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USMLE (Subject) / Musculoskeletal, Skin, and Connective Tissue (Lesson)

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• Systemic lupus erythematosus Systemic, remitting, and relapsing autoimmune disease. Organ damage primarily due to type III hypersensitivity reaction and, to a lesser degree, a type II hypersensitivity reaction. Associated with deficiency of early complement proteins (eg, C1q, C4, C2) → ↓ clearance of immune complexes.- Classic presentation: rash, joint pain, and fever in female of reproductive age (especially of African-American or Hispanic descent) - Libman-Sacks Endocarditis – nonbacterial, verrucous thrombi usually on mitral or aortic valve and can be present on either surface of the valve (but usually on undersurface). LSE in SLE.- Lupus nephritis (glomerular deposition of DNA-anti-DNA immune complexes) can be nephritic or nephrotic (causing hematuria or proteinuria). Most common and severe type is diffuse proliferative. - Common causes of death in SLE: renal disease (most common), infections, cardiovascular disease (accelerated CAD). Presentation: Rash (malar or discoid), arthritis (nonerosive), serositis (eg, pleuritis, pericarditis), hematologic disorders (eg, cytopenias), oral/nasopharyngeal ulcers (usually painless), renal disease, photosensitivity, neurologic disorders (eg, seizures, psychosis). 1. Antinuclear antibodies (ANA)2. Antibodies to double-stranded DNA (anti-dsDNA)3. Anti-Smith antibodies (anti-Sm)4. Anti-phospholipid antibodies (→ false positives on syphilis tests)5. Antihistone antibodies – drug-induced lupus
• Drugs known for causing a lupus-like syndrome - procainamide (antirhythmic agent Ia) - quinidine (antirhythmic agent Ia) - hydralazine (muscle relaxant)
• Scleroderma (systemic sclerosis) Triad of autoimmunity, noninflammatory vasculopathy, and collagen desposition with fibrosis.- Commonly sclerosis of skin, manifesting as puffy, taut skin without wrinkles, fingertip pitting. - Can involve other systems, eg, renal (scleroderma renal crisis; treat with ACE inhibitors), pulmonary (interstitial fibrosis, pulmonary HTN), GI (esophageal dysmotility and reflux), cardiovascular.- 75% female. 2 major types:Diffuse scleroderma – widespread skin involvement, rapid progression, early visceral involvement. Associated with anti-Scl-70 antibody (anti-DNA topoisomerase I antibody). Limited scleroderma – limited skin involvement confined to fingers and face. Also with CREST syndrome:C: Calcinosis cutis (calcium deposits in the skin), anti-centromere antibodyR: Raynaud's phenomenon E: Esophageal dysmotilityS: Sclerodactyly (thickening of the skin on the fingers and hands)T: Telangiectasia (dilation of capillaries causing red spots)- More benign clinical course - Anti-centromere antibodies (specific to limited scleroderma)- Scl-70 antibodies (specific to diffuse scleroderma) Do not respond well to immunosuppressants (steroids) → therapy with pencillamine (inhibits IL-1)
• Osteoarthritis Degeneration of articular cartilage. Chondrocytes mediate degradation and inadequate repair. Predisposing factors: Age, female, obesity, joint trauma Presentation: Pain in weight-bearing joints after use (eg, at the end of the day), improving with rest. Asymmetric joint involvement. Knee cartilage loss begins medially ("bowlegged"). No systemic symptoms.  - ESR (erythrocyte sedimentation rate) not elevated, because inflammation is localized to the joint Joint findings: Osteophytes (bone spurs), joint space narrowing, subchondral cysts, sclerosis. Synovial fluid non-inflammatory (WBC <2000/mm3). Involves Heberden's nodes (DIP), and Bouchard's nodes (PIP); not MCP. Therapy: Acetaminophen, NSAIDs (with misoprostol, PPI), intra-articular glucocorticoids
• Rheumatoid arthritis Autoimmune – inflammation induces formation of pannus (proliferative granulation tissue), which erodes articular cartilage and bone.  Predisposing factors: Female, HLA-DR4, smoking, (+) rheumatoid factor (IgM antibody that targets IgG Fc region; in 80%), anti-cyclic citrullinated peptide antibody (more specific) Presentation: Pain, swelling, and morning stiffness lasting >1 hour, improving with use. Symmetric joint involvement. Systemic symptoms (fever, fatigue, weight loss). Joint findings: Erosions, juxta-articular osteopenia, soft tissue swelling, subchondral cysts, joint space narrowing. Deformities: cervical subluxation, ulnar finger deviation, swan neck, boutonniere. Involves MCP, PIP, wrist; not DIP or 1st CMC. Mild leukocytosis (> 2000 WBC/mm3) in synovial fluid. Extraarticular manifestations: Rheumatoid nodules (fibrinoid necrosis with palisading histiocytes) in subcutaneous tissue and lungs (pneumoconiosis → Caplan syndrome), interstitial lung disease, pleuritis, pericarditis, anemia of chronic disease, neutropenia + splenomegaly (Felty syndrome), AA amyloidosis, Sjögren syndrome, scleritis, carpal tunnel syndrome. Therapy: NSAIDs, glucocorticoids, disease-modifying agents (methotrexate, sulfasalazine, hydroxychloroquine, leflunomide), biologic agents (eg, TNF-α inhibitors).
