Seronegative Spondyloarthropathies & Systemic Vasculitides

Distinguish the four HLA-B27 Seronegative Spondyloarthropathies by their axial vs. peripheral joint distribution and extra-articular hallmarks: (1) Ankylosing Spondylitis (AS) presents in men <40 years old with insidious chronic inflammatory lower back and buttock pain lasting >3 months that is worse in the morning (>60 minutes of morning stiffness), IMPROVES WITH EXERCISE/ACTIVITY, and does NOT improve with rest. Progressive sacroiliitis and ossification of the annulus fibrosus (syndesmophytes) fuse the vertebral column into a rigid 'Bamboo Spine' on radiograph, reducing lumbar flexion on the bedside Schober Test (<5 cm expansion) and restricting chest wall expansion (causing a restrictive PFT pattern with apical pulmonary fibrosis). The #1 extra-articular manifestation of AS is Acute Unilateral Anterior Uveitis (Iritis: painful red eye, photophobia, blurred vision), alongside Ascending Aortitis with Aortic Regurgitation and high risk of unstable cervical/thoracic chalk-stick spinal fractures. First-line therapy for Ankylosing Spondylitis is Exercise/Physical Therapy PLUS continuous full-dose NSAIDs (Indomethacin/Naproxen); if NSAIDs fail, escalate directly to a TNF-α Inhibitor (Adalimumab, Etanercept, Infliximab) or IL-17 Inhibitor (Secukinumab) (note: conventional DMARDs like Methotrexate and Sulfasalazine are INEFFECTIVE for axial spine disease!). (2) Psoriatic Arthritis occurs in 20%–30% of patients with psoriasis (scaly salmon-colored plaques on extensor elbows/knees with Auspitz sign and nail pitting / onycholysis), characteristically targeting the Distal Interphalangeal (DIP) joints of the hands and feet with Dactylitis ('sausage digits') and osteolytic 'Pencil-in-Cup' deformity on X-ray (treat mild disease with NSAIDs, moderate-to-severe with Methotrexate or TNF-α / IL-17 / IL-12/23 Inhibitors; avoid systemic corticosteroids in psoriasis as steroid withdrawal triggers life-threatening generalized pustular psoriasis!). (3) Reactive Arthritis (formerly Reiter Syndrome) presents 1 to 4 weeks after either a nongonococcal urogenital infection (Chlamydia trachomatis) or an enteric bacterial gastroenteritis (Campylobacter, Salmonella, Shigella, Yersinia) with the classic triad of 'Can't See (Conjunctivitis or Anterior Uveitis), Can't Pee (Sterile Urethritis / Cerbalanitis circinata), Can't Climb a Tree (Asymmetric lower-extremity Oligoarthritis + Achilles Enthesitis)' plus hyperkeratotic vesicles on the soles (Keratoderma Blennorrhagicum; arthrocentesis is sterile—treat the underlying Chlamydia if present and give NSAIDs).

Boards frequently contrast the seronegative spondyloarthropathies against Rheumatoid Arthritis (RA) (associated with MHC Class II HLA-DR4): in RA, CD4+ T cells and synovial fibroblasts form hyperplastic granulation tissue (Pannus) that erodes articular cartilage and periarticular bone. Unlike Osteoarthritis (which causes asymmetric mechanical joint pain worse at the end of the day, <30 minutes of morning stiffness, joint-space narrowing with subchondral sclerosis/osteophytes, and affects the DIP [Heberden nodes], PIP [Bouchard nodes], and 1st CMC joints) and unlike Psoriatic Arthritis (which hits the DIPs), Rheumatoid Arthritis causes symmetric polyarthritis of the MCP and PIP joints and wrists with >60 minutes of morning stiffness while STRICTLY SPARING THE DIP JOINTS! Late RA deformities include ulnar deviation of the fingers, Swan-Neck deformity (PIP hyperextension + DIP flexion), Boutonniere deformity (PIP flexion + DIP hyperextension), and popliteal Baker cysts (which can rupture into the calf, mimicking a DVT!). Serologically, Rheumatoid Factor (RF, an IgM autoantibody against the Fc portion of IgG) is sensitive (~70%–80%), whereas Anti-Cyclic Citrullinated Peptide (Anti-CCP) antibody has the highest specificity (>95%) for RA. Two critical RA board rules: (1) Cervical Spine Atlantoaxial (C1–C2) Subluxation: chronic pannus erodes the transverse ligament of the atlas (C1); before performing elective endotracheal intubation for surgery in a patient with longstanding RA, always obtain flexion/extension cervical spine radiographs so neck hyperextension during laryngoscopy does not drive the odontoid process (dens) into the upper cervical spinal cord! (2) Immediate DMARD Initiation & Pre-Biologic Screening: every newly diagnosed RA patient must be started immediately on the first-line Disease-Modifying Antirheumatic Drug (DMARD): Methotrexate (folate antimetabolite inhibiting dihydrofolate reductase + AICAR transformylase; always co-prescribe Folic Acid to prevent oral ulcers/macrocytic anemia, and monitor for hepatotoxicity, pancytopenia, and interstitial pneumonitis; strictly teratogenic—use Hydroxychloroquine or Sulfasalazine in pregnancy). Before escalating to a TNF-α Inhibitor (Infliximab, Adalimumab, Etanercept), always screen for Latent Tuberculosis (IGRA [QuantiFERON] or PPD) AND Hepatitis B/C because TNF-α is required to maintain caseating granulomas!

