16.1 Connective Tissue & Collagen Vascular Diseases

Introduction to Collagen Vascular & Connective Tissue Diseases

Connective tissue diseases comprise a spectrum of multisystem autoimmune disorders characterized by chronic immune dysregulation, autoantibody production, immune-complex deposition, and chronic vascular or connective tissue inflammation. For the Caribbean Association of Medical Councils (CAMC) Examination, candidates must master the diagnostic classification criteria, autoantibody profiles, organ-specific emergencies, histopathological hallmarks, and pharmacotherapeutic safety rules governing systemic lupus erythematosus, systemic sclerosis, Sjögren syndrome, inflammatory myopathies, and systemic vasculitides.

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Systemic Lupus Erythematosus (SLE)

Systemic Lupus Erythematosus (SLE) is a prototypical systemic autoimmune disorder characterized by loss of self-tolerance, polyclonal B-cell hyperactivity, production of pathogenic autoantibodies against nuclear and cytoplasmic antigens, and systemic tissue injury mediated by Type III (immune complex) and Type II (antibody-dependent cytotoxic) hypersensitivity reactions.

Epidemiology & Pathogenesis

• Demographics: Marked female predominance during reproductive years (female-to-male ratio 9:1 to 12:1). Higher incidence and greater clinical severity in individuals of African and Caribbean descent.
• Pathogenesis: Defective clearance of apoptotic cell debris exposes nuclear antigens (histones, double-stranded DNA, ribonucleoproteins). Plasmacytoid dendritic cells produce high levels of interferon-alpha (type I interferon signature). B cells differentiate into autoreactive plasma cells producing high-affinity IgG autoantibodies. Antigen-antibody immune complexes deposit in microvascular beds (skin, renal glomeruli, synovial membranes, pleuropericardium), activating the classical complement cascade (consuming C3 and C4) and recruiting neutrophils and macrophages via Fc-receptor signaling.

2019 ACR/EULAR Classification Criteria for SLE

The 2019 EULAR/ACR criteria classify SLE for research; clinical diagnosis remains a physician assessment. Apply the following classification rules:

1. Mandatory Entry Criterion:
   • Antinuclear Antibody (ANA) titer >= 1:80 tested on human epithelial type 2 (HEp-2) cells by indirect immunofluorescence (or equivalent positive test). If absent, SLE is not classified.
2. Weighted Additive Clinical & Immunological Domains:
   • Only the highest-weighted criterion within each domain is counted toward the total score. Criteria are counted only if no more likely alternative etiology explains the manifestation.
   • A cumulative score of >= 10 points (with at least one clinical domain criterion) classifies a patient as having SLE.

Clinical Manifestations by Organ System

• Cutaneous: Acute malar erythema spares the nasolabial folds (distinguishing it from rosacea and seborrheic dermatitis); photosensitivity; discoid lesions feature scarring, follicular plugging, and central hypopigmentation.
• Musculoskeletal: Jaccoud arthropathy represents a non-erosive, reducible joint subluxation and ulnar deviation caused by ligamentous laxity rather than bone destruction.
• Hematologic: Autoimmune hemolytic anemia (extravascular, spherocytes, elevated LDH, low haptoglobin), immune thrombocytopenia, and leukopenia/lymphopenia.
• Cardiovascular: Libman-Sacks endocarditis (verrucous, sterile, non-bacterial vegetations on both surfaces of valve leaflets, predominantly mitral and aortic valves, predisposing to embolic stroke and superimposed bacterial endocarditis).
• Neuropsychiatric (NPSLE): Lupus cerebritis, transverse myelitis, peripheral neuropathy, and cognitive dysfunction.

Lupus Nephritis: ISN/RPS Histopathological Classification

Lupus nephritis develops in up to 50% to 60% of SLE patients and is the major determinant of long-term morbidity and survival. Renal biopsy is mandatory in any SLE patient with unexplained proteinuria (> 0.5 g/24 h or protein-to-creatinine ratio > 0.5) or active urinary sediment (dysmorphic RBCs, RBC casts).

