138 139. Causes that contribute to the development of edema syndrome. 140. Classification of acute circulatory failure. The role of disturbances in osmotic and hydrostatic pressure in the formation of edema. 141. Diagnostic criteria for edema syndrome in heart diseases. 142. Diagnostic criteria for edema syndrome in kidney diseases: 143. Diagnostic criteria for nephrotic syndrome. 144. Mechanisms of edema formation in chronic heart failure. 145. The mechanism of edema formation in nephritic syndrome 146. Mechanisms of edema formation in liver cirrhosis and portal hypertension 147. Laboratory markers for diagnosing the causes of edema 148. Principles of treatment of acute and chronic circulatory failure. 149. Classification of joint diseases, 150. Diagnostic criteria for rheumatic polyarthritis. 151. Diagnostic criteria for rheumatoid arthritis. 152. Diagnostic criteria for Felty's syndrome 153. Diagnostic criteria for Still's syndrome 154. Diagnostic criteria for Reiter's syndrome 155. Diagnostic criteria for systemic lupus erythematosus 156. Diagnostic criteria for systemic sclerosis. 157. Diagnostic criteria for dermatomyositis 158. Diagnostic criteria for deforming osteoarthritis 159. Diagnostic criteria for gout. 160. The role of glucocorticosteroids in the treatment of rheumatoid arthritis. 161. Use of cytostatics in the treatment of rheumatoid arthritis.

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Questions 138–161: Edema Syndromes, Circulatory Failure & Rheumatology

138–139. Causes Contributing to Edema Syndrome

Edema forms when fluid accumulates in the interstitial space. Principal contributing causes:

Category	Examples
Cardiac	Chronic heart failure (CHF), constrictive pericarditis
Renal	Nephrotic syndrome, nephritic syndrome, chronic kidney disease
Hepatic	Liver cirrhosis, portal hypertension
Oncotic pressure reduction	Malnutrition, protein-losing enteropathy
Venous/lymphatic obstruction	DVT, lymphedema, tumor compression
Iatrogenic	NSAIDs, calcium channel blockers, corticosteroids
Idiopathic	Cyclic/idiopathic edema (mainly women)

140. Classification of Acute Circulatory Failure & Role of Osmotic/Hydrostatic Pressure in Edema

Acute circulatory failure (acute heart failure) classification:

Acute decompensated CHF – gradual worsening of chronic HF
Hypertensive acute HF – high BP, preserved LV function, pulmonary edema
Pulmonary edema – severe respiratory distress, bilateral crackles, hypoxia
Cardiogenic shock – hypotension + hypoperfusion (SBP <90 mmHg, urine output <0.5 mL/kg/h)
High-output failure – thyrotoxicosis, severe anemia, AV fistula
Right HF – isolated RV failure (e.g., pulmonary embolism)

Role of osmotic and hydrostatic pressure (Starling forces):

Fluid movement across the capillary wall is governed by:

Net filtration = (Pc − Pi) − σ(πc − πi)

↑ Capillary hydrostatic pressure (Pc): venous hypertension (HF, portal hypertension) → pushes fluid into interstitium
↓ Plasma oncotic/osmotic pressure (πc): hypoalbuminemia (nephrotic syndrome, cirrhosis, malnutrition) → reduces the force that retains fluid in vessels
↑ Capillary permeability: inflammation, sepsis → protein leaks out, raising interstitial oncotic pressure
Lymphatic obstruction: impairs removal of interstitial fluid

— Comprehensive Clinical Nephrology, 7th Ed.; Goldman-Cecil Medicine

141. Diagnostic Criteria for Edema in Heart Diseases

Classic features of cardiac edema:

Bilateral, dependent, pitting edema (ankles, sacrum in bed-bound patients)
Worsens at end of day; improves with elevation and diuretics
Associated with: raised JVP, S3 gallop, displaced apex, cardiomegaly on CXR
Orthopnea, paroxysmal nocturnal dyspnea, bilateral basal crackles
No periorbital edema (edema distributes by gravity)
ECG/echo abnormalities confirming cardiac dysfunction
↑ BNP/NT-proBNP (>125 pg/mL in chronic HF)
CXR: cardiomegaly, pulmonary congestion, Kerley B lines

142. Diagnostic Criteria for Edema in Kidney Diseases

Nephrotic edema: See Q.143 below.

