Vasculitis refers to a heterogeneous group of disorders characterized by inflammation of blood vessel walls, leading to vessel wall necrosis, tissue ischemia, and end-organ damage. It is a high-yield concept on USMLE Step 2 CK, often tested through systemic symptoms such as fever, weight loss, malaise, along with organ-specific findings like renal dysfunction, mononeuritis multiplex, skin rash, or pulmonary symptoms. Vasculitides are broadly classified by the size of the affected vessels into large-, medium-, and small-vessel vasculitis, which helps guide diagnosis and management.

Large-vessel vasculitis includes giant cell arteritis (temporal arteritis) and Takayasu arteritis, which affect the aorta and its major branches. Giant cell arteritis presents in elderly patients with headache, jaw claudication, vision changes, and elevated ESR, and is a medical emergency due to the risk of irreversible blindness. Takayasu arteritis, more common in young Asian women, presents with absent pulses or blood pressure discrepancies.

Medium-vessel vasculitis, such as polyarteritis nodosa (PAN) and Kawasaki disease, affects muscular arteries and leads to organ ischemia, often presenting with abdominal pain, renal involvement, skin nodules, and neuropathy. PAN is often ANCA-negative and associated with hepatitis B, while Kawasaki disease is seen in children with fever, rash, conjunctivitis, strawberry tongue, and coronary artery aneurysms.

Small-vessel vasculitis affects arterioles, capillaries, and venules and includes granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), and IgA vasculitis (Henoch-Schönlein purpura). These often present with glomerulonephritis, palpable purpura, hematuria, pulmonary infiltrates, or mononeuritis multiplex. ANCA serologies (c-ANCA for GPA, p-ANCA for MPA/EGPA) are essential diagnostic tools.

Diagnosis involves a combination of clinical features, laboratory studies (ESR, CRP, ANCA, complement levels), imaging, and biopsy of affected tissues, which confirms vascular inflammation. Treatment typically involves high-dose corticosteroids, often combined with immunosuppressive agents like cyclophosphamide, methotrexate, or rituximab, depending on disease severity and type.

Diagnosing vasculitis requires a careful integration of clinical presentation, laboratory markers, imaging studies, and sometimes tissue biopsy, as it often presents with nonspecific systemic symptoms such as fever, fatigue, weight loss, and malaise, alongside organ-specific signs like rash, hematuria, neuropathy, pulmonary infiltrates, or ischemic symptoms. On USMLE Step 2 CK, the key to diagnosis lies in recognizing patterns of organ involvement, vessel size classification, and selecting the most appropriate tests to confirm or narrow the differential.

Initial workup begins with basic labs such as CBC, ESR, CRP, which often show anemia of chronic disease, leukocytosis, elevated inflammatory markers, and renal function tests if kidney involvement is suspected. Urinalysis may reveal hematuria, proteinuria, or red cell casts in small-vessel vasculitides like GPA (Granulomatosis with polyangiitis) or MPA (Microscopic polyangiitis).

Serologic testing is crucial and includes ANCA antibodies:

• c-ANCA (anti-PR3) is associated with GPA,

• p-ANCA (anti-MPO) is linked to MPA and EGPA (Eosinophilic granulomatosis with polyangiitis).
  Other markers include ANA, rheumatoid factor, complement levels (low in immune-complex mediated vasculitis), cryoglobulins, and hepatitis B/C serologies (especially in polyarteritis nodosa and cryoglobulinemic vasculitis).

Imaging studies aid in detecting vascular inflammation and organ damage. Chest X-ray or CT scan may show pulmonary infiltrates, nodules, or cavities in GPA, while CT angiography or MR angiography is used in large-vessel vasculitis like Takayasu arteritis or giant cell arteritis to assess vessel narrowing or aneurysms.

When feasible, tissue biopsy remains the gold standard for definitive diagnosis. Biopsy of affected tissue (e.g., temporal artery in GCA, kidney in small-vessel vasculitis, skin or nerve in systemic vasculitis) typically reveals necrotizing or granulomatous inflammation within blood vessels.

Kawasaki disease is an acute, self-limited vasculitis of medium-sized arteries, primarily affecting children under 5 years of age, and is a leading cause of acquired heart disease in children in developed countries. Although primarily a pediatric condition, it is a high-yield topic for USMLE Step 2 CK, especially in cases involving prolonged fever and mucocutaneous inflammation. The pathogenesis is not fully understood but is thought to involve immune dysregulation in genetically predisposed individuals, often triggered by an infectious agent.