• Ankylosing spondylitis Seronegative spondyloarthritis. Symmetric involvement of spine and sacroiliac joints → ankylosis (joint fusion), uveitis, aortic regurgitation.- Arthritis without rheumatoid factor. - Strongly associated with the HLA-B27 haplotype- Primarily in men - Bamboo spine (vertebral fusion) on x-ray.- Can cause restrictive lung disease due to limited chest wall expansion (costovertebral and costosternal ankylosis).
• Reiter's syndrome - spondyloarthropathy  - characterized by the triad of1. Arthritis2. Urethritis3. Conjunctivitis - associated with HLA-B27
• Gower's sign indicates weakness of the proximal muscles, namely those of the lower limb - describes a patient that has to use their hands and arms to "walk" up their own body from a squatting position due to lack of hip and thigh muscle strength - seen in patients with Duchenne muscular dystrophy
• Duchenne's muscular dystrophy - 2/3 X-linked recessive; 1/3 secondary spontaneous mutation in dystrophin gene - pseudohypertrophy of the calf muscles - positive Gower's sign (proximal muscle weakness)
• Myotonic dystrophy - autosomal dominant - expansion of trinucleotide repeat sequence in region of the myotonin protein kinase gene --> amplification phenomenon - generalized muscle weakness - when patient shakes hand, he is unable to relax grip for an extended period
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• Sciatica - pain distributed in the area that the sciatic nerve innervates - arises from L4-S3 - If L4-L5 disk is herniated, symptoms reflect the distribution of the L5 dermatome, because the L5 nerve root descends immediately posterior to the L4-L5 disk and is susceptible to compression (exits through intervetebral foramen between L5-S1 though)
• Gout Acute inflammatory monoarthritis caused by precipitation of monosodium urate crystals in joints.- Risk factors: male sex, hypertension, obesity, diabetes, dyslipidemia, hyperuricemia.  Strongest risk factor is hyperuricemia, which can be caused by:- Underexcretion of uric acid (90%) – largely idiopathic, potentiated by renal railure, can be exacerbated by certain medications (eg, thiazide diuretics).- Overproduction of uric acid (10%) – Lesch-Nyhan syndrome, PRPP excess, ↑ cell turnover (eg, tumor lysis syndrome), von Gierke disease. Symptoms:- Asymmetric joint distribution (classically MTP joint in the big toe [podagra]). - Joint is swollen, red, and painful. - Tophus formation (often on external ear, olecranon bursa, or Achilles tendon).- Acute attack tends to occur after a large meal with foods rich in purines (eg, red meat, seafood), trauma, surgery, dehydration, diuresis, or alcohol consumption (alcohol metabolites compete for same excretion sites in kidney as uric acid → ↓ uric acid secretion and subsequent buildup in blood). - Synovial fluid shows numerous neutrophils with needle-shaped, negatively birefringent monosodium urate crystals under polarized light.- Hyperuricemia ist neither sensitive nor specific for gout! Therapy:- Acute: NSAIDs (eg, indomethacin), glucocorticoids, colchicine- Chronic (preventive): xanthine oxidase inhibitors (eg, allopurinol, febuxostat)