Nephritic edema:

Abrupt onset, less severe than nephrotic (+++)
Associated with hypertension, raised JVP (volume overload mechanism)
Hematuria (brown/smoky urine), RBC casts
↑ Serum creatinine (reduced GFR), oliguria
Proteinuria usually sub-nephrotic (<3.5 g/day)
Normal or slightly reduced serum albumin

Chronic kidney disease edema:

Progressive fluid retention due to reduced GFR
Hypertension, hyperkalemia, metabolic acidosis
Anemia (EPO deficiency)

143. Diagnostic Criteria for Nephrotic Syndrome

Classic tetrad:

Proteinuria ≥3.5 g/24 hours (massive)
Hypoalbuminemia (<30 g/L)
Edema – massive, soft, pitting; periorbital in the morning; can involve genitals, ascites, pleural effusions
Hyperlipidemia (↑ LDL, total cholesterol, triglycerides; compensatory hepatic synthesis)

Additional: Lipiduria (oval fat bodies, fatty casts on urinalysis), hypercoagulability (loss of antithrombin III, protein C/S), ↑ risk of thromboembolic events.

Onset is insidious; normal BP; normal JVP; serum albumin low.

— Comprehensive Clinical Nephrology, 7th Ed.; Henry's Clinical Diagnosis & Management

144. Mechanisms of Edema Formation in Chronic Heart Failure

↓ Cardiac output → RAAS activation: Reduced renal perfusion → renin → angiotensin II → aldosterone → Na⁺ and water retention
↑ Venous hydrostatic pressure: Backward failure raises venous pressure → fluid forced into interstitium
Sympathetic activation: Renal vasoconstriction → further Na⁺ retention
ADH secretion: Hypovolemia and angiotensin II stimulate ADH → free water retention
↓ ANP response: Impaired natriuretic peptide response fails to counteract Na⁺ retention
Hypoalbuminemia (chronic severe CHF with cardiac cachexia): further reduces oncotic pressure

Result: Net accumulation of fluid in interstitial space, most marked in dependent regions.

145. Mechanism of Edema Formation in Nephritic Syndrome

Glomerular inflammation → ↓ GFR → Na⁺ and water retention (primary renal Na⁺ retention — NOT hypoalbuminemia)
↑ Circulating volume → raises capillary hydrostatic pressure
Hypertension follows from volume overload
Pulmonary edema can occur without cardiac disease (volume overload mechanism)
Serum albumin is usually normal or only slightly reduced, distinguishing this from nephrotic edema

Key distinction: Nephritic edema is driven by volume overload (high JVP, hypertension), while nephrotic edema is driven by oncotic pressure loss (low albumin, low JVP).

— Comprehensive Clinical Nephrology, 7th Ed.

146. Mechanisms of Edema in Liver Cirrhosis and Portal Hypertension

↑ Portal venous pressure (portal hypertension): Directly elevates sinusoidal and splanchnic capillary hydrostatic pressure → ascites and peripheral edema
Hypoalbuminemia: Reduced synthetic function → ↓ plasma oncotic pressure
Splanchnic vasodilation (NO-mediated): Effective arterial hypovolemia → RAAS + sympathetic activation → renal Na⁺ retention
ADH excess (hypervolemic hyponatremia): Free water retention
Hepatic lymph overflow: Exceeds thoracic duct capacity → ascites
Secondary hyperaldosteronism: Perpetuates Na⁺ and water retention