The diagnosis is clinical and based on the presence of fever for ≥5 days plus four of the five following criteria:

1. Bilateral non-exudative conjunctivitis

2. Oral mucosal changes (e.g., red, cracked lips; “strawberry tongue”)

3. Polymorphous rash

4. Cervical lymphadenopathy (usually unilateral >1.5 cm)

5. Extremity changes (e.g., erythema and edema of hands/feet, desquamation of fingers and toes)

Laboratory findings include elevated ESR and CRP, leukocytosis, thrombocytosis (in subacute phase), elevated liver enzymes, and sterile pyuria. The most feared complication is coronary artery aneurysm, which can lead to myocardial infarction or sudden death, making echocardiography essential at diagnosis and during follow-up.

Incomplete (atypical) Kawasaki disease may be seen in infants or older children who do not meet full criteria but have suggestive findings; these cases require heightened suspicion and echocardiographic evaluation.

Treatment should be initiated promptly with intravenous immunoglobulin (IVIG) and high-dose aspirin, which dramatically reduce the risk of coronary complications. After the acute phase, low-dose aspirin is continued for antiplatelet effect until coronary arteries are confirmed normal on follow-up imaging.

Takayasu arteritis is a chronic, granulomatous large-vessel vasculitis that primarily affects the aorta and its major branches, and is most commonly seen in young women under the age of 40, particularly of Asian descent. It is a high-yield vasculitis on USMLE Step 2 CK, frequently tested through presentations of constitutional symptoms, followed by vascular insufficiency, such as limb claudication, diminished or absent peripheral pulses, and discrepancy in blood pressures between arms. For this reason, it is also called the "pulseless disease."

In the early "systemic" phase, patients often present with nonspecific symptoms like fever, fatigue, weight loss, arthralgias, and night sweats. As the disease progresses to the "occlusive" phase, signs of vascular ischemia develop, including arm or leg claudication, dizziness, syncope, visual disturbances, or transient ischemic attacks, depending on which arteries are involved. Carotidynia (pain over the carotid artery) and bruits over large arteries may also be noted on examination.

Laboratory studies typically show elevated ESR and CRP, but are nonspecific. The definitive diagnosis is made by imaging, especially CT angiography, MR angiography, or conventional angiography, which reveal segmental stenosis, occlusion, or aneurysmal dilation of the aorta or its branches, often with “string of beads” or tapered narrowing appearance.

Treatment begins with high-dose systemic corticosteroids (e.g., prednisone) to control inflammation. In patients with refractory or relapsing disease, steroid-sparing agents like methotrexate, azathioprine, or biologic agents (e.g., tocilizumab) may be used. Surgical or endovascular interventions (e.g., angioplasty or bypass) may be necessary for severe stenosis or organ-threatening ischemia after disease control.

Giant Cell Arteritis (GCA), also known as Temporal Arteritis, is a granulomatous large-vessel vasculitis that primarily affects the branches of the external carotid artery, especially the temporal artery, and is a high-yield emergency condition on USMLE Step 2 CK due to its potential to cause irreversible vision loss. It most commonly affects women over the age of 50, particularly those of Northern European descent, and is strongly associated with polymyalgia rheumatica (PMR). The disease is characterized by inflammatory infiltration of large and medium-sized arteries, leading to luminal narrowing and ischemia.

Patients typically present with a new-onset, localized headache, usually in the temporal region, accompanied by scalp tenderness, jaw claudication (pain with chewing), and visual disturbances such as transient vision loss (amaurosis fugax) or diplopia, which may progress to permanent blindness if left untreated. Systemic symptoms such as fatigue, fever, weight loss, and myalgias are also common. Examination may reveal a tender, thickened, or pulseless temporal artery, and reduced pulse in the affected region.

Laboratory findings include a markedly elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), which are highly sensitive markers of inflammation. Definitive diagnosis is made by temporal artery biopsy, which shows granulomatous inflammation with multinucleated giant cells, but treatment should never be delayed for biopsy if vision symptoms are present.