• Lesch-Nyhan syndrome - deficiency of the enzyme hypoxanthine-guanine phosphoribosyl transferase (HGPRT)--> purines are not reused but instead degraded into uric acid  - X-linked recessive - central nervous system symtoms, tend to engage in self-mutilation
• Uric acid production - hypoglycemia increases uric acid production by reducing cellular ATP production --> increased levels of cellular adenosine --> substrate for purine catabolism - alcohol is believed to exacerbate gout by causing hypoglycemia
• Treatment of an acute gout attack 1. Colchicine- inhibits microtubule polymerization and so prevents phagocytosis of uric acid crystals by macrophages/neutrophils (phagocytosis elicits the inflammatory response)- used cautiously because it can cause pronounced nausea, vomiting, diarrhea 2. Indomethacin- NSAID- inhibits inflammatory response
• Fibromyalgia Rheumatologic disorder characterized by widespread musculoskeletal pain associated with "tender points," stiffness, paresthesias, poor sleep, fatigue, cognitive disturbance.- Most common in women 20-50 years old. - Associated with obesity, anxiety, depression, stress(overweight and depressed middle-aged woman who is unhappily married with the additional stress of raising children) Treatment: regular exercise, antidepressants (TCAs, SNRIs), neuropathic pain agents (eg, gabapentin)
• Polymyositis/dermatomyositis - ↑ CK, ⊕ ANA (nonspecific), ⊕ anti-Jo-1 (histidyl-tRNA synthetase, specific), ⊕ anti-SRP (specific), ⊕ anti-Mi-2 (specific) antibodies.- Both disorders associated with interstitial lung disease. Polymyositis: Autoimmune inflammatory myopathy resulting in muscle destruction, muscle pain, and proximal muscle weakness. Characterized by endomysial inflammation with CD8+ T-cells. Dermatomyositis: Clinically similar to polymyositis, but also involves malar rash (similar to that in SLE but involves nasolabial folds), Gottron papules, heliotrope (violaceous periorbital) rash, "shawl and face" rash, darkening and thickening of fingertips and sides resulting in irregular, "dirty"-appearing marks. ↑ risk of occult malignancy. Perimysial inflammation and atrophy with CD4+ T cells. Treatment: steroids followed by long-term immunosuppressant therapy (eg, methotrexate) - Similar symptoms caused by trichinosis (roundworm, larvae in undercooked pork)
• Osteopetrosis Failure of normal bone resorption due to defective osteoclasts → thickened, dense bones that are prone to fracture. Persistence of primary spongiosa in the medullary canal.- Mutations (eg, carbonic anhydrase II) impair ability of osteoclast to generate acidic environment necessary for bone resorption. - Overgrowth of cortical bone fills marrow space → pancytopenia, extramedullary hematopoiesis. - Can result in cranial nerve impingement and palsies due to narrowed foramina. - Early age of onset (vs Paget disesase) - Normal calcium, phosphorus, ALP, PTH.- X-ray shows diffuse symmetric sclerosis (bone-in-bone, "stone bone"). - Bone marrow transplant is potenitally curative as osteoclasts are derived from monocytes.
