6.4 Hypersensitivity Reactions, Immunodeficiencies & Autoimmunity

6.4 Hypersensitivity Reactions, Immunodeficiencies & Autoimmunity

Independent study guide by OpenExamPrep.

Core Examination Pearl: Board examiners heavily test the four Gell-Coombs hypersensitivity reaction types with their clinical prototypes, the clinical pharmacology of local anesthetic allergies (esters vs. amides and the role of PABA and methylparaben), the classical pediatric immunodeficiencies (SCID, Bruton's, DiGeorge), and the podiatric manifestations of Rheumatoid Arthritis versus HLA-B27 seronegative spondyloarthropathies (especially Reactive Arthritis and keratoderma blennorrhagica).

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1. The Gell & Coombs Classification of Hypersensitivity Reactions

Hypersensitivity reactions represent exaggerated or inappropriate immune responses that result in host tissue destruction and disease. Philip Gell and Robin Coombs classified these reactions into four pathophysiological categories:

+-----------------------------------------------------------------------------------------+
|                        THE GELL & COOMBS HYPERSENSITIVITY MATRIX                        |
+-----------+-----------------------+-----------------------------+-----------------------+
| Type      | Pathophysiologic Mech | Primary Immune Mediators    | Clinical Prototypes   |
+-----------+-----------------------+-----------------------------+-----------------------+
| Type I    | Immediate /           | IgE cross-linking on mast   | • Anaphylaxis         |
|           | Anaphylactic          | cells; Histamine, LTC4-E4   | • Allergic asthma     |
|           | (Minutes)             | PGD2; Eosinophils (IL-5)    | • Acute urticaria     |
+-----------+-----------------------+-----------------------------+-----------------------+
| Type II   | Cytotoxic / Antibody- | IgG or IgM against tissue   | • Goodpasture syn     |
|           | Mediated              | antigens; Complement lysis, | • Myasthenia gravis   |
|           | (Hours to days)       | ADCC (NK cells), or agonism | • Graves disease      |
+-----------+-----------------------+-----------------------------+-----------------------+
| Type III  | Immune Complex-       | Soluble antigen-antibody    | • Serum sickness      |
|           | Mediated              | complexes in vessels; C5a,  | • SLE (nephritis)     |
|           | (Hours to days)       | neutrophil leukocytoclasia  | • Post-strep GN       |
+-----------+-----------------------+-----------------------------+-----------------------+
| Type IV   | Delayed-Type (DTH) /  | Sensitized CD4+ Th1 (IFN-g, | • PPD skin test       |
|           | Cell-Mediated         | macrophages) or CD8+ CTLs;  | • Contact dermatitis  |
|           | (24 to 72 hours)      | NO antibodies or complement | • Topical antibiotic  |
+-----------+-----------------------+-----------------------------+-----------------------+

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2. Type I (Immediate) Hypersensitivity & Podiatric Anesthetic Allergy

Immunological Mechanism

• Sensitization Phase: Initial exposure to an allergen drives CD4+ Th2 differentiation. Th2 cells secrete IL-4 and IL-13, stimulating B-cell class switching to IgE. Secreted IgE binds with extreme affinity to Fc$\epsilon$RI receptors on the surface of tissue mast cells and circulating basophils, priming the cells.
• Effector Phase (Re-exposure): Multivalent allergen cross-links membrane-bound IgE-Fc$\epsilon$RI complexes, triggering intracellular phosphorylation cascades that drive:
  • Immediate Phase (Minutes): Explosive degranulation releasing preformed chemical mediators: Histamine (binds H1 receptors, inducing endothelial cell contraction, rapid vasodilation, and bronchial smooth muscle spasm), Tryptase (serum marker of mast cell activation), and Heparin.
  • Late Phase (2 to 8 Hours): De novo synthesis and release of arachidonic acid metabolites via 5-lipoxygenase: Leukotrienes $\text{LTC}_4$, $\text{LTD}_4$, and $\text{LTE}_4$ (collectively termed slow-reacting substance of anaphylaxis; 1,000 times more potent than histamine in causing prolonged bronchoconstriction and vascular permeability) and Prostaglandin $\text{PGD}_2$, alongside cytokines (TNF-$\alpha$, IL-5 recruiting eosinophils).