Compare the large- and medium-vessel vasculitides by age, geography, and organ tropism: (1) Large-Vessel Vasculitis shows granulomatous inflammation of the aorta and its major branches with a fragmented internal elastic lamina and multinucleated giant cells, separated strictly by an Age 50 cutoff: Giant Cell (Temporal) Arteritis occurs in patients ≥50 years old (affecting carotid branches: temporal/ophthalmic arteries), whereas Takayasu Arteritis ('Pulseless Disease') occurs in young Asian women <40 years old, affecting the aortic arch and great vessels (subclavian, carotid, renal arteries)—presenting with fever/night sweats, upper-extremity claudication, absent or weak radial/brachial pulses, a >10–20 mmHg blood pressure discrepancy between the left and right arms, carotid/subclavian bruits, and renovascular hypertension (treat both with high-dose Corticosteroids). (2) Polyarteritis Nodosa (PAN) is a necrotizing Medium-Vessel Vasculitis of muscular arteries (strongly associated with Chronic Hepatitis B [HBsAg+ in 30%]) that causes transmural fibrinoid necrosis with lesions of different histological ages and 'string-of-beads' microaneurysms on visceral angiography affecting the Kidneys (renovascular hypertension and renal infarcts WITHOUT glomerulonephritis!), Mesenteric arteries (postprandial abdominal angina/melena), Skin (livedo reticularis, punched-out ulcers), and Peripheral Nerves (mononeuritis multiplex: wrist drop / foot drop). CRITICAL BOARD RULE: Polyarteritis Nodosa STRICTLY SPARES THE LUNGS (pulmonary capillaries) and is ANCA-NEGATIVE! Treat PAN with Corticosteroids + Cyclophosphamide (plus Entecavir/Tenofovir if HBV+). (3) Thromboangiitis Obliterans (Buerger Disease) is a segmental thrombosing medium/small-vessel vasculitis in young male heavy cigarette smokers (<40 years) presenting with distal digital ischemia, ulceration/autoamputation of fingers and toes, superficial migratory thrombophlebitis, and Raynaud phenomenon (angiography shows 'corkscrew collaterals'; the ONLY definitive treatment is complete SMOKING CESSATION!).

The three ANCA-Associated Small-Vessel Vasculitides all cause Pauci-Immune Rapidly Progressive (Crescentic) Glomerulonephritis (RPGN — negative immunofluorescence!) and pulmonary capillaritis (alveolar hemorrhage), separated by their ANCA target and upper-airway vs. asthma phenotype: (1) Granulomatosis with Polyangiitis (GPA, formerly Wegener's) is associated with c-ANCA (cytoplasmic ANCA targeting Proteinase-3 [Anti-PR3, >90%]) and necrotizing granulomas, presenting with the classic Triad: Upper Respiratory Tract (chronic purulent/bloody sinusitis, nasal septal perforation, 'saddle-nose' deformity, otitis media) + Lower Respiratory Tract (multiple bilateral nodular cavitary lung infiltrates, hemoptysis) + Kidneys (pauci-immune crescentic RPGN with RBC casts; treat with High-Dose Corticosteroids + Rituximab or Cyclophosphamide). (2) Eosinophilic Granulomatosis with Polyangiitis (EGPA, formerly Churg-Strauss) is associated with p-ANCA (perinuclear ANCA targeting Myeloperoxidase [Anti-MPO, ~40%–60%]) and necrotizing granulomas, presenting with Adult-Onset Refractory Asthma, Chronic Rhinosinusitis with Nasal Polyps, Marked Peripheral Eosinophilia (>10% or >1,500/μL), Mononeuritis Multiplex, and RPGN/Myocarditis. (3) Microscopic Polyangiitis (MPA) is associated with p-ANCA (Anti-MPO, >70%) and causes pulmonary-renal syndrome (alveolar hemorrhage + pauci-immune RPGN) and palpable purpura WITHOUT granulomas, WITHOUT upper-airway saddle-nose destruction, and WITHOUT asthma/eosinophilia! Finally, contrast these with IgA Vasculitis (Henoch-Schönlein Purpura [HSP])—the #1 systemic vasculitis of childhood, occurring 1–2 weeks after an upper respiratory infection via mucosal IgA1 immune-complex deposition—which presents with the classic Tetrad (with a NORMAL platelet count and normal PT/PTT!): (1) Palpable Purpura on the buttocks and lower extremities, (2) Arthralgias/Arthritis (knees/ankles), (3) Colicky Abdominal Pain / GI bleeding (can cause ileo-ileal intussusception with currant-jelly stools!), and (4) IgA Nephropathy hematuria.