147. Laboratory Markers for Diagnosing Causes of Edema

Test	Cardiac	Nephrotic	Nephritic	Hepatic
BNP / NT-proBNP	↑↑	Normal	Normal	Mildly ↑
Serum albumin	Normal/↓	↓↓	Normal/↓	↓↓
Urine protein	Trace	≥3.5 g/day	1–3 g/day	Trace
Urine RBCs/casts	Absent	Absent	RBC casts	Absent
Serum creatinine	↑ (cardiorenal)	Normal/↑	↑	Normal/↑
LFTs / PT	Normal	Normal	Normal	↑ PT, ↑ bilirubin
ANA, Anti-dsDNA	—	—	↑ in lupus nephritis	—
ASLO	—	—	↑ in post-strep GN	—
Complement (C3/C4)	Normal	Normal/↓	↓ (post-strep, lupus)	Normal
Lipids	Normal	↑↑	Normal	↑
Echocardiogram	Abnormal	Normal	Normal	Normal

148. Principles of Treatment of Acute and Chronic Circulatory Failure

Acute circulatory failure / acute HF:

Oxygen/CPAP for hypoxia; mechanical ventilation if needed
IV diuretics (furosemide) – rapid decongestion
Vasodilators (nitrates, nitroprusside) in hypertensive pulmonary edema
Inotropes (dobutamine, levosimendan) in cardiogenic shock with low output
Vasopressors (norepinephrine) in shock with severe hypotension
Treat precipitating cause (ACS, arrhythmia, infection)

Chronic circulatory failure (chronic HF):

ACE inhibitors / ARBs / ARNIs (sacubitril-valsartan) – reduce mortality, afterload
Beta-blockers (carvedilol, bisoprolol, metoprolol) – reduce mortality
Mineralocorticoid antagonists (spironolactone, eplerenone) – antialdosterone
SGLT2 inhibitors (empagliflozin, dapagliflozin) – reduce hospitalizations
Loop diuretics (furosemide) – symptom relief, decongestion
Ivabradine – rate control when beta-blockers insufficient
Device therapy: ICD (sudden death prevention), CRT (dyssynchrony), mechanical circulatory support
Heart transplantation – end-stage refractory failure

149. Classification of Joint Diseases

Category	Examples
Inflammatory	Rheumatoid arthritis, juvenile idiopathic arthritis, reactive arthritis
Crystal-induced	Gout (urate), pseudogout (CPPD)
Connective tissue	SLE, systemic sclerosis, dermatomyositis, Sjögren's
Spondyloarthritis	Ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome
Degenerative	Osteoarthritis
Infectious	Septic arthritis, Lyme arthritis
Metabolic	Hemochromatosis, alkaptonuria
Paraneoplastic / other	Hypertrophic osteoarthropathy

150. Diagnostic Criteria for Rheumatic (Acute Rheumatic Fever) Polyarthritis

Jones Criteria (2015 revision):

Major criteria:

Carditis (clinical or subclinical/echocardiographic)
Migratory polyarthritis (large joints: knees, ankles, wrists; very tender; responds dramatically to NSAIDs)
Chorea (Sydenham's chorea)
Erythema marginatum
Subcutaneous nodules

Minor criteria: Fever, elevated ESR/CRP, prolonged PR interval

Diagnosis: 2 major, or 1 major + 2 minor, PLUS evidence of preceding streptococcal infection (↑ ASLO, positive throat culture, recent scarlet fever).

Features of rheumatic polyarthritis specifically:

Migratory (flits from joint to joint)
Asymmetric, affects large joints
Exquisitely tender, warm, swollen
Self-limiting (days per joint)
Does not cause permanent joint damage

151. Diagnostic Criteria for Rheumatoid Arthritis

2010 ACR/EULAR Classification Criteria (score ≥6/10 = definite RA):

Domain	Points
Joint involvement: 1 large joint	0
2–10 large joints	1
1–3 small joints	2
4–10 small joints	3
>10 joints (≥1 small)	5
Serology: RF or ACPA negative	0
Low-positive RF or ACPA	2
High-positive RF or ACPA (>3× ULN)	3
Acute-phase reactants: Normal CRP and ESR	0
Abnormal CRP or ESR	1
Duration: <6 weeks	0
≥6 weeks	1

Key clinical features: symmetric small joint synovitis (PIP, MCP, wrist, MTP), morning stiffness >1 hour, rheumatoid nodules, extra-articular features (Sjögren's, interstitial lung disease, vasculitis).