Clinical Podiatric Pharmacology: Local Anesthetic Adverse Reactions

In podiatric clinical practice, adverse reactions following local anesthetic infiltration are common, but true IgE-mediated Type I allergic anaphylaxis accounts for less than 1% of all adverse events. The clinician must accurately differentiate true allergic reactions from non-allergic systemic toxicity:

+-----------------------------------------------------------------------------------------+
|                    LOCAL ANESTHETIC CLASSES & ALLERGENIC MECHANISMS                     |
+-----------------------+-----------------------------+-----------------------------------+
| Chemical Class        | Representative Agents       | Allergenic & Metabolic Profile    |
+-----------------------+-----------------------------+-----------------------------------+
| **Ester Class**       | • Procaine (Novocain)       | • Metabolized by plasma           |
| (Contains one 'i')    | • Chloroprocaine (Nesacaine)|   pseudocholinesterase to         |
|                       | • Tetracaine (Pontocaine)   |   **Para-Aminobenzoic Acid (PABA)**|
|                       | • Cocaine                   | • **High potential for Type I &   |
|                       |                             |   Type IV allergic reactions**    |
+-----------------------+-----------------------------+-----------------------------------+
| **Amide Class**       | • Lidoc**a**ine (Xylocaine) | • Metabolized by hepatic P450     |
| (Contains two 'i's)   | • Bupiv**a**caine (Marcaine)| • **True allergy extraordinarily  |
|                       | • Mepiv**a**caine (Carbocain|   rare (<0.1%)**                  |
|                       | • Ropiv**a**caine (Naropin) | • Reactions usually caused by     |
|                       |                             |   **Methylparaben** preservative  |
+-----------------------+-----------------------------+-----------------------------------+

• Epinephrine Reactions: Intravascular injection of epinephrine causes transient tachycardia, palpitations, diaphoresis, tremulousness, and hypertension, often misinterpreted by the patient as an "allergy."
• Vasovagal Syncope: Neurocardiogenic reaction characterized by bradycardia, hypotension, pallor, and diaphoresis, responding promptly to Trendelenburg positioning.
• Local Anesthetic Systemic Toxicity (LAST): Accidental intravascular injection of large anesthetic volumes causes biphasic CNS excitation (perioral numbness, metallic taste, tinnitus, seizures) followed by CNS depression and catastrophic cardiovascular collapse (arrhythmias, refractory asystole; particularly with bupivacaine). Reversible with 20% Intralipid emulsion therapy.

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3. Type II (Cytotoxic) Hypersensitivity

Type II hypersensitivity is mediated by IgG or IgM antibodies directed against fixed, endogenous cellular or tissue-specific antigens. Antigen-antibody binding causes pathology via three distinct mechanisms:

1. Complement-Dependent Cytotoxicity (CDC): Antibodies bind cell-surface antigens and activate the classical complement cascade. C3b deposition leads to opsonization and phagocytosis by splenic macrophages, or terminal assembly of the Membrane Attack Complex (MAC) causes direct osmotic lysis.
   • Clinical Prototypes: Autoimmune Hemolytic Anemia (AIHA) (warm IgG vs. cold IgM antibodies against RBCs; confirmed via direct Coombs test), Immune Thrombocytopenic Purpura (ITP) (anti-GpIIb/IIIa antibodies), and Acute Hemolytic Transfusion Reactions (ABO incompatibility).
2. Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC): IgG antibodies coat target cells. The Fc region of bound IgG is engaged by CD16 (Fc$\gamma$RIII) receptors on Natural Killer (NK) cells, neutrophils, and macrophages, triggering the release of perforin and granzymes that induce target cell apoptosis.
3. Antibody-Mediated Cellular Dysfunction (Receptor Targeting): Autoantibodies bind to functional cell-surface receptors without provoking cell destruction, acting as agonists or antagonists:
   • Myasthenia Gravis: Autoantibodies against nicotinic acetylcholine receptors (anti-AChR) at the motor endplate competitively block neuromuscular transmission and induce receptor internalization, causing progressive fatigable muscle weakness and ptosis.
   • Graves Disease: Autoantibodies against the TSH receptor (Thyroid-Stimulating Immunoglobulins / TSI) act as continuous agonists, stimulating autonomous thyroid follicular cell proliferation and hyperthyroidism.
   • Pemphigus Vulgaris: Autoantibodies directed against desmoglein-1 and desmoglein-3 within epithelial desmosomes cause intraepidermal acantholysis with flaccid, fragile blisters and a positive Nikolsky sign.
   • Bullous Pemphigoid: Autoantibodies directed against hemidesmosomal proteins (BP180 and BP230) at the dermoepidermal junction provoke subepidermal blister formation with tense bullae and a negative Nikolsky sign.
   • Goodpasture Syndrome: Autoantibodies against the non-collagenous domain of the $\alpha_3$ chain of Type IV collagen in basement membranes, producing linear immunofluorescence in renal glomeruli (crescentic glomerulonephritis) and pulmonary alveoli (pulmonary hemorrhage).
   • Acute Rheumatic Fever: Antibodies against group A streptococcal M protein cross-react with human cardiac myosin and sarcolemmal antigens (molecular mimicry).