Immediate treatment with high-dose corticosteroids (e.g., prednisone) is essential to prevent vision loss. In patients with visual symptoms, intravenous methylprednisolone may be initiated. Temporal artery biopsy should ideally be performed within 1–2 weeks of starting steroids, as histologic findings can still be detected. Tocilizumab, an IL-6 receptor inhibitor, may be used in steroid-refractory or relapsing cases.

Polyarteritis Nodosa (PAN) is a rare, necrotizing vasculitis of medium-sized arteries, leading to segmental transmural inflammation that can result in aneurysm formation, thrombosis, and tissue ischemia. It is a high-yield vasculitis on USMLE Step 2 CK, classically associated with hepatitis B virus (HBV) and affecting multiple organ systems, but notably spares the lungs, distinguishing it from other systemic vasculitides. PAN typically presents in middle-aged adults with constitutional symptoms such as fever, weight loss, malaise, and fatigue, followed by organ-specific ischemic manifestations.

Clinical features include renal involvement (e.g., hypertension, infarcts, but without glomerulonephritis), gastrointestinal symptoms (e.g., postprandial abdominal pain, mesenteric ischemia, nausea), mononeuritis multiplex (asymmetric sensorimotor neuropathy), cutaneous findings (e.g., livedo reticularis, purpura, subcutaneous nodules), and testicular pain. PAN can also cause myalgias, arthralgias, and digital gangrene due to vascular occlusion.

Diagnosis is based on a combination of clinical findings, elevated inflammatory markers (ESR, CRP), and angiography, which typically shows microaneurysms, segmental narrowing, and "beading" of medium-sized arteries, especially in the renal, mesenteric, and hepatic vessels. Biopsy of affected tissue (e.g., nerve, skin, muscle) reveals transmural inflammation with fibrinoid necrosis. Importantly, PAN is typically ANCA-negative, helping differentiate it from small-vessel vasculitis.

Treatment involves high-dose corticosteroids, which are the mainstay of therapy. In severe or organ-threatening disease, or in HBV-associated PAN, cyclophosphamide is added for immunosuppression, while antiviral therapy and plasmapheresis are used in HBV-related cases. Close monitoring for disease relapse or treatment-related toxicity is necessary.

Cryoglobulinemic vasculitis is a small-vessel immune complex-mediated vasculitis caused by the deposition of cryoglobulins—immunoglobulins that precipitate at cold temperatures—in the skin, kidneys, and peripheral nerves, leading to inflammation and vascular injury. It is a high-yield vasculitis on USMLE Step 2 CK, especially in association with chronic hepatitis C infection, the most common underlying etiology. The condition may also be seen in autoimmune diseases (e.g., systemic lupus erythematosus, Sjögren syndrome) and hematologic malignancies (e.g., multiple myeloma, Waldenström macroglobulinemia).

Patients typically present with the classic triad of palpable purpura, arthralgias, and glomerulonephritis. Other manifestations may include fatigue, peripheral neuropathy (mononeuritis multiplex), Raynaud phenomenon, livedo reticularis, and ulcers or digital ischemia. Renal involvement may manifest as hematuria, proteinuria, and nephritic-range kidney injury, often resembling membranoproliferative glomerulonephritis (MPGN). Low complement levels, especially low C4, are characteristic and help differentiate cryoglobulinemic vasculitis from other small-vessel vasculitides.

Diagnosis involves detection of cryoglobulins in the serum, although results can be affected by temperature and handling. Supporting labs include positive rheumatoid factor (RF), low C4, and HCV serologies. Skin or renal biopsy may show immune complex deposition and leukocytoclastic vasculitis.

Management focuses on treating the underlying cause. In HCV-associated cryoglobulinemia, the mainstay is direct-acting antiviral (DAA) therapy. In cases with severe or life-threatening organ involvement (e.g., rapidly progressive glomerulonephritis or neuropathy), immunosuppressive therapy with corticosteroids, rituximab, and sometimes plasmapheresis is indicated.

Churg-Strauss Syndrome, now known as Eosinophilic Granulomatosis with Polyangiitis (EGPA), is a rare ANCA-associated small-vessel vasculitis characterized by asthma, eosinophilia, and systemic vasculitis involving multiple organs. It is a high-yield topic on USMLE Step 2 CK, especially in patients with adult-onset asthma, chronic rhinosinusitis, and peripheral eosinophilia who later develop neurologic, cardiac, or renal complications. The disease progresses through three phases: an allergic phase (asthma, allergic rhinitis, nasal polyps), an eosinophilic phase (marked peripheral eosinophilia and eosinophilic tissue infiltration, especially in the lungs and GI tract), and a vasculitic phase, which involves systemic necrotizing vasculitis of small- and medium-sized vessels.