Laboratory: RF +ve (~75%), anti-CCP/ACPA (more specific), ↑ CRP/ESR, normocytic anemia.

— Goldman-Cecil Medicine

152. Diagnostic Criteria for Felty Syndrome

Felty syndrome is a triad occurring in long-standing, severe, seropositive RA:

Rheumatoid arthritis (usually seropositive, RF/ACPA +ve, erosive disease)
Splenomegaly
Neutropenia (ANC <2.0 × 10⁹/L)

Additional features: hepatomegaly, thrombocytopenia, lymphadenopathy, fever, leg ulcers, ↑ susceptibility to infections (especially gram-positive bacteria), hyperpigmentation of skin.

Note: Must distinguish from Large Granular Lymphocyte (LGL) syndrome — clonal proliferation of large granular lymphocytes with near-complete neutropenia.

— Goldman-Cecil Medicine

153. Diagnostic Criteria for Still's Disease (Adult-onset Still's Disease)

Yamaguchi Criteria (most widely used); ≥5 criteria required, ≥2 must be major:

Major criteria:

Quotidian (daily spiking) fever ≥39°C lasting ≥1 week
Arthralgia or arthritis lasting ≥2 weeks
Typical salmon-colored evanescent rash
Leukocytosis (≥10,000/mm³, ≥80% granulocytes)

Minor criteria:

Sore throat
Lymphadenopathy and/or splenomegaly
↑ Liver enzymes (AST/ALT)
ANA and RF negative

Exclusion criteria: infections, malignancy, other rheumatic disease.

Hallmark lab: Markedly elevated serum ferritin (often >5× normal); highly specific when >5,000 µg/L with glycosylated ferritin fraction <20%.

154. Diagnostic Criteria for Reiter's Syndrome (Reactive Arthritis)

Classic triad (rarely all present simultaneously):

Asymmetric oligoarthritis (predominantly lower limbs — knees, ankles, feet)
Non-gonococcal urethritis (or cervicitis)
Conjunctivitis (or anterior uveitis)

Additional features:

Keratoderma blenorrhagica (hyperkeratotic skin lesions on palms/soles)
Circinate balanitis (painless penile lesion)
Oral ulcers (painless)
Enthesitis (Achilles tendinitis, plantar fasciitis)
Sausage digits (dactylitis)
HLA-B27 positive (~80%)

Trigger: Preceded by genitourinary (Chlamydia) or gastrointestinal (Salmonella, Shigella, Campylobacter, Yersinia) infection.

Diagnosis: Clinical; supportive tests: HLA-B27, elevated CRP/ESR, urethral swab/culture, joint aspiration (sterile).

155. Diagnostic Criteria for Systemic Lupus Erythematosus (SLE)

2019 EULAR/ACR Classification Criteria:

Entry criterion: ANA titer ≥1:80 (if absent, do not classify as SLE)

Additive weighted criteria (score ≥10 = SLE):

Domain	Finding	Points
Constitutional	Fever	2
Neuropsychiatric	Delirium	2
	Psychosis	3
	Seizure	5
Mucocutaneous	Non-scarring alopecia	2
	Oral ulcers	2
	Subacute cutaneous/discoid lupus	4
	Acute cutaneous lupus (malar rash)	6
Musculoskeletal	Joint involvement	6
Serosal	Pleural/pericardial effusion	5
	Acute pericarditis	6
Hematologic	Leukopenia	3
	Thrombocytopenia	4
	Autoimmune hemolysis	4
Renal	Proteinuria >0.5 g/24h	4
	Biopsy: class II/V lupus nephritis	8
	Biopsy: class III/IV lupus nephritis	10
Antiphospholipid Ab	aCL or anti-β2GPI	2
Complement	Low C3 OR C4	3
	Low C3 AND C4	4
SLE-specific Ab	Anti-dsDNA	6

Key antibodies: ANA (sensitive, not specific), anti-dsDNA (specific, correlates with disease activity), anti-Sm (most specific), anti-Ro/La, antiphospholipid antibodies.