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4. Type III (Immune Complex-Mediated) Hypersensitivity

Type III hypersensitivity is initiated when soluble antigen-antibody complexes (typically occurring in slight antigen excess) form in the circulation and fail to be cleared by the mononuclear phagocyte system.

Pathogenesis of Immune Complex Vasculitis

1. Circulating Deposition: Small, soluble antigen-antibody complexes circulate and deposit within high-pressure filtration microvasculature: the renal glomerular basement membrane, synovial microvessels, and dermal postcapillary venules.
2. Complement Activation: Deposited complexes activate the classical complement cascade, liberating potent anaphylatoxins C3a and C5a.
3. Neutrophilic Infiltration & Leukocytoclasia: C5a attracts massive numbers of neutrophils to the vessel wall. Neutrophils attempt to phagocytose the basement membrane-bound complexes ("frustrated phagocytosis"), releasing lysosomal elastases, proteases, and reactive oxygen species that digest the vascular wall. This produces fibrinoid necrosis, microthrombi, and nuclear fragmentation of dying neutrophils (leukocytoclastic vasculitis).

Clinical Prototypes of Type III Reactions

• Systemic Lupus Erythematosus (SLE): Deposition of DNA-anti-dsDNA complexes in renal glomeruli (lupus nephritis) producing a granular, "lumpy-bumpy" pattern on immunofluorescence.
• Post-Streptococcal Glomerulonephritis (PSGN): Nephritogenic streptococcal antigen-antibody complexes deposit in subepithelial humps 1 to 3 weeks after pharyngeal or impetiginous streptococcal infection.
• Serum Sickness: A systemic prototype occurring 7 to 14 days following administration of foreign animal serum (e.g., horse antivenom) or chimeric monoclonal antibodies. Manifests with fever, generalized urticaria, polyarthralgia, lymphadenopathy, and hypocomplementemia (low C3/C4).
• Arthus Reaction: A localized cutaneous Type III reaction occurring 4 to 12 hours after intradermal injection of an antigen into an individual with high circulating IgG levels (e.g., tetanus-diphtheria booster). Rapid immune complex formation within dermal arterioles causes acute local edema, hemorrhage, and ischemic necrosis.
• Polyarteritis Nodosa (PAN): Systemic necrotizing vasculitis of medium-sized muscular arteries; approximately 30% of cases are mediated by chronic Hepatitis B surface antigen-antibody (HBsAg-anti-HBs) complexes.

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5. Type IV (Delayed-Type / Cell-Mediated) Hypersensitivity

Type IV hypersensitivity is completely cell-mediated by sensitized T lymphocytes; it is entirely independent of antibodies and complement. Manifestations require 24 to 72 hours to evolve (hence "delayed").

Effector Pathways

1. CD4+ Th1 DTH (Delayed-Type Hypersensitivity): Sensitized CD4+ memory Th1 cells recognize peptide-MHC II on local APCs and secrete massive quantities of IFN-$\gamma$ and TNF-$\alpha$. IFN-$\gamma$ powerfully activates tissue macrophages, inducing their transformation into epithelioid histiocytes and multinucleated Langhans giant cells, driving granuloma formation.
2. CD8+ CTL Direct Cytotoxicity: Sensitized CD8+ cytotoxic T lymphocytes recognize target cells displaying haptenated or foreign peptides on MHC Class I, executing lethal target cell lysis via perforin-granzyme release and Fas-FasL apoptosis.