Common clinical features include asthma exacerbations, mononeuritis multiplex (painful, asymmetric neuropathy), skin manifestations such as palpable purpura or nodules, pulmonary infiltrates, gastrointestinal symptoms like abdominal pain or bleeding, and cardiac involvement, which is a leading cause of mortality. Renal involvement is usually milder compared to other ANCA-associated vasculitides.

Laboratory findings include marked eosinophilia, elevated ESR/CRP, and positive p-ANCA (MPO-ANCA) in about 40–60% of cases. Chest imaging may show transient, patchy pulmonary infiltrates, while nerve conduction studies can help identify peripheral neuropathy. Biopsy of affected tissue is diagnostic and shows eosinophilic infiltration, granulomatous inflammation, and necrotizing vasculitis.

Treatment depends on severity. For mild to moderate disease (without life-threatening organ involvement), systemic corticosteroids (e.g., prednisone) are often sufficient. In severe or refractory cases with cardiac, renal, or neurologic involvement, immunosuppressive agents such as cyclophosphamide or rituximab are added. Long-term management may require steroid-sparing agents like azathioprine or methotrexate.

Behçet’s disease is a chronic, relapsing, multisystem inflammatory disorder classified as a variable-vessel vasculitis, affecting both arteries and veins of all sizes. It is most prevalent in individuals from the Middle East, Mediterranean, and East Asia, and is a high-yield condition for USMLE Step 2 CK, often tested in vignettes involving recurrent oral and genital ulcers, ocular inflammation, and skin lesions. The exact etiology is unclear, but it is believed to be autoimmune in nature, often triggered by infectious or environmental factors in genetically predisposed individuals (notably those with HLA-B51).

The hallmark features include recurrent, painful oral aphthous ulcers, which are often the first symptom, followed by recurrent genital ulcers, typically deeper and more scarring. Eye involvement is common and may present as uveitis, retinal vasculitis, or optic neuritis, potentially leading to vision loss if not treated promptly. Additional systemic features include erythema nodosum-like lesions, pseudofolliculitis, arthritis, gastrointestinal ulcers, venous thrombosis, and CNS involvement such as meningoencephalitis or cerebral venous sinus thrombosis.

Pathergy test, where a small skin prick causes a papular or pustular lesion within 24–48 hours, may be positive and is a unique diagnostic clue, though not universally present. Diagnosis is clinical and based on International Criteria for Behçet’s Disease (ICBD), which considers oral ulcers plus a combination of genital ulcers, eye lesions, skin lesions, and positive pathergy.

Treatment depends on severity and organ involvement. Colchicine is used for mucocutaneous and joint symptoms, while systemic corticosteroids are used for more severe flares. Immunosuppressive agents like azathioprine, cyclosporine, or cyclophosphamide are used in patients with ocular, neurologic, or vascular involvement. TNF-alpha inhibitors (e.g., infliximab) may be effective in refractory cases, especially with ocular or CNS disease.

Microscopic polyangiitis (MPA) is a pauci-immune, necrotizing small-vessel vasculitis that affects capillaries, venules, and arterioles, with a strong association with perinuclear ANCA (p-ANCA) directed against myeloperoxidase (MPO). It is a high-yield vasculitis for USMLE Step 2 CK, often presenting with systemic symptoms such as fever, weight loss, malaise, and organ-specific involvement, most notably of the kidneys and lungs. Unlike granulomatosis with polyangiitis (GPA), MPA does not cause granulomatous inflammation, and upper respiratory tract involvement is uncommon, which helps in differentiation.

The renal manifestations are significant and often present as rapidly progressive glomerulonephritis (RPGN) with hematuria, proteinuria, and red blood cell casts on urinalysis. Pulmonary involvement includes alveolar hemorrhage, leading to hemoptysis, dyspnea, and diffuse pulmonary infiltrates on imaging, often mimicking pneumonia or ARDS. Patients may also exhibit mononeuritis multiplex, cutaneous purpura, or gastrointestinal ischemia due to systemic vasculitis.