Evidence-Based Pharmacotherapy for SLE & Lupus Nephritis

1. Universal Baseline Therapy — Hydroxychloroquine (HCQ):
   • Mandatory for ALL patients with SLE throughout life, including during pregnancy and lactation, unless strictly contraindicated (pre-existing maculopathy).
   • Dosing: <= 5.0 mg/kg actual body weight per day to minimize retinal toxicity.
   • Benefits: Reduces disease flares by 50%, prevents accrual of permanent organ damage, reduces thrombotic events, improves lipid profiles, and significantly extends overall survival.
   • Toxicity Monitoring: Baseline comprehensive ophthalmological exam (visual fields, spectral-domain OCT), followed by annual screening starting after 5 years of therapy (or earlier in high-risk patients with renal impairment or high doses) to detect irreversible chloroquine/hydroxychloroquine retinopathy ("bull's-eye" maculopathy).
2. Proliferative Lupus Nephritis (Class III / IV) Induction Protocol:
   • Corticosteroids: Pulse IV Methylprednisolone (500 to 1,000 mg daily for 3 consecutive days), followed by oral Prednisone (0.5 to 1.0 mg/kg/day, tapered systematically over 6 months).
   • Immunosuppressive Induction: Combined with either:
     • Mycophenolate Mofetil (MMF): 2 to 3 g/day orally (first-line in patients of African or Caribbean ancestry, as trials demonstrate superior efficacy and lower toxicity compared to cyclophosphamide).
     • Intravenous Cyclophosphamide: High-dose NIH regimen (0.5 to 1.0 g/m² monthly for 6 months) OR Low-dose Euro-Lupus regimen (500 mg IV every 2 weeks for 6 doses total). Co-administer Mesna and aggressive hydration to prevent acrolein-induced hemorrhagic cystitis and bladder carcinoma.
3. Maintenance Therapy for Lupus Nephritis:
   • Continue oral Mycophenolate Mofetil (MMF) (1 to 2 g/day) or oral Azathioprine (2 mg/kg/day) for at least 3 to 5 years following complete renal remission, combined with low-dose prednisone (<= 5 to 7.5 mg/day) and universal HCQ.
4. Refractory or Targeted Biologic Therapy:
   • Belimumab: Human monoclonal antibody inhibiting B-lymphocyte stimulator (BLyS / BAFF); approved as add-on therapy for active SLE and active lupus nephritis.
   • Anifrolumab: Monoclonal antibody targeting type I interferon receptor subunit 1 (IFNAR1); approved for moderate-to-severe SLE refractory to standard therapy.
   • Rituximab: Anti-CD20 monoclonal antibody; utilized off-label for severe, refractory lupus nephritis or life-threatening hematologic complications (refractory autoimmune hemolytic anemia, severe refractory ITP).

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Systemic Sclerosis (Scleroderma)

Systemic Sclerosis (SSc) is a chronic multisystem autoimmune connective tissue disease characterized by a clinical triad of: (1) widespread microvascular endothelial injury and obliteration, (2) immune activation with autoantibody production, and (3) progressive tissue fibrosis driven by excessive accumulation of extracellular matrix (collagen types I and III) in skin and visceral organs.

Classification: Limited vs Diffuse Cutaneous Systemic Sclerosis

+---------------------------------------------------------------------------------------------------+
|                         SYSTEMIC SCLEROSIS: SUBTYPE COMPARISON MATRIX                             |
+---------------------------------------------------------------------------------------------------+
| FEATURE                 | LIMITED CUTANEOUS (lcSSc)            | DIFFUSE CUTANEOUS (dcSSc)        |
+-------------------------+--------------------------------------+----------------------------------+
| Extent of Skin Thickening| Distal to elbows & knees; face only | Proximal limbs (arms, thighs) &  |
|                         | (spares trunk and abdomen)           | trunk/abdomen; rapid progression |
| Historical Syndrome     | CREST Syndrome                       | Systemic Scleroderma             |
| Autoantibody Profile    | Anti-Centromere Antibodies (ACA)     | Anti-Scl-70 (Topoisomerase I)    |
|                         | (associated with limited disease)              | Anti-RNA Polymerase III          |
| Pulmonary Pathology     | Isolated Pulmonary Arterial          | Early, progressive Interstitial   |
|                         | Hypertension (PAH; late onset)       | Lung Disease (ILD / Fibrosis)    |
| Renal Complication      | Rare Scleroderma Renal Crisis        | High risk of Scleroderma Renal   |
|                         |                                      | Crisis (SRC; especially anti-RNA)|
| Raynaud's Onset         | Precedes skin changes by years/decades| Precedes skin by months or onset |
|                         |                                      | occurs simultaneously            |
| Capillaroscopy          | Dilated capillary loops (giant loops)| Severe avascular areas, capillary|
|                         | with minimal drop-out                | hemorrhage & marked drop-out     |
| Overall Prognosis       | Better short-term; late PAH mortality| Poorer; early mortality from ILD |
|                         |                                      | or Scleroderma Renal Crisis      |
+---------------------------------------------------------------------------------------------------+