Clinical Prototypes in Podiatric Medicine

• Tuberculin PPD Skin Test (Mantoux Test): Intradermal injection of purified protein derivative from Mycobacterium tuberculosis. Sensitized Th1 memory cells secrete IFN-$\gamma$, attracting macrophages and inducing induration peaked at 48 to 72 hours.
• Allergic Contact Dermatitis: Low-molecular-weight lipophilic chemical haptens penetrate the stratum corneum and covalently bind to self-proteins in the skin. Epidermal Langerhans cells internalize the haptenated conjugate and migrate to regional lymph nodes to prime naive T cells. Upon subsequent topical re-exposure, primed effector T cells home to the epidermis, causing spongiosis, microvesiculation, intense pruritus, and erythema within 24 to 48 hours.
  • Common Triggers: Urushiol (poison ivy/oak), nickel (footwear eyelets, buckles), and topical antimicrobial ointments used routinely in podiatry: Neomycin and Bacitracin. Podiatric surgeons frequently misdiagnose postoperative contact dermatitis from triple antibiotic ointment as an acute surgical site wound infection!
• Other Type IV Conditions: Multiple Sclerosis, Type 1 Diabetes Mellitus (CTL-mediated destruction of pancreatic $\beta$-cells), Hashimoto thyroiditis, and acute and chronic cellular organ transplant rejection.

Table 1: Comprehensive Comparison of Gell & Coombs Hypersensitivity Types

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6. Congenital Primary Immunodeficiency Disorders

+-----------------------------------------------------------------------------------------+
|                         PRIMARY CONGENITAL IMMUNODEFICIENCIES                           |
+-----------------------+-----------------------------+-----------------------------------+
| Disorder              | Underlying Molecular Defect | Clinical & Immunological Hallmarks|
+-----------------------+-----------------------------+-----------------------------------+
| **Severe Combined**   | • X-linked: **IL2RG** defect| • **Absent T cells AND B cells**  |
| **Immunodeficiency**  |   (common gamma chain)      | • **Absent thymic shadow**        |
| **(SCID)**            | • Autosomal Recessive:      | • Opportunistic PCP, Candida thrus|
|                       |   **ADA deficiency**        | • Live vaccines contraindicated   |
+-----------------------+-----------------------------+-----------------------------------+
| **X-Linked**          | • Mutation in **BTK**       | • **Pre-B cell arrest** in marrow |
| **Agammaglobulinemia**|   (Bruton Tyrosine Kinase)  | • **Absent mature B cells** (CD19)|
| **(Bruton's / XLA)**  | • X-linked recessive        | • Undetectable IgG, IgM, IgA      |
|                       |                             | • Encapsulated bacteria after 6 mo|
+-----------------------+-----------------------------+-----------------------------------+
| **DiGeorge Syndrome** | • **22q11.2 microdeletion** | • **CATCH-22 triad**              |
| **(Thymic**           | • Failure of 3rd & 4th      | • **Thymic aplasia** (T-cell def) |
| ** Hypoplasia)**      |   pharyngeal pouches        | • **Parathyroid aplasia** (tetany)|
|                       |                             | • Conotruncal cardiac defects     |
+-----------------------+-----------------------------+-----------------------------------+

1. Severe Combined Immunodeficiency (SCID)

• Pathophysiology: Characterized by profound defects in cellular and humoral immunity with absent functional T cells and secondary B-cell dysfunction.
  • X-Linked SCID (~50% of cases): Mutation in the IL2RG gene encoding the common $\gamma$-chain subunit shared by cytokine receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. The inability to signal through the IL-7 receptor halts T-cell development in the thymus; absent IL-15 signaling prevents NK-cell maturation.
  • Autosomal Recessive SCID (~15% of cases): Deficiency of Adenosine Deaminase (ADA). Lack of ADA results in the intracellular accumulation of toxic deoxyadenosine and dATP, which inhibits ribonucleotide reductase and starves rapidly dividing lymphoblasts of dNTPs, exerting profound, selective lymphotoxicity against immature T and B lymphocytes.
• Clinical Presentation: Manifests in the first months of life with failure to thrive, chronic intractable diarrhea, recurrent severe viral infections (CMV, RSV), opportunistic fungal infections (Pneumocystis jirovecii, oral candidiasis), and disseminated bacterial sepsis. Physical examination reveals absent tonsils and lymph nodes; chest radiography demonstrates complete absence of the thymic shadow. Live vaccines (e.g., BCG, rotavirus, MMR) are strictly lethal.