— Goldman-Cecil Medicine

156. Diagnostic Criteria for Systemic Sclerosis (Scleroderma)

2013 ACR/EULAR Criteria (score ≥9 = definite SSc):

Finding	Points
Skin thickening of fingers extending proximal to MCPs	9 (sufficient alone)
Skin thickening of fingers (puffy/sclerodactyly)	2–4
Fingertip lesions (digital ulcers/pitting scars)	2–3
Telangiectasias	2
Abnormal nailfold capillaries	2
Pulmonary hypertension and/or ILD	2
Raynaud's phenomenon	3
SSc-related antibodies (ACA, anti-topoisomerase I/Scl-70, anti-RNA Pol III)	3

Two subtypes:

Limited cutaneous SSc (lcSSc): Skin involvement distal to elbows/knees; CREST syndrome (Calcinosis, Raynaud's, Esophageal dysmotility, Sclerodactyly, Telangiectasia); anti-centromere Ab
Diffuse cutaneous SSc (dcSSc): Skin involvement proximal to elbows/knees + truncal; anti-Scl-70 (topoisomerase I); rapid progression; interstitial lung disease, renal crisis

157. Diagnostic Criteria for Dermatomyositis

Bohan & Peter / 2017 EULAR/ACR criteria:

Muscle features:

Proximal muscle weakness (symmetric)
↑ Muscle enzymes: CK, LDH, aldolase, AST
Myopathic EMG
Muscle biopsy: perifascicular atrophy, inflammatory infiltrate (perivascular)
MRI: signal abnormalities in affected muscles

Skin features (required for dermatomyositis):

Heliotrope rash (violaceous periorbital discoloration)
Gottron's papules (erythematous papules over MCP, PIP, DIP joints)
Gottron's sign (erythema over extensor surfaces)
V-sign, Shawl sign, mechanic's hands
Periungual nailfold capillary changes

Antibodies: Anti-Jo-1 (anti-synthetase syndrome — myositis + ILD + arthritis + mechanic's hands + Raynaud's), anti-Mi-2, anti-MDA5.

Important: Association with malignancy (particularly ovarian, lung, GI, breast, lymphoma) — cancer screen mandatory.

158. Diagnostic Criteria for Deforming Osteoarthritis

Clinical diagnosis (ACR criteria):

Hand OA:

Hand pain, aching, or stiffness + ≥3 of:
1. Hard tissue enlargement of ≥2 of 10 selected joints
2. Hard tissue enlargement of ≥2 DIP joints
3. <3 swollen MCP joints
4. Deformity of ≥1 of 10 selected joints

Knee OA:

Knee pain + ≥3 of: age >50, stiffness <30 min, crepitus, bony tenderness, bony enlargement, no warmth; OR knee pain + osteophytes on X-ray

Radiological features (Kellgren-Lawrence grading):

Doubtful joint space narrowing, possible osteophytes
Definite osteophytes, possible JSN
Multiple osteophytes, definite JSN, some sclerosis
Large osteophytes, marked JSN, severe sclerosis, bony deformity

Clinical hallmarks: Heberden's nodes (DIP), Bouchard's nodes (PIP), pain worse with activity, improves with rest, no systemic features.

159. Diagnostic Criteria for Gout

2015 ACR/EULAR Criteria (score ≥8 = gout):

Sufficient criterion: Monosodium urate (MSU) crystals in synovial fluid or tophus (needle-shaped, negatively birefringent under polarized light) → immediate classification.