CREST Syndrome in Limited Cutaneous SSc

• C — Calcinosis Cutis: Painful, chalky, subcutaneous insoluble calcium hydroxyapatite deposits occurring over pressure points (fingertips, olecranon, prepatellar bursae), predisposing to ulceration and secondary infection.
• R — Raynaud's Phenomenon: Reversible, episodic digital vasospasm in response to cold exposure or emotional stress, displaying the classic triphasic color changes: White (ischemic pallor) -> Blue (cyanotic deoxygenation) -> Red (reactive hyperemic rubor with throbbing pain). Secondary Raynaud in SSc produces painful digital pitting scars, ischemic ulcerations, and dry gangrene.
• E — Esophageal Dysmotility: Smooth muscle atrophy and fibrosis of the lower two-thirds of the esophagus with lower esophageal sphincter (LES) incompetence, resulting in severe gastroesophageal reflux disease (GERD), erosive esophagitis and peptic strictures. Gastric Antral Vascular Ectasia (GAVE; "watermelon stomach") is a separate gastric vascular complication that may cause bleeding.
• S — Sclerodactyly: Symmetrical, shiny, taut skin thickening over the fingers with loss of normal skin folds, flexion contractures ("claw-hand" deformity), and reduced range of motion.
• T — Telangiectasias: Mat-like, dilated superficial capillaries and venules on the face, lips, oral mucosa, and palms.

Scleroderma Renal Crisis (SRC) — A Hypertensive Emergency

Scleroderma Renal Crisis is a life-threatening complication occurring in 10% to 15% of patients with diffuse cutaneous systemic sclerosis (dcSSc), especially within the first 4 years of diagnosis and in those with anti-RNA polymerase III antibodies.

• Pathophysiological Mechanism: Acute endarterial intimal proliferation of renal arcuate and interlobular arteries causes sudden luminal obliteration, renal cortical hypoperfusion, and intense activation of the renin-angiotensin-aldosterone system (RAAS), driving extreme hyperreninemic vasoconstriction.
• Clinical Presentation:
  • Abrupt onset of severe, malignant hypertension (blood pressure typically > 180/110 mmHg; however, ~10% are normotensive SRC, which carries a worse prognosis).
  • Acute oliguric or anuric renal failure (rapid doubling of serum creatinine).
  • Microangiopathic Hemolytic Anemia (MAHA): Coombs-negative hemolytic anemia, fragmented erythrocytes (schistocytes / helmet cells on peripheral blood film), thrombocytopenia, and elevated LDH.
  • Encephalopathy: Severe headache, visual disturbances, papilledema, and seizures.
• Emergency Pharmacotherapy:
  • Immediate First-Line Drug: Angiotensin-Converting Enzyme (ACE) Inhibitors (e.g., short-acting oral Captopril starting at 6.25 to 12.5 mg every 8 hours, titrated rapidly upward to maximum doses). ACE inhibitors halt hyperreninemic vasoconstriction, reverse renal ischemia, and prevent permanent dialysis dependency.
  • Blood pressure control: With acute neurologic or cardiac compromise, obtain critical-care support for prompt controlled reduction. Otherwise reduce systolic BP gradually, about 10% per day, avoiding hypotension and impaired renal perfusion.
  • Dialysis: Initiate hemodialysis if oliguria or uremia persists; renal recovery may occur up to 12 to 24 months after crisis under continuous ACE inhibitor maintenance.
• CRITICAL CONTRAINDICATION / SAFETY WARNING:
  • Systemic corticosteroids increase SRC risk, particularly at prednisone doses >= 15 mg/day or equivalent. Minimize exposure in adults with systemic sclerosis; use only for a clear indication, such as significant overlap myositis, with close blood-pressure and renal-function monitoring.