2. X-Linked Agammaglobulinemia (XLA / Bruton's Disease)

• Pathophysiology: Mutation in the BTK gene on the X chromosome, which encodes Bruton Tyrosine Kinase. BTK is an essential intracellular signaling enzyme downstream of the pre-B cell receptor. Its deficiency arrests B-cell development at the pre-B cell stage within bone marrow; pre-B cells cannot mature into naive B cells or exit the marrow.
• Clinical Presentation: Symptoms begin after 6 months of age, coinciding with the physiological catabolism of protective transplacental maternal IgG. Characterized by recurrent, severe, invasive sinopulmonary and skin infections with encapsulated pyogenic bacteria (Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus), and persistent enteroviral infections (Echovirus, Coxsackievirus) due to lack of neutralizing secretory antibodies.
• Laboratory Hallmarks: Complete absence of circulating mature B cells (CD19+, CD20+); normal numbers and function of CD3+ T cells; all immunoglobulin isotypes (IgG, IgM, IgA, IgE) are virtually undetectable. Secondary lymphoid tissues lack germinal centers; tonsils are markedly hypoplastic or absent.

3. DiGeorge Syndrome (22q11.2 Deletion / Thymic Hypoplasia)

• Pathophysiology: Microdeletion on chromosome 22q11.2 caused by aberrant neural crest migration and failure of development of the third and fourth pharyngeal pouches.
• The CATCH-22 Clinical Manifestations:
  • Conotruncal cardiac malformations (Tetralogy of Fallot, truncus arteriosus, interrupted aortic arch).
  • Abnormal facies (micrognathia, low-set ears, hypertelorism, short philtrum).
  • Thymic hypoplasia / aplasia: Severe deficiency of mature T lymphocytes (CD3+ T cells); profound vulnerability to viral, fungal, and opportunistic infections; absent thymic shadow on infant chest X-ray.
  • Cleft palate.
  • Hypocalcemia secondary to parathyroid gland aplasia/hypoplasia: manifests as neonatal tetany, carpopedal spasms, and seizures secondary to undetectable PTH.

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7. Autoimmune Connective Tissue Diseases in Podiatric Practice

1. Rheumatoid Arthritis (RA)

• Pathogenesis: Chronic systemic autoimmune disease characterized by symmetric, erosive synovitis of peripheral diarthrodial joints. Autoreactive CD4+ Th1 and Th17 cells infiltrate the synovial membrane, stimulating synovial fibroblasts, osteoclasts, and macrophages via TNF-$\alpha$, IL-1, and IL-6. This promotes hyperplastic proliferation of the synovium into an invasive, vascularized inflammatory tissue called pannus. The pannus releases matrix metalloproteinases and cathepsins that erode articular cartilage and subchondral bone.
• Serologic Diagnostic Markers:
  • Anti-Cyclic Citrullinated Peptide (anti-CCP / ACPA): Directed against citrullinated filaggrin/vimentin peptides. High sensitivity (~75%) and exceptional specificity (>95–98%); correlates with aggressive, erosive joint destruction.
  • Rheumatoid Factor (RF): An IgM autoantibody directed against the Fc portion of human IgG. Present in ~75–80% of patients; lower specificity than anti-CCP (can be elevated in hepatitis C, SLE, Sjögren syndrome, and endocarditis).
• Lower Extremity Podiatric Manifestations:
  • Symmetrical polyarthritis predilecting the metatarsophalangeal (MTP) joints (earliest sites of foot involvement, especially 2nd through 5th MTPs) and subtalar/talonavicular joints.
  • Hallux Valgus: Erosive destruction of the medial collateral ligament and first metatarsal head allows lateral deviation of the great toe.
  • Fibular Deviation of Lesser Toes: MTP joint capsule laxity and extensor digitorum longus pull cause the lesser digits to drift laterally toward the fibular border.
  • Dorsal MTP Subluxation / Dislocation ("Cock-Up" Toes): Proximal phalanges subluxate dorsally onto metatarsal heads, displacing the protective plantar fat pad distally into the sulcus. The denuded metatarsal heads project directly plantarward into the skin, causing severe, intractable metatarsalgia ("walking on stones or marbles") and painful intractable plantar keratoses (IPKs).
  • Rheumatoid Nodules: Fibrinoid necrosis surrounded by a palisade of histiocytes, located over pressure points (Achilles tendon, plantar heel).