Diagnosis involves detection of elevated inflammatory markers (ESR, CRP), positive p-ANCA (MPO-ANCA), and signs of renal and pulmonary involvement. Renal biopsy confirms the diagnosis and typically shows pauci-immune crescentic glomerulonephritis without significant immune complex deposition on immunofluorescence, distinguishing it from immune-complex mediated glomerulonephritis (e.g., lupus, IgA nephropathy).

Treatment includes high-dose corticosteroids in combination with immunosuppressive agents such as cyclophosphamide or rituximab, especially in patients with severe or life-threatening organ involvement. Plasma exchange may be used in select patients with pulmonary hemorrhage or severe renal failure. Maintenance therapy with azathioprine or methotrexate is used to prevent relapse after induction.

Fibromyalgia is a chronic pain syndrome characterized by widespread musculoskeletal pain, fatigue, sleep disturbances, and cognitive dysfunction (often referred to as "fibro fog"). It is a functional somatic disorder, meaning it involves altered pain perception without underlying inflammation or structural damage, and is a high-yield diagnosis on USMLE Step 2 CK, especially in middle-aged women with normal laboratory and imaging studies despite significant symptom burden. The pathogenesis is thought to involve central sensitization, with increased neuronal response to pain stimuli and altered neurotransmitter levels.

Patients typically present with diffuse body aches, morning stiffness, nonrestorative sleep, and fatigue, often worsened by stress, cold, or overexertion. Cognitive symptoms may include difficulty concentrating or memory impairment, and many patients have comorbid conditions like irritable bowel syndrome (IBS), depression, or anxiety. On exam, there is tenderness at specific soft tissue points (formerly "tender points"), but no joint swelling, warmth, or objective signs of inflammation.

Diagnosis is clinical and based on criteria from the American College of Rheumatology, which include widespread pain for at least 3 months and associated symptoms like fatigue and cognitive issues, in the absence of other identifiable causes. Laboratory tests such as ESR, CRP, ANA, and TSH are often ordered to exclude inflammatory or endocrine causes, but are typically normal in fibromyalgia.

Treatment focuses on a multimodal approach centered around patient education, exercise (especially aerobic and strength training), cognitive behavioral therapy (CBT), and sleep hygiene. Pharmacologic options include tricyclic antidepressants (e.g., amitriptyline), SNRIs (e.g., duloxetine, milnacipran), and antiepileptics (e.g., pregabalin), all of which help modulate central pain pathways. Opioids are not effective and should be avoided due to risk of dependence and lack of benefit.

Psoriatic arthritis (PsA) is a seronegative spondyloarthropathy associated with chronic psoriasis, characterized by inflammatory arthritis, enthesitis, and dactylitis, often presenting years after the onset of skin disease. It is a high-yield topic on USMLE Step 2 CK, especially in patients with a history of psoriasis who develop joint pain, swelling, or stiffness, particularly involving the distal interphalangeal (DIP) joints, which are not typically involved in rheumatoid arthritis. PsA can have a highly variable presentation, ranging from oligoarthritis to symmetric polyarthritis, mimicking rheumatoid arthritis, or axial disease resembling ankylosing spondylitis.

Key features include morning stiffness, joint swelling, and pain, most often affecting the DIP joints, sacroiliac joints, or spine. Dactylitis ("sausage digits") is a classic finding due to diffuse inflammation of the flexor tendon sheath. Enthesitis (inflammation at tendon or ligament insertion sites) commonly affects the Achilles tendon or plantar fascia. Skin findings such as erythematous plaques with silvery scale, nail pitting, and onycholysis often coexist and aid diagnosis.

Laboratory findings are nonspecific. Rheumatoid factor (RF) and anti-CCP antibodies are typically negative, helping distinguish PsA from rheumatoid arthritis. ESR and CRP are often elevated during active disease. Imaging may show pencil-in-cup deformities, joint space narrowing, and new bone formation—distinct from erosions seen in RA.

Management involves a stepwise approach based on disease severity and pattern. NSAIDs are used for mild peripheral arthritis. For moderate to severe disease, disease-modifying antirheumatic drugs (DMARDs) such as methotrexate or sulfasalazine are used. In patients with axial involvement or inadequate response to conventional DMARDs, biologic agents like TNF-alpha inhibitors (e.g., etanercept, infliximab) or IL-17 inhibitors (e.g., secukinumab) are preferred. Skin and nail psoriasis also improve with biologic therapy. Steroids are used cautiously, as withdrawal may exacerbate psoriasis.

