal muscle weakness may be more prominent
Thought to have an autoimmune origin- Association with other autoimmune and connective tissue disease:
- Detection of autoantibodies
- Response to immunosuppression (not inclusion body myositis)
Dermatomyositis
Afflicts children and adults
- Characteristic rash affecting the upper eyelids, face, and trunk
- Increased association with an underlying malignancy (usually carcinoma) in males
- Polymyositis and inclusion body myositis have a much reduced risk of underlying malignancy compared to dermatomyositis in adults.
Pathogenesis:
- Immune complex formation with IgG, IgM and complement including C5-9 membrane attack complexes in the walls of blood vessels
- NOT direct attack on muscle; also affects dermis as vascular attack occurs here too
Histology:
- Microangiopathy with loss of capillaries,
- perifascicular atrophy
- Perivascular infiltrates of B and T cells, predominance of CD4+ T cells
- Muscle infarcts
- Skin rash also related to the microangiopathy
Polymyositis
Inflammation focused on the muscle fibers themselves:
- No microangiopathy as in dermatomyositis
- Perifascicular atrophy absent
- CD8+ T cell mediated cell injury
- Frequent association between anti-Jo-1 (recognizes a histidyl-tRNA synthetase) as well as interstitial lung disease, Raynaud phenomenon, and nonerosive arthritis
Inclusion body myositis
Inflammatory features similar to polymyositis, but seen in 60+ years
Path:
- Rimmed vacuoles (best seen on modified Gomori Trichrome Stain)
- Increase in ragged red fibers
- Congo Red positive amyloid (Texas red optics) material including: Beta Amyloid, phosphorylated tau, alpha synuclein, ubiquitin, presenilins, parkin, etc.
- Intravacuolar and intranuclear filamentous inclusions (EM)
Treatment:
- IVIG
- Non responsive to immunosuppression (lymphocytes respond to muscle damage- don’t cause it!)
Nemaline myopathy
Heterogeneous group of muscle diseases characterized by the formation of rod like structures
- Autosomal dominant and recessive forms
Path:
Nemaline structures are electron dense and resemble Z-band material
Type II Glycogenosis
AKA: Acid Maltase Deficiency, alpha 1,4 Glucosidase Deficiency, Pompe Disease
- Various mutations
Pathogenesis:
- Acid Maltase is a lysosomal enzyme responsible for glycogen breakdown.
- Deficiency results in lysosomal storage of glycogen (membrane bound)
Clinical:
- More severe the earlier the age of onset
- In the neonatal form, there is macroglossia, cardiac, liver, and skeletal muscle storage. CNS also affected. Severe hypotonia
- Later onset and adult forms, clinical expression limited to muscle, progressive muscle weakness.
Type V Glycogenosis
AKA: McArdle Disease, Myophosphorylase Deficiency
- Usually not progressive or debilitating
Myophosphorylase is skeletal muscle specific
- Deficiency results in an inability to cleave glycogen and release glucose for energy utilization during physical exertion
Clinical:
- Muscle cramping
- Avoid strenuous exercise otherwise muscle necrosis, myoglobinuria and renal failure
Diagnosis:
- Absence of myophosphorylase,
- PAS positive storage of non-membrane bound glycogen
Type VII glycogenosis
Phosphofructokinase Deficiency
- Less common than McArdles but similar syndrome since it interferes with glucose utilization
- Slight anemia and hemolysis because of shared subunits of the enzyme in erythrocytes and muscle
Lipid storage myopathies
Clinical: Exercise intolerance
Path: Excess accumulation of neutral lipids (not CPT)
Disorders of :
- Deficient transport of fatty acids into mitochondria (carnitine deficiency syndromes and CPT deficiency)
- Defects in enzymes of Beta oxidation pathway
- Abnormalities of respiratory chain enzymes
- Defects in triglyceride metabolism
Carnitine deficiency
Carnitine synthesized in the liver
- Required for transport of LCFAs into mitochondria
- Autosomal recessive
Clinical:
- Progressive muscle weakness and atrophy
- Signs of denervation and peripheral neuropathy
- Massive accumulation of lipid in muscle
Treatment:
Oral carnitine may help
Carnitine Palmitoyl Transferase deficiency
Path:
Inability to metabolize LCFAs due to inability to transport them into the mitochondria
Clinical:
- Prolonged exercise results in muscular pain, myoglobinuria
- Prolonged fasting can do the same
Histo: No light microscopic changes
Mitochondrial diseases
Maternal inheritance for mitochondrial gene encoded proteins and tRNAs.