• Achondroplasia Failure of longitudinal bone growth (endochondral ossification) → short limbs. - Large head relative to limbs. - Constitutive activation of fibroblast growth factor receptor (FGFR3) actually inhibits chondrocyte proliferation.- >85% of mutations occur sporadically.- Autosomal dominant with full penetrance (homozygosity is lethal).- Associated with ↑ paternal age. - Most common cause of dwarfism. Presentation:- Rhizomelia (shortened proximal extremities)- Brachydactyly (shortened digitis) in a trident configuration (space between 3rd and 4th digits)- Macrocephaly, midface hypoplasia, frontal bossing- Increased risk of spinal stenosis and resultant nerve root compression 
• Paget disease of bone (osteitis deformans) Common, localized disorder of bone remodeling caused by ↑ osteoclastic activity followed by ↑ osteoblastic activity that forms poor-quality bone. - Serum Ca2+, phosphorus and PTH levels are normal. - ↑ ALP  - Mosaic pattern of woven and lamellar bone (osteocytes within lacunae in chaotic juxtapositions).- Long bone chalk-stick fractures. - ↑ blood fow from ↑ arteriovenous shunts may cause high-output heart failure.- ↑ risk of osteogenic sarcoma. - Hat size can be increased due to skull thickening.- Hearing loss is common due to auditory foramen narrowing. Stages of Paget disease:- Lytic – osteoclasts- Mixed – osteoclasts + osteoblasts- Sclerotic – osteoblasts- Quiescent – minimal osteoclast/osteoblast activity Treatment: bisphosphonates
• Osteogenesis imperfecta - genetic defects in type I collagen weaken bone
• Osteomalacia/rickets Defective mineralization of osteoid (osteomalacia) or cartilaginous growth plates (rickets, only in children).- Most commonly due to vitamin D deficiency. - X-rays show osteopenia and "Looser zones" (pseudofractures) in osteomalacia, epiphyseal widening and metaphyseal cupping/fraying in rickets. - Children with rickets have pathologic bow legs (genu varum), bead-like costochondral junctions (rachitic rosary), craniotabes (soft skull). - ↓ vitamin D → ↓ serum Ca2+ → ↑ PTH secretion → ↓ in serum PO43-- Hyperactivity of osteoblasts → ↑ ALP
• Wegener's granulomatosis - vasculitis with necrotizing granulomas in the lung and necrotizing glomerulonephritis - hemoptysis (blood-tinged sputum), hematuria - c-ANCA positive - chest x-ray: bilateral nodular and cavitary infiltrates Treatment: cylophosphamide and corticosteroids
• Kawasaki syndrome - inflammation of middle-sized blood vessles - mucocutaneous lymph node syndrome - mostly in children < 5 years - mucosal inflammation- cutaneous maculopapular rash- lymph node enlargement- unexplained high fever- "strawberry tongue" - cardiac complications (coronary arteries inflammed)
• Polyarteritis nodosa - inflammation of tunica media of medium-sized muscular arteries (renal, visceral vessles) - fever, myalgia, fatigue, abdominal pain - 30% associated with hepatitis B virus (HbsAg-positive) - multiple aneurysms and constrictions on arteriogram Treatment: corticosteroids, cyclophosphamide
• Henoch-Schönlein purpura - IgA vasculitis - maculopapular petechial rash on buttocks/lower extremities - glomerulonephritis (--> hematuria) - abdominal pain, melena - most common systemic vasculitis in children
• Thromboangiitis obliterans = Bürger's disease - inflammatory occlusive disease of the arteries of the distal extremities - male smokers under the age of 40 - distal extremity cold intolerance Treatment: quit smoking
• Takayasu arteritis - "pulseless disease" - granulomatous thickening of aortic arch - elevated ESR - primarily affects Asian females < 40 year old - different blood pressures in the arms, weak pulses in upper extremity- femoral and dorsalis pedis pulses strong - fever, arthritis, myalgia, skin nodules
• "Unhappy triad" 1. medial collateral ligament (MCL) 2. medial meniscus 3. anterior cruciate ligament (ACL) - positive anterior drawer sign --> tearing of the ACL- abnormal passive abduction --> torn MCL
• Osteitis fibrosa cystica - caused by hyperparathyroidism - characterized by "brown tumors" (cystic spaces lined by osteoclasts, filled with fibrous stroma) - high serum calcium, low serum phosphorus, high alkaline phosphatase
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• Polymyalgia rheumatica Pain and stiffness in proximal muscles (eg, shoulders and hips), often with fever, malaise, weight loss.- Does not cause muscular weakness.- More common in women >50 years of age- Associated with temporal (giant cell) arteritis. - ↑ ESR, ↑ CRP, normal CK Treatment: Rapid response to low-dose corticosteroids
• Sjögren syndrome Autoimmune disorder characterized by destruction of exocrine glands (especially lacrimal and salivary) by lymphocytic infiltrates.- Predominantly affects women 40-60 years old. Findings:- Inflammatory joint pain- Keratoconjunctivitis sicca (↓ tear production and subsequent corneal damage)- Xerostoma (↓ saliva production)- Presence of antinuclear antibodies, rheumatoid factor, antiribonucleoprotein antibodies: SS-A (anti-Ro) and/or SS-B (anti-La)- Bilateral parotid enlargement- Focal lymphocytic sialadenitis on labial salivary gland biopsy can confirm diagnosis. - Anti-SSA and anti-SSB may also be seen in SLE. ⊕ Anti-SSA in pregnant women with SLE → ↑ risk of congenital heart block in the newborn. Complications: dental caries; mucosa-associated lymphoid tissue (MALT) lymphoma (may present as parotid enlargement).