2. Systemic Lupus Erythematosus (SLE)

• Pathogenesis: Type III hypersensitivity disease characterized by loss of immune tolerance to nuclear self-antigens, defective clearance of apoptotic nuclear debris, and deposition of circulating immune complexes in multi-organ vascular beds.
• Diagnostic Autoantibodies:
  • Antinuclear Antibodies (ANA): Screening test with >98% sensitivity, but low specificity.
  • Anti-double-stranded DNA (anti-dsDNA): High specificity (>95%); serum titers correlate directly with disease flares and the severity of lupus nephritis.
  • Anti-Smith (anti-Sm): Highly specific for SLE; directed against core proteins of small nuclear ribonucleoproteins (snRNPs); does not correlate with disease activity.
  • Antiphospholipid Antibodies: (Lupus anticoagulant, anticardiolipin, anti-$\beta_2$-glycoprotein I). Induce a hypercoagulable state with recurrent deep vein thrombosis (DVT) in the lower extremities, arterial occlusion, and recurrent pregnancy loss.
• Lower Extremity Manifestations:
  • Jaccoud's Arthropathy: Deforming arthropathy of MTP and PIP joints characterized by ulnar/fibular deviation and reducible subluxations without bony erosion on radiographs (distinguishing it from the destructive erosions of RA).
  • Raynaud Phenomenon: Reversible digital vasospasm induced by cold or stress, producing classic triphasic color changes (white pallor, blue cyanosis, red reactive hyperemia).
  • Livedo Reticularis: Violaceous, reticulated, net-like vascular mottling of the skin of the lower legs and feet caused by microvascular stasis.

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8. HLA-B27 Seronegative Spondyloarthropathies

The seronegative spondyloarthropathies are a unified group of inflammatory joint diseases characterized by strong genetic association with HLA-B27 (MHC Class I allele), absence of Rheumatoid Factor (RF negative / seronegative), prominent axial spine involvement (sacroiliitis), asymmetric peripheral oligoarthritis, and enthesitis (inflammation at the insertions of ligaments, tendons, or joint capsules into bone):

1. Ankylosing Spondylitis

• Predominantly affects young males (HLA-B27 positive in >90% of patients).
• Starts with bilateral sacroiliitis, ascending to vertebral syndesmophyte bridging and fusion ("bamboo spine").
• Lower Extremity Hallmarks: Severe, recalcitrant Achilles enthesitis and plantar fasciitis with proliferative calcaneal traction spurs at tendinous insertions.

2. Psoriatic Arthritis (PsA)

• Develops in ~15–30% of patients with cutaneous psoriasis.
• Clinical Patterns: Involves the Distal Interphalangeal (DIP) joints of toes and fingers (rarely involved in RA), accompanied by psoriatic nail dystrophy (nail pitting, onycholysis, oil-drop stains).
• Dactylitis ("Sausage Digit"): Uniform, diffuse, painful swelling of an entire digit resulting from concurrent flexor tenosynovitis and joint synovitis.
• Radiographic Hallmark: "Pencil-in-Cup" deformity (osteolysis of the head of the proximal phalanx tapering into a pencil shape, which rests within the excavated, expanded cup of the adjacent distal phalanx base).

3. Reactive Arthritis (Reiter Syndrome)

• Triggering Infection: Develops 1 to 4 weeks following an antecedent genitourinary infection (most commonly Chlamydia trachomatis) or gastrointestinal dysentery (Campylobacter jejuni, Salmonella enterica, Shigella flexneri, Yersinia enterocolitica).
• The Classic Clinical Triad:

  "Can't see, can't pee, can't climb a tree"

  1. Nongonococcal Urethritis / Cervicitis ("Can't pee")
  2. Conjunctivitis / Anterior Uveitis ("Can't see")
  3. Asymmetric Oligoarthritis & Enthesitis ("Can't climb a tree") — Predilects the knees, ankles, and MTP joints, with prominent Achilles tendinitis and retrocalcaneal bursitis.
• Dermatologic Podiatric Hallmarks:
  • Keratoderma Blennorrhagica: Pathognomonic hyperkeratotic, crusty, brownish-red pustular plaques and papules on the soles of the feet and palms, clinically and histologically indistinguishable from pustular psoriasis.
  • Circinate Balanitis: Painless, shallow serpiginous erosions on the glans penis.
  • Diffuse subungual hyperkeratosis and yellowish nail plate thickening.

Table 2: Rheumatoid Arthritis vs. HLA-B27 Seronegative Spondyloarthropathies