Scoring criteria:

Domain	Finding	Points
Pattern of joint involvement	Ankle or midfoot (without 1st MTP)	1
	1st MTP involved	2
Characteristics of episode	Erythema, inability to bear touch, great difficulty walking	1–3
Time course	Typical acute episode (max <24h, resolution <14d)	1–2
Serum urate	<4 mg/dL	−4
	≥6 to <8 mg/dL	2
	≥8 to <10 mg/dL	3
	≥10 mg/dL	4
Synovial fluid analysis	MSU negative	−2
Imaging	Double contour sign on US / tophus on DECT	4
	Gout-related erosion on X-ray	4

Classic acute attack: Sudden onset monoarthritis (often 1st MTP – podagra), exquisitely tender, erythematous, self-limiting; triggered by alcohol, purine-rich diet, diuretics, dehydration.

160. Role of Glucocorticosteroids in the Treatment of Rheumatoid Arthritis

Uses:

Bridge therapy: Rapid symptom control while waiting for slow-acting DMARDs (MTX takes 6–12 weeks to work); given as short courses (prednisolone ≤7.5–10 mg/day)
Acute flare management: Short-term moderate-dose oral or IM corticosteroids
Intra-articular injection: Triamcinolone or methylprednisolone for single inflamed joint

Mechanism: Potent anti-inflammatory — suppress NF-κB, reduce cytokine production (TNF, IL-1, IL-6), inhibit phospholipase A2 and prostaglandin synthesis.

Role in disease modification: Low-dose, long-term glucocorticoids slow radiographic progression, acting as a "cheap DMARD," but this must be balanced against cumulative toxicity.

Adverse effects (limiting long-term use): osteoporosis (bisphosphonate prophylaxis required), Cushing's syndrome, hyperglycemia, hypertension, infection risk, adrenal suppression, cataracts, avascular necrosis.

Current guidelines (EULAR 2019): Use lowest effective dose for shortest duration; always taper; not recommended as sole long-term treatment.

— Goldman-Cecil Medicine

161. Use of Cytostatics (DMARDs) in the Treatment of Rheumatoid Arthritis

Conventional synthetic DMARDs (csDMARDs):

Drug	Dose	Key Notes
Methotrexate (MTX)	15–25 mg/week (oral or SC)	First-line DMARD; folate supplementation required; monitor LFTs, CBC; contraindicated in pregnancy
Leflunomide	10–20 mg/day	Alternative to MTX; inhibits pyrimidine synthesis; teratogenic
Sulfasalazine	1–3 g/day	Effective; monitor CBC (esp. WBC first 6 months)
Hydroxychloroquine	200–400 mg/day (≤5 mg/kg)	Least toxic; no blood monitoring; annual ophthalmology exam after 5 years
Triple therapy	MTX + SSZ + HCQ	Efficacy similar to biologic + MTX; more economical

Biologic DMARDs (bDMARDs): Used when csDMARDs fail:

Anti-TNF agents: Etanercept, infliximab, adalimumab, golimumab, certolizumab
Anti-IL-6 receptor: Tocilizumab, sarilumab (superior to rituximab in trials)
B-cell depletion: Rituximab (anti-CD20)
T-cell co-stimulation blockade: Abatacept (CTLA4-Ig)
JAK inhibitors (tsDMARDs): Tofacitinib, baricitinib, upadacitinib

Cytostatic mechanism: MTX inhibits dihydrofolate reductase → ↓ purine/pyrimidine synthesis → inhibits rapidly dividing immune cells and ↓ inflammatory mediators.

Treatment strategy (treat-to-target):

Start MTX ± short glucocorticoid bridge
Target: clinical remission or low disease activity by 6 months
If inadequate response at 3 months → adjust/add DMARD
If MTX fails → add biologic or JAK inhibitor
Reassess every 3 months until target achieved

— Goldman-Cecil Medicine, Goldman-Cecil Medicine RA Treatment Flowchart

Key sources: Goldman-Cecil Medicine (International Edition), Comprehensive Clinical Nephrology 7th Ed., Tietz Textbook of Laboratory Medicine 7th Ed., Henry's Clinical Diagnosis & Management by Laboratory Methods

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