- Nuclear-encoded mitochondrial proteins are autosomally inherited
- Disease expression related to proportion of mutant mitochondria
Energy hungry organs especially CNS and muscle (cardiac and skeletal) are affected most:
- CNS= death of neurons
Path:
- Accumulation of mitochondria (SDH)
- Ragged Red fibers (also seen in inclusion body myositis)
- Lipid and glycogen accumulation due to improper metabolism
- Atrophy of muscle fibers
- COX deficiency
- Ultrastructural abnormalities of mitochondria may be seen but are not present in all cases.
Syndromes of mitochondrial disease
- Kearnes-Sayre syndrome (KSS):
- progressive ophthalmoplegia, retinal pigmentary degeneration, cardiac arrhythmias
- large deletions of mtDNA - Chronic Progressive External Opthalmoplegia
- Similar to KSS (only really seen in eyes): genetically autosomal dominant and recessive inheritance via nDNA
- polymerase gamma (deletions), helicase, ANT1 (adenine nucleotide translocator-1) - MELAS-mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes
- mutation in leucine tRNA mitochondrial-encoded gene - MERRF-myoclonic epilepsy and ragged red fibers.
- mutation in the lysine tRNA mitochondrial-encoded gene
Trichinosis
Trichinella spiralis:
- Acquired from ingestion of undercooked meat from infected animals (mostly pork)
- Encysted larva develop into adult worms within intestine.
- Female worms release larvae that penetrate gut and encyst in skeletal muscle
Clinical:
- often asymptomatic
- pain, tenderness, eosinphilia, periorbital edema
- infection of brain or myocardium may be fatal
Rhabdomyolysis
Risk Factors:
- Secondary to metabolic myopathies
- Crush injuries
- May complicate influenza
- Heat stroke
- Malignant hyperthermia
- Alcoholism
- Sepsis
Other causes:
- Noninflammatory destruction of fibers with phagocytosis
- Myoglobinuria and renal failure
- HMG CoA reductase inhibitors (Cholesterol lowering drugs such as Lipitor).
Drug-induced myopathy
Caused by:
- Steroids
- Chloroquine
- Colchicine
- Omeprazole
- Statins= HMGCoA reductase inhibitors
Critical illness myopathy
Also known as Acute Quadriplegic Myopathy, or Myosin Heavy Chain Depletion Syndrome:
- Classically results from the use of high-dose steroids and neuromuscular blocking agents.
- Profound loss of myosin (thick filaments) with preservation of other sarcomeric structure.
- Discontinuation of corticosteroids often results in reappearance of myosin filaments and recovery
- Cause unknown
Spinal muscular atrophy
Degeneration of anterior horn cells
- Second most common, lethal, autosomal recessive disorder after cystic fibrosis
- Type I (Werdnig-Hoffman Disease, Infantile Spinal Muscular Atrophy):
- Progressive and severe weakness in early infancy, death within 1-2 years.
- Histology: atrophy of type I and II fibers with clusters of surviving hypertrophied type I fibers. - Type II Intermediate
- Type III Kugelberg-Welander Disease, Juvenile Spinal Muscular Atrophy:
- Later onset, not necessarily progressive
- Fiber type grouping
- Degenerating and regenerating fibers
Myasthenia Gravis
- Weakness with repetitive motion; waxes and wanes
- 10% overall mortality associated with respiratory insufficiency due to muscle weakness
- Autoimmune attack on Ach receptors on motor endplates results in decreased numbers of receptors
Cause:
- 40% have thymomas
- 75% of remaining patients have thymic hyperplasia
Light microscopy:
- Sparse lymphocytic infiltration
- Type II fiber atrophy
Ultrastructure:
- Decreased folds at neuromuscular junction
Treatment:
- Thymectomy, immunosuppression, Ach-esterase inhibitors, plasmaphoresis
Lambert-Eaton syndrome
Paraneoplastic disorder characterized by:
- muscle weakness, wasting and fatigue of the proximal limbs and trunk
Usually associated with small cell CA of the lung but may be associated with other malignancies or may occur in isolation.
IgG against voltage-sensitive calcium channels that are expressed in motor nerve terminals and in the cells of lung cancer
- The calcium channels are necessary for release of Ach
Systemic Lupus Erythemaosus: epidemiology
- Incidence of 1.8 to 35 cases per 100,000/ year in general population
- Prevalence fluctauates from 250000 to 1.5 million cases of lupus.