Gout is a crystal-induced inflammatory arthritis caused by monosodium urate crystal deposition in joints due to hyperuricemia, leading to acute episodes of severe joint inflammation. It is a high-yield topic on USMLE Step 2 CK, commonly tested through classic presentations of sudden-onset monoarticular arthritis, often involving the first metatarsophalangeal (MTP) joint—known as podagra. Other commonly affected sites include the ankle, knee, and midfoot. Gout occurs due to either overproduction or, more commonly, underexcretion of uric acid, and is associated with obesity, alcohol use (especially beer), high-purine diets (red meat, seafood), thiazide and loop diuretics, renal disease, and tumor lysis syndrome in cancer patients.

Clinically, patients present with intensely painful, red, hot, swollen joints, often waking them from sleep. Attacks usually peak within 24 hours and may resolve spontaneously over several days. Tophi—firm, subcutaneous urate crystal deposits—may develop in chronic gout, along with joint deformity and renal complications such as uric acid nephrolithiasis.

Diagnosis is confirmed by arthrocentesis, which reveals negatively birefringent, needle-shaped monosodium urate crystals under polarized light microscopy. Serum uric acid levels may be elevated but can be normal during an acute attack, so should not be solely relied upon. X-rays may show "punched-out" erosions with overhanging edges in advanced disease.

Acute attacks are treated with NSAIDs (e.g., indomethacin), colchicine, or glucocorticoids, depending on comorbidities and contraindications. Colchicine is especially useful when started early but can cause GI side effects. Steroids are preferred in patients with renal insufficiency or peptic ulcer disease. Chronic management involves urate-lowering therapy (ULT) such as allopurinol or febuxostat, started only after the acute attack resolves, and titrated to a target serum uric acid <6 mg/dL. Prophylactic colchicine or NSAIDs may be given when initiating ULT to prevent flare.

Pseudogout, also known as calcium pyrophosphate deposition disease (CPPD), is an inflammatory crystal arthropathy caused by the deposition of calcium pyrophosphate dihydrate crystals in the joints. It typically presents as acute monoarthritis, often mimicking gout, but is distinguished by its crystal composition and joint involvement. It is a high-yield condition on USMLE Step 2 CK, particularly in elderly patients presenting with sudden-onset joint pain, most commonly affecting the knee, but also the wrist, shoulder, or ankle. Pseudogout is associated with aging and several metabolic disorders, including hyperparathyroidism, hemochromatosis, hypothyroidism, and hypomagnesemia, which may be tested as part of the underlying workup.

Clinically, pseudogout presents with acute joint pain, swelling, warmth, and decreased range of motion, often indistinguishable from other causes of monoarthritis. Systemic symptoms such as low-grade fever may be present. Unlike gout, which typically involves the first MTP joint, pseudogout often involves larger joints, and the attacks tend to be less abrupt and more prolonged.

Definitive diagnosis is made by joint aspiration and synovial fluid analysis, which reveals rhomboid-shaped, positively birefringent calcium pyrophosphate crystals under polarized light microscopy. The synovial fluid is inflammatory, with an elevated white blood cell count. X-rays may show chondrocalcinosis (calcification of cartilage), particularly in the menisci of the knee or triangular fibrocartilage of the wrist, which serves as a diagnostic clue even in asymptomatic patients.

Management of acute pseudogout flares includes NSAIDs, colchicine, or intra-articular glucocorticoid injections, depending on patient comorbidities. In patients with contraindications to NSAIDs or colchicine (e.g., renal impairment), systemic corticosteroids may be used. Unlike gout, urate-lowering therapy is not used, and long-term management focuses on addressing underlying metabolic conditions and preventing recurrence with low-dose colchicine in select cases.

Adult-Onset Still’s Disease (AOSD) is a rare systemic autoinflammatory disorder characterized by a triad of daily spiking fevers, arthralgia or arthritis, and a distinctive evanescent salmon-colored rash, often accompanied by leukocytosis and elevated inflammatory markers. It is a diagnosis of exclusion and a high-yield zebra on USMLE Step 2 CK, particularly in adults under 40 presenting with unexplained fever, joint pain, and rash, in the absence of infection, malignancy, or autoimmune disease. Though its exact etiology is unknown, it is thought to involve abnormal innate immune activation, with elevated levels of interleukin-1 (IL-1), IL-6, and ferritin.