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Sjögren Syndrome

Primary Sjögren Syndrome is a chronic, slowly progressive autoimmune epithelitis characterized by lymphocytic infiltration (predominantly CD4+ T helper cells and B cells) of exocrine glands, leading to glandular destruction and exocrine failure.

Clinical Presentation & Diagnostic Hallmark

• Glandular Features:
  • Keratoconjunctivitis Sicca (Dry Eyes): Sensation of sand or grit in eyes, burning, photophobia, reduced tear production. Confirmed by Schirmer test (abnormal when filter paper placed inside the lower conjunctival fornix wets < 5 mm at 5 minutes) and ocular surface staining with rose bengal or fluorescein.
  • Xerostomia (Dry Mouth): Difficulty speaking or swallowing dry crackers without drinking liquids ("cracker sign"), rampant dental caries (especially cervical root caries), oral candidiasis, and recurrent bilateral parotid or submandibular gland swelling.
• Extraglandular Manifestations: Symmetrical non-erosive polyarthralgias, Raynaud phenomenon, cutaneous vasculitis (palpable purpura from cryoglobulinemia), interstitial lung disease, and interstitial nephritis (distal renal tubular acidosis [Type 1 RTA] with hypokalemia and nephrocalcinosis).
• Serology:
  • Anti-SSA / Ro: Positive in 60% to 70% of primary Sjögren syndrome. Crosses the placenta in pregnant women and binds to fetal cardiac conduction tissue, conferring a 2% to 3% risk of congenital complete heart block and neonatal lupus.
  • Anti-SSB / La: Positive in 40% to 50% of patients; highly specific when present alongside anti-SSA/Ro.
  • Rheumatoid Factor (RF) and ANA: Positive in > 70% of patients.
• Gold Standard Diagnostic Test: Minor salivary gland (labial lip) biopsy demonstrating focal lymphocytic sialadenitis with a focus score >= 1 (defined as >= 50 mononuclear cells per 4 mm² of glandular tissue).

The Malignancy Risk: B-Cell Non-Hodgkin Lymphoma

Patients with primary Sjögren syndrome carry a 44-fold increased relative risk of developing B-cell non-Hodgkin lymphoma compared to the general population. The most common histological subtype is Marginal Zone B-Cell Lymphoma (MALToma) of the parotid gland, followed by diffuse large B-cell lymphoma (DLBCL).

• Clinical Red Flags for Lymphoma Transformation:
  1. Persistent, firm, asymmetrical, or hard enlargement of a parotid gland.
  2. New-onset palpable purpura (cryoglobulinemic leukocytoclastic vasculitis).
  3. Persistent hypocomplementemia (profoundly low C4 levels).
  4. Disappearance of previously elevated Rheumatoid Factor or emergence of a monoclonal serum/urinary paraprotein band.

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Inflammatory Myopathies: Polymyositis & Dermatomyositis

Polymyositis (PM) and Dermatomyositis (DM) are systemic autoimmune myopathies characterized by skeletal muscle inflammation leading to symmetrical proximal muscle weakness. Although clinically overlapping, they represent distinct pathophysiological entities with different immunopathological mechanisms, cutaneous markers, and oncological implications.

Pathophysiological & Histopathological Comparison

Pathognomonic Cutaneous Hallmarks of Dermatomyositis

1. Gottron Papules: Symmetrical, violaceous, flat-topped inflammatory papules and plaques over the dorsal aspects of the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints (distinguishing DM from SLE, which characteristically involves the interphalangeal spaces while sparing the bony knuckles).
2. Heliotrope Rash: Violaceous (purplish-lilac) erythema and edematous discoloration over the upper eyelids and periorbital tissues, resembling the heliotrope flower.
3. Shawl Sign & V-Sign: Confluent, photosensitive, violaceous maculopapular erythema distributed across the posterior neck and upper back/shoulders (shawl distribution) or anterior neck and upper chest (V-neck distribution).
4. Mechanic's Hands: Hyperkeratosis, scaling, and painful linear fissuring over the palmar and lateral surfaces of the digits; strongly associated with the anti-synthetase syndrome.
5. Gottron Sign: Macular violaceous erythema over extensor bony prominences (elbows, patellae, medial malleoli).