- Women>Men – 9:1 ratio
- African Americans>Hispanics>Whites
- Usual onset between 15-45 years (60% cases)
SLE: Pathogenesis
Etiology is unknown • SLE is an autoimmune disease • Genetic factors – HLA association (HLA DR2/HLA DR3) • Environment factors – Sunlight, drugs, chemicals, foods – Bacterial or viral infections – More associated with flares and exacerbations • Hormonal factors – Increased estrogen and prolactin levels - Flares during pregnancy (vs RA)
Immune changes:
- Abnormal complement components (C1q, C4, etc )
- Fc Receptor abnormalities
- -> delay in clearing dying (apoptotic) cells, exposing more autoantigens.
SLE: Clinical manifestations
Protean, may mimic Infectious Mononucleosis, lymphoma, etc
- Criteria derived to establish/rule out diagnosis (patients might not fulfill criteria initially, but most will manifest over time):
1. Malar rash: Fixed erythema, flat or raised, sparing the nasolabial folds
- Discoid rash : Raised patches, adherent keratotic scaling, follicular plugging; older lesions may cause scarring
- Photosensitivity: skin rash from sunlight; feel worse after sun exposure
- Oral ulcers: usually painless
- Arthritis: nonerosive, inflammatory in 2+ peripheral joints
- Serositis: pleuritis, pericarditis
- Renal disorder: persistent proteinuria, cellular casts
- Neurologic disorder: seizures, psychosis
- Hematologic disorder: hemolytic anemia, leukopenia (< 4000/mm3), lymphopenia (< 1500/mm3) or thrombocytopenia (< 100,000/mm3)
- Immunologic disorder: antibodies to dsDNA or SM or positive antiphospholipid antibodies (IgG or IgM, lupus anticoagulant, false-positive serologic test for syphillis- may see antibody to treponema phospholipids)
- Antinuclear antibody positive
SLE: clinical features at first presentation
- Arthritis (55%)
- Skin involvement (25%)
- Nephritis (5%)
- Fever (5%)
- Other (15%)
Organ involvement in course of SLE:
Joints 90%:
- Arthritis and/or artharlgias are the most common presenting manifestation of SLE
- Most cases: Symmetrical.
- Unlike RA, is usually non-erosive ( at xrays) w/ subluxations, initially reversible.
- Involve periarticular surfaces.
- Increase frequency of tendon rupture.
- Fibromyalgia can overlap joint sx.
Skin
- Rashes 70%: butterfly rash, interarticular dermatitis, palpable purpura
- Discoid Lesions 30%: erythematous, hyperpigmented; flattened; scarred central areas with thin/fragile epidermis; follicular plugging
- Discoid lupus can become systemic lupus
- Alopecia: diffuse 40%
Pleuropericardium 60%
- Serositis: pleuritic pain more frequent than effusions
- Fluid exudative with normal glucose
Pulmonary manifestations:
- Pneumonitis
- Pulmonary hemorrhage (small capillary leak)
- PAH
- Shrinking lung syndrome (diaphragm, respiratory muscles)
Cardiac manifestations:
- Most common cause of mortality in SLE is CAD
- Endocarditis in 15-60% (asymptomatic)= Libman-Sacks endocarditis
- Myocarditis in 9%: mild, seen as diastolic dysfunction
- Clots in placental tissue–> miscarriages
Kidney 50%
Raynaud’s 20%
Mucous Membranes 15%
CNS (Seizures/Psychosis) 15%
Renal manifestations of SLE
Lupus nephritis= diffuse proliferative nephritis
Membranous Lupus nephropathy
Labs: Anti-DNA Antibody deposition, low complement
Pathophys:
activation will produce inflammation, occlusion and disruption of glomeruli that translate in:
- Protein urinary excretion (Nephrotic Sd)
- Hematuria (Nephritic Sd)
- Increase on Creatinine levels
- Renal Failure
Class I: Normal glomeruli
a) Nil by all techniques
b) Normal by light but deposits on EM or IF
Class II: Mesangial glomerulonephritis: mesangial cells affected
Class III: Focal glomerulonephritis: endothelial cells affected
Class IV: Diffuse glomerulonephritis: endothelial cells affected
Class V: Diffuse membranous glomerulonephritis: epithelial cells affected
Class VI: Advanced sclerosing glomerulonephritis
Lupus subtypes
Discoid lupus:
- Discoid lesions without syetemic disease
- Can be unaccompanied by ANA or other autoantibodies.