Clinically, AOSD presents with quotidian (once daily) fevers >39°C, often peaking in the evening, associated with arthralgias or symmetric arthritis, especially in the knees, wrists, and ankles. The rash is typically nonpruritic, salmon-pink, and transient, often appearing with fever spikes and disappearing quickly. Additional features include sore throat, hepatosplenomegaly, lymphadenopathy, pleuritis, and pericarditis. A striking laboratory feature is marked hyperferritinemia, often >3,000 ng/mL, which strongly supports the diagnosis when other causes have been ruled out.

Diagnosis is clinical and made after excluding infectious, neoplastic, and autoimmune conditions. Lab tests show elevated ESR/CRP, neutrophilic leukocytosis, anemia of chronic disease, and normal or negative ANA and rheumatoid factor, helping distinguish AOSD from lupus or rheumatoid arthritis.

Treatment depends on disease severity. NSAIDs are used for mild disease or initial symptom control. Glucocorticoids (e.g., prednisone) are the mainstay for moderate to severe disease. For steroid-sparing or refractory cases, disease-modifying antirheumatic drugs (DMARDs) like methotrexate or biologics targeting IL-1 (anakinra) or IL-6 (tocilizumab) are effective options.

Reactive arthritis, historically known as Reiter’s syndrome, is a seronegative spondyloarthropathy that typically occurs 1–4 weeks after a genitourinary or gastrointestinal infection, and is characterized by the classic triad of asymmetric oligoarthritis, conjunctivitis (or uveitis), and urethritis or cervicitis. It is a high-yield topic for USMLE Step 2 CK, especially in young men who develop joint pain after Chlamydia trachomatis infection or enteric infections such as Salmonella, Shigella, Yersinia, or Campylobacter. The condition is strongly associated with the HLA-B27 allele, which is found in approximately 70–80% of affected patients.

Patients typically present with asymmetric arthritis of the lower extremities, particularly the knees, ankles, and feet. Extra-articular features include conjunctivitis, urethral discharge, oral ulcers, and keratoderma blennorrhagicum (hyperkeratotic skin lesions on the soles and palms), as well as circinate balanitis in men. The arthritis is non-suppurative, and joint aspiration reveals sterile inflammatory fluid.

Diagnosis is clinical and based on history of recent infection, characteristic joint findings, and exclusion of other causes of arthritis. Laboratory tests may show elevated ESR/CRP, and NAAT testing for Chlamydia or stool cultures for enteric pathogens can help confirm the antecedent infection. Autoantibodies such as RF and ANA are typically negative, helping differentiate reactive arthritis from rheumatoid arthritis and lupus.

Management includes NSAIDs as first-line therapy for joint inflammation and pain. Antibiotics are indicated only if an active Chlamydia infection is still present. In chronic or severe cases, DMARDs such as sulfasalazine or methotrexate may be used. Corticosteroid injections can be used for persistent monoarthritis, and topical steroids are helpful for mucocutaneous lesions. Most cases resolve within 6 months, though some may become chronic.

Dermatomyositis is an idiopathic inflammatory myopathy characterized by progressive symmetric proximal muscle weakness accompanied by distinctive cutaneous manifestations, and is a high-yield autoimmune condition on USMLE Step 2 CK. It can occur alone or as a paraneoplastic syndrome, particularly in association with ovarian, lung, pancreatic, gastric, or colorectal cancers. The disease is more common in women and may present at any age, with peak incidence in middle adulthood.

Patients typically present with gradual onset of proximal muscle weakness affecting the shoulders, hips, and neck flexors, often leading to difficulty climbing stairs, rising from a chair, or lifting objects overhead. The hallmark skin findings include the heliotrope rash (violaceous discoloration around the eyes with periorbital edema) and Gottron’s papules (violaceous, scaly plaques over the knuckles, elbows, and knees). Other findings may include a shawl sign (rash over the upper back and shoulders), V sign (rash on the anterior chest), mechanic’s hands (rough, cracked skin on the fingertips), and photosensitivity.