Autoantibody Profiles & Anti-Synthetase Syndrome

• Anti-Jo-1 (Anti-Histidyl-tRNA Synthetase): The most frequent myositis-specific antibody (20% to 30%). Diagnostic of the Anti-Synthetase Syndrome, characterized by the clinical pentad: (1) Inflammatory myopathy, (2) Progressive Interstitial Lung Disease (ILD), (3) Symmetrical non-erosive arthritis, (4) Raynaud phenomenon, and (5) Mechanic's hands.
• Anti-Mi-2: Directed against nuclear helicase; associated with classic acute dermatomyositis, extensive Gottron papules, and an excellent, rapid response to corticosteroid therapy.
• Anti-MDA5 (Melanoma Differentiation-Associated Gene 5): Associated with clinically amyopathic dermatomyositis (CADM), rapidly progressive interstitial lung disease (RP-ILD with high mortality), and severe cutaneodigital ulcerations.
• Anti-Signal Recognition Particle (Anti-SRP): Highly specific for severe, acute, steroid-refractory necrotizing autoimmune myopathy with profound dysphagia and cardiac involvement.

Paraneoplastic Screen in Dermatomyositis

Because 20% to 30% of adult dermatomyositis cases represent a paraneoplastic manifestation of an underlying occult malignancy, age- and sex-appropriate comprehensive cancer screening is mandatory upon diagnosis. Common associated malignancies include:

• Ovarian Carcinoma (important association; assess within risk-based screening)
• Lung, Breast, Gastrointestinal (Colorectal, Gastric), and Pancreatic Carcinomas
• Nasopharyngeal Carcinoma (particularly in individuals of Southeast Asian descent)
• Non-Hodgkin Lymphoma
• Recommended Screening: Continue national age- and sex-appropriate screening and assess myositis-associated cancer risk. Perform basic screening at diagnosis; moderate/high-risk adults also need enhanced testing, which may include CT neck/chest/abdomen/pelvis, CA-125 and pelvic ultrasound. High-risk adults need annual basic screening for 3 years; do not prescribe annual ovarian testing universally.

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Systemic Vasculitides

Systemic vasculitides are inflammatory diseases characterized by destruction and necrosis of blood vessel walls, leading to tissue ischemia, vessel occlusion, microaneurysm formation, or rupture. The 2012 Revised International Chapel Hill Consensus Conference (CHCC) categorizes vasculitides primarily according to the predominant caliber of affected vessels.

+-----------------------------------------------------------------------------------------------------------------+
|                        CHAPEL HILL CONSENSUS: SYSTEMIC VASCULITIDES BY CALIBER                                  |
+-----------------------------------------------------------------------------------------------------------------+
| VESSEL SIZE     | DISORDER               | PREDOMINANT VESSELS      | HALLMARK FEATURES                         |
+-----------------+------------------------+--------------------------+-------------------------------------------+
| LARGE VESSEL    | Giant Cell Arteritis   | Extracranial branches of | Age >= 50; temporal headache, jaw         |
|                 | (Temporal Arteritis)   | carotid (temporal, ophth)| claudication, visual loss, ESR > 50-100   |
|                 +------------------------+--------------------------+-------------------------------------------+
|                 | Takayasu Arteritis     | Aorta & primary branch   | Females < 40; pulseless upper limbs,      |
|                 |                        | arteries                 | asymmetric BP > 10 mmHg, arterial bruits  |
+-----------------+------------------------+--------------------------+-------------------------------------------+
| MEDIUM VESSEL   | Polyarteritis Nodosa   | Main visceral arteries & | Spares pulmonary vasculature; livedo      |
|                 | (PAN)                  | their branches           | reticularis, mononeuritis multiplex, HBV  |
|                 +------------------------+--------------------------+-------------------------------------------+
|                 | Kawasaki Disease       | Coronary arteries in     | Paediatric; fever >= 5 days, strawberry   |
|                 |                        | young children           | tongue, coronary aneurysms                |
+-----------------+------------------------+--------------------------+-------------------------------------------+
| SMALL VESSEL    | Granulomatosis with    | Small intraparenchymal   | Upper/lower respiratory granulomas,       |
| (ANCA-          | Polyangiitis (GPA)     | arteries, arterioles,    | crescentic RPGN, c-ANCA (PR3) positive    |
| Associated)     |                        | venules, capillaries     |                                           |
|                 +------------------------+--------------------------+-------------------------------------------+
|                 | Microscopic            | Arterioles, venules,     | Pulmonary-renal syndrome; crescentic      |
|                 | Polyangiitis (MPA)     | capillaries              | RPGN; NO granulomas; p-ANCA (MPO)         |
|                 +------------------------+--------------------------+-------------------------------------------+
|                 | Eosinophilic GPA       | Small vessels,           | Severe asthma, eosinophilia > 1,000/µL,   |
|                 | (Churg-Strauss / EGPA) | extravascular granulomas | transient infiltrates, p-ANCA (40%-50%)   |
+-----------------+------------------------+--------------------------+-------------------------------------------+
| SMALL VESSEL    | IgA Vasculitis         | Capillaries, venules     | Non-thrombocytopenic palpable purpura,    |
| (Immune Complex)| (Henoch-Schönlein)     | with IgA deposits        | arthralgias, abdominal pain, hematuria    |
+-----------------------------------------------------------------------------------------------------------------+