• Pseudogout - deposition of calcium pyrophosphate crystals within the synovia - basophilic, rhomboid crystals that are positively birefringent (as opposed to negatively birefringent, needle-shaped crystals in gout) - usually affects large joints (knee) - > 50 years old - booth sexes affected equally - no treatment
• Sarcoidosis Immune-mediated, widespread noncaseating granulomas, elevated ACE levels, and elevated CD4/CD8 ratio in bronchoalveolar lavage fluid.  - More common in African-American females - Often asymtomatic except for enlarged lymph nodes- Findings include bilateral adenopathy and mediastinal adenopathy Associated with restrictive lung disease (interstitial fibrosis), erythema nodosum, lupus pernio, Bell palsy, epithelioid granulomas including Schaumann and asteroid bodies, uveitis, hypercalcemia (due to elevated conversion of vitamin D to its active form in epithelioid macrophages) Treatment: steroids
• Osteoid osteoma - Adults <25 years old.- Males > females. Location: Cortex of long bones Characteristics: - Presents as bone pain (worse at night) that is relieved by NSAIDs.- Bony mass (<2 cm) with radiolucent osteoid core.
• Osteosarcoma Most common 1° malignant tumor of bone. - Accounts for 20% of 1° bone cancers.- Peak incidence of 1° tumor in males <20 years.- Less common in elderly; usually 2° to predisposing factors, such as Paget disease of bone, bone infarcts, radiation, familial retinoblastoma, Li-Fraumeni syndrome. Location: Metaphysis of long bones (often in knee region). Characteristics:- Pleomorphic osteoid-producing cells (malignant osteoblasts).- Presents as painful enlarging mass or pathologic fractures.- Codman's triangle (from elevation of periosteum) or sunburst pattern on x-ray.- Mixed radiodense and radiolucent areas, periosteal new bone formation. - Aggressive. 1° usually responsive to treatment (surgical en bloc resection, chemotherapy), poor prognosis for 2°.
• Temporal arteritis (giant cell arteritis) - affects medium and small arteries (usually carotid artery) - focal, granulomatous - unilateral headache, jaw claudication, impaired vision (occlusion of ophthalmic artery, which can lead to blindness) - 50% have polymyalgia rheumatica (shoulder and hip muscle pain) - elevated ESR - responds well to steroids
• Child abuse - metaphyseal corner fractures - posterior rib fractures - abnormal bruising - retinal dislocations or hemorrhages
• Erythema nodosum Inflammation of subcutaneous fat - often accompanied by fever and malaise Occurance:- inflammatory-bowel diseases (Crohn disease, ulcerative colitis)- sarcoidosis- drugs (oral contraceptives, sulfonamides)- malignant neoplasms- infections (eg tuberculosis, leprosy)
• Colles' fracture Complete transverse fracture of the distal radius - most commonly in the elderly after forced dorsiflexion - avulsion of the styloid process from the shaft of the radius - "dinner fork" deformity
• Osteonecrosis (avascular necrosis) Infarction of bone and marrow, usually very painful.- Most common site is femoral head (due to insufficiency of medial circumflex femoral artery [posterior]). Causes:- Corticosteroids- Alcoholism- Sickle cell disease- Trauma- Caisson/decompression disease- Legg-Calvé-Perthes disease (idiopathic)- Gaucher disease- Slipped capital femoral epiphysis Radiographic findings: Pathognomonic crescent sign, which indicates subchondral collapse.