Laboratory studies reveal elevated muscle enzymes, including creatine kinase (CK) and aldolase, along with elevated ESR/CRP. Myositis-specific autoantibodies, such as anti-Mi-2 and anti-MDA5, may be present. In cancer-associated cases, anti-TIF1-γ (anti-p155/140) is commonly seen. EMG shows myopathic changes, and MRI of muscle can detect inflammation. Muscle biopsy is confirmatory and shows perifascicular atrophy and inflammatory infiltrates. Skin biopsy may also aid diagnosis.

Treatment begins with high-dose corticosteroids, followed by steroid-sparing agents like methotrexate or azathioprine. IVIG or rituximab may be used in refractory cases. All patients should be screened for malignancy, especially when dermatomyositis presents abruptly or in older adults.

Non-gonococcal septic arthritis is a bacterial infection of the joint space, typically caused by hematogenous spread of organisms, leading to rapid joint destruction if not treated promptly. It is a medical emergency and high-yield condition on USMLE Step 2 CK, especially in patients with underlying joint disease (e.g., rheumatoid arthritis, osteoarthritis), prosthetic joints, immunosuppression, diabetes, or a recent bacteremia or invasive procedure. Unlike gonococcal arthritis, which affects young sexually active adults and often presents with migratory symptoms, non-gonococcal arthritis usually presents with acute monoarthritis, most commonly affecting the knee, followed by the hip, shoulder, and ankle.

Patients present with acute onset of a single swollen, warm, erythematous, and extremely painful joint, often accompanied by fever, malaise, and limited range of motion. The most common causative organism is Staphylococcus aureus, including MRSA, followed by Streptococcus species. In injection drug users, the sternoclavicular or sacroiliac joints may be involved, and Pseudomonas is a common pathogen. In patients with prosthetic joints, coagulase-negative staphylococci are often implicated.

Diagnosis is confirmed by arthrocentesis, with synovial fluid analysis showing purulent fluid, very high white blood cell count (>50,000/mm³) predominantly neutrophils, low glucose, and positive Gram stain and culture. Blood cultures are also helpful and often positive. Imaging such as X-ray may be normal early on but is used to exclude other joint pathology; ultrasound or MRI can help identify joint effusion or soft tissue involvement.

Management involves prompt empiric IV antibiotic therapy tailored to Gram stain and culture results, along with urgent joint drainage—either via repeated needle aspiration, arthroscopic washout, or open surgical drainage, depending on the joint and clinical stability. Empiric antibiotics typically include vancomycin (to cover MRSA) plus ceftriaxone or cefepime, especially if gram-negative organisms are a concern. Therapy is adjusted once culture results are available, and treatment usually continues for 2–4 weeks.

Ankylosing spondylitis (AS) is a chronic, progressive inflammatory disorder primarily affecting the axial skeleton, particularly the sacroiliac joints and spine, leading to fusion of the vertebrae and loss of spinal mobility. It is a seronegative spondyloarthropathy associated with HLA-B27 and is a high-yield topic on USMLE Step 2 CK, especially in young men (typically <40 years) presenting with chronic back pain and stiffness that improves with activity and worsens with rest. Morning stiffness lasting >30 minutes is common, and over time, patients may develop limited spinal flexion, loss of lumbar lordosis, and a forward-stooped posture.

In addition to axial involvement, AS may also cause enthesitis (inflammation at tendon or ligament insertions, particularly the Achilles tendon or plantar fascia), dactylitis, and peripheral arthritis. Extra-articular manifestations include anterior uveitis (painful red eye with photophobia), aortic root dilation, conduction abnormalities, and restrictive lung disease due to reduced chest wall expansion.

Diagnosis is clinical and supported by imaging and lab findings. X-rays of the pelvis show sacroiliitis (bilateral and symmetric sacroiliac joint narrowing and sclerosis), and spinal imaging may reveal vertebral fusion ("bamboo spine") in advanced disease. MRI is more sensitive in early disease and can detect active inflammation. Laboratory studies show elevated ESR and CRP, while rheumatoid factor (RF) and anti-CCP antibodies are negative, distinguishing AS from rheumatoid arthritis.

Management begins with NSAIDs as first-line therapy to control pain and inflammation. Patients who fail NSAID therapy or have severe disease may require TNF-alpha inhibitors (e.g., etanercept, adalimumab) or IL-17 inhibitors (e.g., secukinumab). Physical therapy and regular exercise are crucial for maintaining posture and spinal mobility. Glucocorticoids and DMARDs like methotrexate are less effective for axial symptoms but may be considered for peripheral joint involvement.