Large-Vessel Vasculitides

1. Giant Cell (Temporal) Arteritis (GCA):
   • Demographics: Exclusive to patients age >= 50 years (incidence peaks at 70-80 years; female:male 3:1).
   • Clinical Features: New-onset throbbing temporal or occipital headache, scalp tenderness (pain when brushing hair), jaw claudication (fatigue and pain in masseter muscles while chewing, the single highest positive likelihood ratio finding), and visual symptoms (amaurosis fugax, diplopia, or sudden irreversible unilateral blindness from Anterior Ischemic Optic Neuropathy [AION]).
   • Association: 50% have concurrent Polymyalgia Rheumatica (PMR) (bilateral morning stiffness and aching in shoulder and pelvic girdles lasting > 45 minutes, with normal creatine kinase).
   • Laboratory: Markedly elevated ESR (> 50 to 100 mm/h) and high CRP; normochromic normocytic anemia of chronic disease.
   • Definitive Diagnosis: Temporal artery biopsy showing transmural granulomatous infiltration, CD4+ T cells, histiocytes, multinucleated giant cells, and fragmentation of the internal elastic lamina (minimum biopsy length 1.5 to 2.0 cm due to "skip lesions").
   • CRITICAL CLINICAL EMERGENCY RULE: If GCA is clinically suspected, immediately initiate high-dose systemic corticosteroids (oral Prednisone 40 to 60 mg/day; or IV Methylprednisolone pulse 1,000 mg/day for 3 days if acute visual loss is present) BEFORE performing temporal artery biopsy. Arrange biopsy promptly, preferably within 2 weeks of starting steroids; diagnostic changes can persist longer. Never delay treatment for biopsy because irreversible visual loss may occur.
2. Takayasu Arteritis ("Pulseless Disease"):
   • Granulomatous panarteritis of the aortic arch and its major branches, typically affecting women under 40 years of age (especially of Asian descent).
   • Features: Diminished or absent peripheral pulses (radial, brachial), significant blood pressure discrepancy (> 10 mmHg) between upper extremities, arterial bruits (carotid, subclavian, abdominal), upper limb claudication, renovascular hypertension (renal artery stenosis), and aortic root regurgitation.
   • Treated with systemic corticosteroids, steroid-sparing immunosuppressants (methotrexate, azathioprine), or tocilizumab (anti-IL-6 receptor), followed by surgical revascularization or angioplasty once vascular inflammation is extinguished.

Medium-Vessel Vasculitis: Polyarteritis Nodosa (PAN)