• Lab values in bone disorders Osteoporosis: - Calcium, - phosphate, - ALP, - PTH - ↓ bone mass Osteopetrosis: -/↓ Calcium, - phosphate, - ALP, - PTH - Dense, brittle bones- Ca2+ ↓ in severe, malignant disease Paget disease of bone: - Calcium, - phosphate, ↑ ALP, - PTH - Abnormal "mosaic" bone architecture Primary hyperparathyroidism: ↑ Calcium, ↓ phosphate, ↑ ALP, ↑ PTH - "Brown tumors" due to fibrous replacement of bone, subperiosteal thinning- Idiopathic or parathyroid hyperplasia, adenoma, carcinoma Secondary hyperparathyroidism: ↓ Calcium, ↑ phosphate, ↑ ALP, ↑ PTH - Often as compensation for CKD (↓ PO43- excretion and production of activated vitamin D) Osteomalacia/rickets: ↓ Calcium, ↓ phosphate, ↑ ALP, ↑ PTH - Soft bones- Vitamin D deficiency also causes 2° hyperparathyroidism Hypervitaminosis D: ↑ Calcium, ↑ phosphate, - ALP, ↓ PTH - Caused by oversupplementation or granulomatous disease (eg, sarcoidosis)
• Calcium pyrophosphate deposition disease (pseudogout) Deposition of calcium pyrophosphate crystals within the joint space.- Occurs in patients >50 years old- Both sexes affected equally - Usually idiopathic, sometimes associated with hemochromatosis, hyperparathyroidism, joint trauma. - Pain and swelling with acute inflammation (pseudogout) and/or chronic degeneration (pseudo-osteoarthritis).- Knee most commonly affected joint. - Chondrocalcinosis (cartilage calcification) on x-ray.- Crystals are rhomboid and weakly ⊕ birefringent under polarized light (blue when parallel to light). Acute treatment: NSAIDs, colchicine, glucocorticoidsProphylaxis: colchicine
• Septic arthritis S aureus, Streptococcus, and Neisseria gonorrhoeae are common causes. - Affected joint is swollen, red, and painful.- Synovial fluid purulent (WBC >50,000/mm3). Gonococcal arthritis – STI that presents as either purulent arthritis (eg, knee) or triad of polyarthralgia, tenosynovitis (eg, hand), dermatitis (eg, pustules).
• Seronegative spondyloarthritis Arthritis without rheumatoid factor (no anti-IgG antibody). Strong association with HLA-B27 (MHC class I serotype). Subtypes share variable occurence of inflammatory back pain (associated with morning stiffness, improves with exercise), peripheral arthritis, enthesitis (inflamed insertion sites of tendons, eg, Achilles), dactylitis ("sausage fingers"), uveitis. - Psoriasis arthritis- Ankylosing spondylitis- Inflammatory bowel disease- Reactive arthritis
• Myasthenia gravis Most common neuromuscular junction disease. - Autoantibodies to postsynaptic ACh receptor - Ptosis, diplopia, weakness. Worsens with muscle use. - Improvement after edrophonium (tensilon) test - Associated with thymoma, thymic hyperplasia Treatment: Pyridostigmine
• Lambert-Eaton myasthenic syndrome Autoantibodies to presynaptic Ca2+ channel → ↓ ACh release - Proximal muscle weakness, autonomic symptoms (dry mouth, impotence)- Improves with muscle use - Associated with small cell lung cancer
• Raynaud phenomenon ↓ blood flow to skin due to arteriolar (small vessel) vasospasm in response to cold or stress: color change from white (ischemia) to blue (hypoxia) to red (reperfusion).- Most often in the fingers and toes. - Called Raynaud disease when 1° (idiopathic), Raynaud syndrome when 2° to a disease process such as mixed connective tissue disease, SLE, or CREST syndrome (limited form of systemic sclerosis). - Digital ulceration (critical ischemia) seen in 2° Raynaud syndrome. Treatment: Ca2+ channel blockers
• Types of muscle fibers Type 1 muscle:- Slow twitch: red fibers resulting from ↑ mitochondria and myoglobin concentration (↑ oxidative phosphorylation) → sustained contraction- Proportion ↑ after endurance training. Type 2 muscle:- Fast twitch: white fibers resulting from ↓ mitochondria and myoglobin concentration (↑ anaerobic glycolysis).- Proportion ↑ after weight/resistance training, sprinting.
• Bone formation Endochondral ossification:- Bones of axial skeleton, appendicular skeleton, and base of skull.- Cartilaginous model of bone is first made by chondrocytes. Osteoblasts and osteoclasts later replace with woven bone and then remodel to lamellar bone. In adults, woven bone occurs after fractures and in Paget disease.- Defective in achondroplasia Membranous ossification:- Bones of calvarium, facial bones, and clavicle. Woven bone formed directly without cartilage. Later remodelled to lamellar bone.

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