In Ankylosing Spondylitis, physical exam demonstrates loss of lumbar lordosis, increased occiput-to-wall distance, decreased chest wall expansion (<2.5 cm at the 4th intercostal space), and a positive Schober test (two marks placed at the L5 spinous process and 10 cm superiorly fail to expand to ≥15 cm upon maximal forward spinal flexion). Plain pelvic radiographs reveal bilateral blurring, erosions, and sclerosis of the sacroiliac joints; if plain films are normal in early disease (non-radiographic axial spondyloarthritis), MRI of the sacroiliac joints is the most sensitive test to detect bone marrow edema. Disease-modifying conventional agents like methotrexate and sulfasalazine are ineffective for axial spinal disease; patients failing two consecutive NSAIDs advance directly to anti-TNF-α biologics or IL-17 inhibitors.

A critical board differential compares Reactive Arthritis against Disseminated Gonococcal Infection (DGI) in a sexually active young adult. Reactive arthritis occurs 1–4 weeks after a Chlamydia urethritis or bacterial enteritis, presents with sterile inflammatory synovial fluid (WBC 2,000–50,000/mm³, negative Gram stain and culture), and features mucocutaneous hallmarks (circinate balanitis, keratoderma blennorrhagicum) and conjunctivitis. Conversely, DGI presents acutely with the triad of polyarthralgias, tenosynovitis, and sparse vesiculopustular acral skin lesions (or purulent monoarthritis with synovial WBC >50,000/mm³) and responds to IV ceftriaxone.

Psoriatic Arthritis uniquely targets the distal interphalangeal (DIP) joints alongside dactylitis (diffuse swelling of an entire finger or toe due to combined flexor tenosynovitis and interphalangeal synovitis) and nail matrix disease (pitting, onycholysis). Hand radiographs show periarticular erosions and resorption of the distal phalangeal tuft with bony proliferation at the base of the distal phalanx, creating the pathognomonic pencil-in-cup deformity. Importantly, systemic corticosteroids (oral prednisone tapers) are avoided in psoriatic arthritis because abrupt steroid withdrawal can precipitate life-threatening generalized pustular or erythrodermic psoriasis.

In Giant Cell Arteritis (GCA), occlusion of the posterior ciliary arteries (branches of the ophthalmic artery) causes anterior ischemic optic neuropathy (AION), presenting with sudden, painless, irreversible monocular blindness and a pale, edematous optic disc. Because contralateral eye involvement can occur within days, high-dose IV methylprednisolone (if visual symptoms are present) or oral prednisone (40–60 mg/day) must be started immediately prior to scheduling a temporal artery biopsy. Because GCA affects the vessel in a patchy, segmental fashion (skip lesions), a long biopsy segment (3–5 cm) is obtained, and a negative biopsy does not rule out GCA if clinical suspicion is high. The IL-6 receptor antagonist tocilizumab is approved as a steroid-sparing agent.

Polyarteritis Nodosa (PAN) is an ANCA-negative necrotizing vasculitis of medium-sized muscular arteries strongly linked to chronic Hepatitis B infection (immune complex deposition). Transmural inflammation weakens the elastic lamina, generating microaneurysms and focal stenoses ('string of beads') best visualized on mesenteric or renal CT/catheter angiography. Renal interlobar artery ischemia activates the renin-angiotensin-aldosterone system, causing severe hypertension and renal infarcts without glomerulonephritis (no RBC casts). Involvement of the vasa nervorum produces asymmetric sensorimotor mononeuritis multiplex (e.g., sudden peroneal nerve foot drop plus median nerve neuropathy). Crucially, PAN spares the pulmonary circulation.