• Pathology: Segmental, transmural necrotizing inflammation of medium-sized and small muscular arteries with fibrinoid necrosis, microaneurysms, thrombosis, and secondary infarction. Crucially, PAN spares the pulmonary circulation (spares the lungs) and spares post-capillary venules (no glomerulonephritis).
• Etiology: Strong association with chronic Hepatitis B virus (HBV) infection (HBsAg positive; circulating HBsAg-anti-HBs immune complexes induce vascular injury); also linked to Hepatitis C and hairy cell leukemia.
• Clinical Manifestations:
  • Cutaneous: Livedo reticularis (violaceous, reticulated vascular lace-like mottling), subcutaneous nodules along artery courses, digital ischemia, and painful cutaneous ulcers.
  • Neurological: Mononeuritis Multiplex (asymmetrical, painful, sensorimotor peripheral neuropathy involving >= 2 non-contiguous nerve trunks, e.g., right radial nerve wrist drop plus left peroneal nerve foot drop, secondary to ischemic infarction of the vasa nervorum).
  • Renal: Renovascular hypertension, renal microaneurysms, and multiple cortical renal infarctions (due to arcuate/interlobular artery arteritis). Renal failure occurs without primary glomerulonephritis (urinary sediment shows minimal or no red cell casts).
  • Gastrointestinal: Severe postprandial abdominal pain ("intestinal angina"), bowel ischemia, bleeding, or perforation.
• Angiographic Hallmark: Mesenteric or renal visceral catheter angiography (or CT/MR angiography) reveals multiple microaneurysms (1 to 5 mm) alternating with segmental arterial stenoses, producing the classic "string-of-pearls" (or "rosary") sign.
• Therapy: Corticosteroids plus oral/IV Cyclophosphamide for severe idiopathic PAN; in HBV-associated PAN, therapy combines short-course corticosteroids, antiviral therapy (Entecavir or Tenofovir), and plasma exchange (plasmapheresis) to clear circulating immune complexes.

Small-Vessel Vasculitides

1. Granulomatosis with Polyangiitis (GPA, formerly Wegener's):
   • Necrotizing granulomatous small-vessel vasculitis characterized by the classic pulmonary-renal-airway triad:
     1. Upper Respiratory Tract (90%): Chronic severe destructive sinusitis, purulent/bloody rhinorrhea, mucosal ulcerations, cartilaginous nasal septum perforation resulting in saddle-nose deformity, and subglottic stenosis causing stridor.
     2. Lower Respiratory Tract (85%): Cough, dyspnea, hemoptysis; chest imaging shows multiple bilateral nodular densities with central cavitation.
     3. Renal (80%): Pauci-immune necrotizing crescentic Rapidly Progressive Glomerulonephritis (RPGN) presenting with hematuria, red cell casts, proteinuria, and rapid azotemia.
   • Immunological Serology: Strongly positive for c-ANCA (cytoplasmic ANCA) directed against Proteinase 3 (PR3) in > 80% to 90% of active systemic cases.
   • Management: Induction with high-dose corticosteroids combined with either Rituximab (anti-CD20) or Cyclophosphamide; maintenance with Rituximab, Azathioprine, or Methotrexate.
2. Microscopic Polyangiitis (MPA):
   • Non-granulomatous necrotizing small-vessel vasculitis that manifests primarily as a pulmonary-renal syndrome (diffuse alveolar hemorrhage from pulmonary capillaritis plus pauci-immune crescentic RPGN). Unlike GPA, it lacks destructive upper respiratory granulomas, cavitary nodules, and asthma.
   • Serology: Strongly positive for p-ANCA (perinuclear ANCA) directed against Myeloperoxidase (MPO) in 70% to 85% of cases.
3. IgA Vasculitis (Henoch-Schönlein Purpura [HSP]):
   • Leukocytoclastic small-vessel vasculitis caused by vascular and tissue deposition of IgA1-containing immune complexes following an upper respiratory tract infection (often streptococcal or viral).
   • Demographics: Most frequent in children aged 3 to 10 years, but occurs in adults with higher renal morbidity.
   • Pathognomonic Clinical Tetrad:
     1. Palpable Purpura: Non-thrombocytopenic, raised, violaceous purpuric macules and papules characteristically distributed symmetrically over the buttocks, lower extremities, and extensor surfaces. Normal platelet count differentiates HSP from ITP and TTP.
     2. Arthralgias / Non-Destructive Arthritis: Transient, painful swelling of large weight-bearing joints (ankles and knees) without long-term joint deformity.
     3. Gastrointestinal Symptoms: Severe colicky, periumbilical abdominal pain, vomiting, occult or gross gastrointestinal bleeding, and risk of ileoileal intussusception (mucosal edema acts as a lead point).
     4. Renal Involvement (IgA Nephropathy / Berger's-like): Microscopic hematuria, red cell casts, proteinuria; may progress to nephrotic syndrome or crescentic glomerulonephritis.
   • Diagnostic Confirmation: Skin punch biopsy of purpuric lesion demonstrating leukocytoclastic vasculitis with prominent perivascular IgA and C3 deposition on direct immunofluorescence.
   • Therapy: Primarily supportive (adequate hydration, NSAIDs for joint pain); oral corticosteroids (prednisone 1 mg/kg/day) provide rapid relief of severe abdominal colic and soft tissue edema but do not prevent chronic renal progression. Rapidly progressive nephritis requires urgent nephrology-led immunosuppression, often glucocorticoids plus cyclophosphamide; crescents alone do not establish that indication.