- 10% of patients with discoid lupus will develop the systemic illness.
Drug induced lupus:
- Procainamide
- Hydralazine
- induce the production of antinuclear antibodies, especially anti‑histone antibodies, and occasionally a SLE‑like illness.
Drug- induced lupus characterized by:
- fever,
- hematological abnormalities such as an autoimmune hemolytic anemia or autoimmune thrombocytopenia, or serositis.
- Skin, renal and neurologic manifestations are uncommon.
Neonatal lupus/congenital lupus:
- Produced by transplacental acquisition of autoantibodies, specifically anti‑Ro (SS‑A),
- Produce in the neonate a transient photosensitive rash, congenital complete heart block, thrombocytopenia or rarely hepatobiliary dysfunction
- Syndrome recedes 9 months after delivery
- Screen mothers for ANA to prevent heart-block or other deadly problems in infant
SLE Lab findings
Anti‑double stranded DNA (renal findings)
Anti‑RNP, anti‑Smith,
Anti‑ SSA (Ro), anti‑ SSB (La)
Anticardiolipin, Glycoprotein, VDRL ( APS)
Complements:
C3, C4, CH50
Other testing:
CBC, CMP, UA, CxR
Hematological findings of SLE:
- Anemia
- Thrombocytopenia
- Leukocytopenia
- Lymphopenia
Sjogren’s Syndrome
Chronic, autoimmune inflammatory disorder of exocrine (moisture producing) glands.
- This produces a diminished lacrimal and salivary secretion (“sicca syndrome”) in association with autoantibody production.
Epidemiology:
- More frequent in middle aged patients (40-50’s).
- More frequent in Caucasian Population.
- 9:1 ratio of women:men.
- Estimated prevalence 2-3 million people in the US. ( but varies between 0.3 -3%)
- 2nd most common autoimmune rheumatic disease after rheumatoid arthritis.
Primary Sjogren’s: development of dry eyes, dry mouth in previously healthy person (no known connective tissue disease)
Secondary Sjogren’s: Associated with other autoimmune rheumatic disease- classically RA. Also seen with SLE, Systemic sclerosis
- See Polymyositis, polyarteritis nodosa, relapsing polychondritis, primary biliary sclerosis
Sjogren’s: clinical symptoms
In most patients- slow and benign course.
- Initial manifestations can be non-specific and usually many years elapse from the initial symptoms to the full-blown development of the syndrome.
- Dry eyes and dry mouth are the presenting or initial manifestation in approximately 85% of cases
- The classic triad of symptoms is dry eyes (keratoconjunctivitis sicca), dry mouth (xerostomia) and arthritis
Sjogren’s: Ocular glandular involvement
Chronic inflammation of lacrimal glands:
- produce decrease in tear production
- Diminished tear production leads to the destruction of both corneal and conjunctival epithelium and a constellation of clinical findings termed keratoconjunctivitis sicca (KCS).
Physical signs:
- Dilation of the conjunctival vessels, pericorneal injection, (red eye)
- Irregularity of the corneal image and
lacrimal gland enlargement.
- The patient usually complains of a burning, sandy or scratchy sensation under the lids, itchiness, redness and photosensitivity.
- Failure to treat dry eyes may result in complications such as corneal ulcers or melting, corneal perforation, loss of vision, bacterial conjunctivitis or blepharitis (inflammation of the eyelids).
Diagnostic questions:
- Symptoms of dry eyes for at least 3 months?
- A foreign body sensation in the eyes?
- Use of artificial tears 3 or more times per day?
Sjogren’s: Oral glandular involvement
- Dry mouth (xerostomia)–> decreased saliva
- Difficulty swalling food, inability to speak, change in taste, burning sensation, increased in dental caries
- Physical exam: dry, erythematous, sticky oral mucosa, dental caries, scanty/cloudy saliva, angular chelitis
- Parotid, major salivary gland enlargement in 60% patients (episodic or chronic, unilateral–> bilateral)
Complications:
- accelerated caries, loss of dentition, poor fitting dentures,
- oral candidiasis (yeast infection with Candida albicans),
- sialolithiasis (salivary gland stones),
- sialostenosis (salivary gland strictures),
- bacterial sialadenitis (infection),
- disturbed sleep (related to nocturnal fluid ingestion),
- depression and weight loss (related to oral discomfort, dysphagia etc.).