Kawasaki Disease is the leading cause of acquired heart disease in children in developed nations. Untreated patients develop coronary artery aneurysms in 20–25% of cases, predisposing to coronary thrombosis, myocardial infarction, and sudden death. All patients require baseline and follow-up transthoracic echocardiography and immediate treatment within 10 days of fever onset with a single high-dose infusion of Intravenous Immunoglobulin (IVIG) plus high-dose Aspirin—representing one of the rare pediatric indications for aspirin despite the theoretical risk of Reye syndrome.

On board vignettes, all three ANCA vasculitides can present with pauci-immune crescentic glomerulonephritis (hematuria, red blood cell casts, rising creatinine) and palpable purpura. First, check for asthma and peripheral eosinophilia (>10%): their presence establishes EGPA (Churg-Strauss), which is p-ANCA (MPO) positive. Second, if asthma and eosinophilia are absent, inspect the upper respiratory tract and chest CT: destructive nasopharyngeal disease (chronic bloody sinusitis, septal perforation, saddle-nose deformity) and cavitary pulmonary nodules with granulomas on biopsy establish GPA (Wegener), which is c-ANCA (PR3) positive. If granulomas, cavitary nodules, and upper airway destruction are absent, diagnose MPA (p-ANCA/MPO positive).

IgA Vasculitis (HSP) is the most common systemic vasculitis of childhood, typically triggered 1–2 weeks after an upper respiratory infection when galactose-deficient IgA1 immune complexes deposit in small vessels. Unlike idiopathic intussusception (which occurs at the ileocecal junction in infants 6–36 months old), submucosal bowel wall hematomas in HSP act as pathological lead points causing ileoileal intussusception. Children presenting with severe colicky abdominal pain and currant-jelly stools require abdominal ultrasound (target sign). While most cases of HSP resolve spontaneously with hydration and NSAIDs (avoiding NSAIDs if renal insufficiency is present), patients require urinalysis and blood pressure monitoring for 6 months to detect delayed IgA nephropathy.

Behçet Syndrome is unique among vasculitides for involving vessels of all sizes on both the arterial and venous sides, causing superficial thrombophlebitis, dural venous sinus thrombosis, and pulmonary artery aneurysms (presenting with massive hemoptysis). Skin hyper-reactivity is demonstrated by the pathergy phenomenon, where minor trauma or a sterile needle prick induces an erythematous papule or pustule within 24–48 hours. In Mixed Cryoglobulinemia, immunoglobulins precipitate in vitro at temperatures <37°C and redissolve upon rewarming; serology universally shows positive Hepatitis C RNA, positive Rheumatoid Factor, and depressed C4 levels.

Patients with Polymyalgia Rheumatica (PMR) report profound bilateral shoulder, neck, and hip girdle stiffness that is worst upon awakening and makes raising the arms above the shoulders or getting out of bed difficult. However, because the pathology is subacromial/subdeltoid and trochanteric bursitis rather than myofiber necrosis, serum CK is completely normal and objective muscle strength is 5/5 once pain is overcome. Initiating low-dose oral prednisone (15–20 mg daily) serves as both treatment and a diagnostic confirmation, as symptoms resolve within days; every PMR patient must be educated to report new headaches, visual changes, or jaw claudication immediately due to the risk of concurrent Giant Cell Arteritis.

Fibromyalgia results from dysregulated central nervous system pain processing (central sensitization), characterized by elevated cerebrospinal fluid substance P and glutamate levels alongside diminished descending serotonergic-noradrenergic inhibitory tone. Diagnosis is clinical when widespread pain persists for ≥3 months across multiple body regions with normal ESR, CRP, CK, and TSH. First-line therapy combines graduated low-impact aerobic exercise (swimming, walking), sleep hygiene, and cognitive-behavioral therapy. FDA-approved and first-line medications include SNRIs (duloxetine, milnacipran), gabapentinoids (pregabalin), and tricyclic antidepressants (amitriptyline) or cyclobenzaprine; corticosteroids, NSAIDs, and opioids are ineffective and contraindicated.

Before diagnosing PMR or polymyositis in an older adult with proximal myalgias, clinicians must always review the medication list and check a serum TSH and Creatine Kinase (CK). Both statin-induced myopathy (potentiated by fibrates such as gemfibrozil or CYP3A4 inhibitors) and hypothyroid myopathy cause proximal muscle aching with an elevated serum CK and normal ESR—whereas PMR exhibits an elevated ESR with a normal CK.