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Worked Clinical Scenarios

Scenario 1: Young Female with Multisystem Manifestations & Active Sediment

• Presentation: A 24-year-old woman of Afro-Caribbean descent presents to clinic with a 3-month history of fatigue, intermittent low-grade fever, bilateral symmetric polyarthralgias of the hands and wrists, and an erythematous facial rash over her cheeks that worsens after sun exposure and spares her nasolabial folds. Urinalysis demonstrates 3+ protein and 2+ blood, with microscopic examination revealing dysmorphic erythrocytes and red blood cell casts. Laboratory testing shows hemoglobin 9.2 g/dL, leukocytes 3,100/µL, platelets 110,000/µL, serum creatinine 1.4 mg/dL (baseline 0.7 mg/dL), ANA 1:640 (speckled pattern), anti-dsDNA positive at 1:160, and markedly depressed complement levels (C3 42 mg/dL, normal 90-180; C4 6 mg/dL, normal 16-47).
• Diagnostic Assessment: With ANA entry met and no better explanation, documented malar rash (6), leukopenia (3), low C3/C4 (4) and anti-dsDNA (6) total 19 points, meeting SLE classification. Do not add fever, joint or proteinuria points without their qualifying definitions or measurements. Proteinuria, red cell casts and rising creatinine strongly suggest lupus nephritis and require urgent renal evaluation.
• Management Action: She requires urgent percutaneous renal biopsy to determine ISN/RPS histopathological class. Given the active nephritic sediment and azotemia, proliferative lupus nephritis (Class III or IV) is highly probable. Induction pharmacotherapy must be initiated promptly with high-dose intravenous pulse Methylprednisolone (1 g daily for 3 days) followed by oral Prednisone plus oral Mycophenolate Mofetil (MMF, 2 to 3 g daily, the preferred agent in patients of African/Caribbean descent). Universal baseline Hydroxychloroquine (<= 5 mg/kg/day) must be initiated concurrently, with baseline ophthalmological documentation.

Scenario 2: Scleroderma Renal Crisis Precipitated by Corticosteroids

• Presentation: A 48-year-old woman with a 2-year history of diffuse cutaneous systemic sclerosis (characterized by progressive skin tightening of the arms, chest, and face, Raynaud phenomenon, and anti-RNA polymerase III antibodies) is prescribed oral Prednisone 30 mg daily by her primary care provider for worsening hand joint pain. Ten days later, she presents to the emergency department with severe throbbing headache, blurred vision, orthopnea, and decreased urine output. Her blood pressure is 210/118 mmHg (baseline 115/75 mmHg). Laboratory results reveal acute oliguric kidney injury with serum creatinine 3.8 mg/dL (baseline 0.9 mg/dL). Peripheral blood film demonstrates marked schistocytes, polychromasia, and thrombocytopenia (platelets 68,000/µL). Serum LDH is 1,240 U/L, and direct Coombs test is negative.
• Diagnostic Assessment: This patient has developed Scleroderma Renal Crisis (SRC) with Microangiopathic Hemolytic Anemia (MAHA), directly precipitated by moderate-dose systemic corticosteroid therapy. Corticosteroids stimulate renal endothelial injury and unmask profound hyperreninemic vasoconstriction in systemic sclerosis.
• Management Action: Corticosteroids must be immediately discontinued. The emergency drug of choice is an oral ACE inhibitor, specifically short-acting Captopril (6.25 to 12.5 mg initial test dose, titrated rapidly every 8 hours up to 50-100 mg three times daily) to directly block the intense intrarenal renin-angiotensin cascade. Her visual symptoms and orthopnea require urgent assessment for hypertensive neurologic/cardiac compromise, with monitored prompt BP control and critical-care support; avoid uncontrolled hypotension. Hemodialysis must be initiated if pulmonary edema, refractory acidosis, or severe uremia develops, with continuous ACE inhibitor maintenance to permit long-term renal recovery.