Diagnostic questions:
- Symptoms of dry mouth for at least 3 months?
- Recurrent or persistently swollen salivary glands?
- Need for liquids to swallow dry foods?
Sjogren’s: pathogenesis
More CD4 than CD8
- The subsequent local production of lymphokines, cytokines and antibodies is eventually followed by fibrosis (scarring) and fatty tissue replacement of normal glandular parenchyma.
- Disruption of neural innervation may also affect glandular secretion and cause diminished function.
- This process leads to permanent glandular destruction and irreversible dysfunction
Sjogren’s: differential diagnosis, diagnostic evaluation
3/4 standard criteria:
- Objective documentation of dry eyes
- Schirmer’s test: measures tear production on strip of paper in eye duct (normal > 10mm/5 min)
- Rose Bengal/ fluorescien corneal staining: ocular surface irregularity or damage due to dryness
- Tear break film test: tear film stability between last blink and appearance of dark, non-fluorescent areas in tear film (normal > 10 seconds) - Objective documentation of dry mouth
- Oral examination: diminished salivary pool, loss of glistening of tongue, mucous membranes, erythema, fissures on tongue
- Sialometry: Measure salivary flow using Lashley cup; circular cup connected to plastic tube, collect parotid saliva (placed over Stensen’s duct)- normal resting = 0.1 ml/min, after citric acid = 0.5-1.5 ml/min
- Salivary scintigraphy: nuclear medicine test to measure isotope uptake into glands (saliva formation) plus stimulated salivary discharge
- Sialography: inject contrast medium into salivary ducts followed by routine x-rays (MRI) - Demonstration of autoimmunity through blood tests
- Positive ANA, Rheumatoid Factor (> 1:160)
- Positive anti-SSA (Ro) or anti-SSB (La) - Confirmation of histologic involvement by salivary gland biopsy
- Labial minor salivary gland biopsy on inner aspect of lip
- Findings: focal lymphocytic sialadenitis= accumulation of 50+ mononuclear cells around salivary gland acini, ducts - Divide number of foci by glandular surface area= focus score
- Focus score > 1/4 mm3= Sjogren’s
Sjogren’s: extraglandular manifestations
Arthritis:
- 50% experience arthritis in disease
- May precede overt sicca manifestations
- Arthralgias, morning stiffness, intermittent synovitis, chronic polyarthritis
- Non-erosive changes in hands
Skin:
- Raynaud’s
Pulmonary:
- Frequent, not important
- Dry cough secondary to dryness of tracheobronchial mucosa (xerotrachea) or dyspnea due to airway obstruction
- Recurrent broncho-pneumonia
- Interstitial lung disease
- **Lymphoma should be suspected when lung nodules/hilar or mediastinal lymphs visible on CXR
CNS: peripheral, cranial neuropathy
Kidneys: interstitial nephritis, renal tubular acidosis
Differential diagnosis of Sicca Syndrome
Amyloidosis Chronic sialadenitis Diabetes mellitus Eosinophilia-myalgia syndrome Graft-versus-host disease Medication-related dryness ( anticholinergics, antidepresants, etc) Mouth breathing Multiple sclerosis Radiation injury Sarcoidosis Salivary diffuse infiltrative lymphocytosis syndrome (HIV related) Silicone breast implant disease Sjogren’s syndrome (1º or 2º) Type 5 hyperlipidemia IgG4 disease
Sjogren’s: Lab findings
Abnormal liver functions tests Antinuclear antibodies Anti-SS(Ro) or anti-SS(La) marker autoantibodies Elevated ESR** Elevated serum B2 microglobulin** Leukopenia Lymphopenia Normocytic normochromic anemia Polyclonal gammopathy Rheumatoid factor**
**= indicative of disease activity
Sjogren’s: treatment
Immunosuppression: -** Hydroxychloroquine - Azathioprine - Methotrexate - Rituximab - Corticosteroids - Cyclophosphamide - Cyclosporine All improve extra-glandular manifestations (fatigue, arthritis, interstitial pneumonitis, CNS involvment), but do not improve dry eyes/dry mouth - Can decrease disease progression
Sialogogues (stimulate saliva flow)/ Tear stimulants work best to relieve symptoms in patients with glandular functionality:
- Pilocarpine (older drug): cholinergic agonist (M3 receptors)- can cause sweating, urinary frequency
- Ceviniline: newer secretagogues
