12-phase flow (12)

1. 1FRAME
   Frame as the prototypic INTRAEPIDERMAL IgG-anti-desmoglein acantholytic autoimmune blistering disease — pemphigus VULGARIS (mucosal-dominant, anti-Dsg3 ± Dsg1, flaccid, Nikolsky+, suprabasal split, historically fatal untreated) vs pemphigus FOLIACEUS (superficial, anti-Dsg1, no mucosa) — managed on a RITUXIMAB-FIRST evidence-based ladder. PARANEOPLASTIC pemphigus (severe stomatitis + polymorphous + occult neoplasm) is the not-to-miss recognised here; drug-induced (thiol/ACEi) is reconciled here; secondary infection/sepsis from erosions is the leading cause of death and is escalated/routed.
   advance: intraepidermal autoimmune-bullous framing set; PV-vs-PF phenotype + paraneoplastic + drug-induced + infection escape routes noted
2. 2ENTRY
   Recognise chronic painful non-healing oral (± conjunctival/genital/oesophageal) erosions — often the first and for months the only sign of PV — OR flaccid Nikolsky-positive cutaneous bullae OR superficial scaly-crusted non-mucosal erosions (PF) OR severe stomatitis + polymorphous eruption (paraneoplastic) OR a thiol/ACEi-preceded eruption; capture mucosal extent up front.
   inputs: mucosal_involvement_extent
   actions: workup.chronic_pruritus
   advance: entry trigger present; mucosal-involvement extent recorded
3. 3CONTEXT
   Build diagnosis context: flaccid/Nikolsky+ (intraepidermal pemphigus) vs tense/Nikolsky− (subepidermal pemphigoid) blister morphology; the PV (mucosal/deep, anti-Dsg3 ± Dsg1) vs PF (superficial, anti-Dsg1, no mucosa) phenotype split; and a rigorous DRUG RECONCILIATION for thiol drugs (D-penicillamine, thiopronine) and ACE inhibitors / other non-thiol triggers (drug-induced pemphigus — withdrawal can be disease-modifying).
   inputs: blister_morphology_flaccid_vs_tense, lesion_depth_phenotype_pv_vs_pf, drug_reconciliation_thiol_acei
   actions: workup.chronic_pruritus
   advance: pemphigus clinically supported; PV-vs-PF phenotype provisionally assigned; culprit drug identified/withdrawn if present
4. 4RED_FLAGS
   Extensive PV with secondary infection / sepsis (denuded eroded skin → bacteraemia — the LEADING cause of death) or large-BSA erosions with fluid/protein loss → admit + infection/sepsis pathway + aggressive systemic therapy. Severe oral/oesophageal erosions impairing intake → admission + nutrition support. Rituximab infection / HBV-reactivation event → urgent management. Severe refractory haemorrhagic stomatitis + polymorphous eruption = paraneoplastic-pemphigus flag → urgent malignancy workup.
   inputs: secondary_infection_or_sepsis_signs, oral_oesophageal_intake_impairment
   actions: panel.cbc, panel.inflammation
   advance: infection/sepsis, large-BSA fluid loss, intake impairment, rituximab-event and paraneoplastic flags screened and escalated/routed if present
5. 5INITIAL_WORKUP
   The autoimmune-bullous diagnostic set: PERILESIONAL skin biopsy for DIF (INTERCELLULAR "chicken-wire" IgG ± C3 throughout the epidermis — GOLD STANDARD, the decisive pivot vs the LINEAR-BMZ pattern of bullous pemphigoid) + a separate LESIONAL H&E (suprabasal acantholytic "tombstone-row" cleft in PV; subcorneal/granular split in PF); serum anti-Dsg3 (mucosal/PV) + anti-Dsg1 (cutaneous/PF) ELISA (confirms dx + phenotype + activity baseline); CBC/LFT and pre-rituximab latent-TB + HBV/HCV screen. Biopsy two sites — DIF perilesional, H&E lesional.
   inputs: perilesional_skin_dif, anti_dsg1_dsg3_elisa, lesional_h_e_acantholysis, infection_screen_tb_hbv_hcv, cbc_with_differential
   actions: panel.cbc, panel.lft, panel.renal
   advance: perilesional DIF + lesional H&E sent; anti-Dsg1/Dsg3 ELISA drawn; pre-rituximab safety screen if escalation likely
6. 6BRANCHING_WORKUP
   Autoimmune-bullous decision tree on DIF + serology: INTERCELLULAR IgG/C3 DIF + anti-Dsg1/3 → pemphigus (suprabasal/anti-Dsg3 = PV; subcorneal/anti-Dsg1 = PF); LINEAR-BMZ DIF + anti-BP180 → bullous pemphigoid (route derm.bullous-pemphigoid.core.v1). If severe refractory stomatitis + polymorphous lichenoid/EM-like eruption ± anti-PLAKIN antibodies / positive RAT-BLADDER IIF → PARANEOPLASTIC pemphigus → CT chest/abdomen/pelvis + lymphoproliferative workup + oncology (Castleman/NHL/CLL/thymoma). DIF-negative full-thickness necrosis + drug latency → SJS/TEN (route derm.sjs-ten.core.v1); erosive oral-only with Wickham striae/lichenoid DIF → erosive oral lichen planus (route derm.lichen-planus.core.v1).
   inputs: paraneoplastic_features_stomatitis_polymorphous, indirect_if_monkey_oesophagus_rat_bladder, lymphoproliferative_or_neoplasm_history
   actions: workup.chronic_pruritus
   advance: DIF pattern + serology assign PV/PF OR an alternative bullous/erosive diagnosis is assigned + routed; paraneoplastic neoplasm workup launched if atypical/refractory
7. 7DIFFERENTIAL
   Terminal autoimmune/blistering/erosive differential with named pivots: pemphigus vulgaris/foliaceus vs bullous pemphigoid (tense, non-mucosal, elderly, Nikolsky−, LINEAR-BMZ DIF, anti-BP180 pivot — route derm.bullous-pemphigoid.core.v1) vs mucous-membrane pemphigoid (scarring predominantly-mucosal, linear-BMZ pivot) vs paraneoplastic pemphigus (severe stomatitis + polymorphous + occult neoplasm + anti-plakin/rat-bladder pivot — route to onc.lymphoproliferative-malignancy.core.v1) vs SJS/TEN (acute drug latency, dusky targetoid, full-thickness, DIF-negative pivot — route derm.sjs-ten.core.v1) vs erosive oral lichen planus / aphthous / herpetic / Behçet (erosive-oral pivots — route derm.lichen-planus.core.v1) vs Hailey-Hailey / Darier (familial acantholytic, DIF-negative pivot) vs IgA pemphigus (intercellular IgA, pustular pivot) vs bullous impetigo / SSSS (subcorneal toxin, paediatric pivot). Drug-induced status is a within-pemphigus modifier, not an alternative.
   advance: single best diagnosis + PV/PF phenotype selected; drug-induced and paraneoplastic status flagged; mimics routed
8. 8RISK_STRATIFICATION
   Severity = BSA + number/extent of mucosal sites + erosion burden + infection + intake/nutrition (Harman moderate vs severe strata used in Ritux 3; PDAI/ABSIS used clinically — schema-blocked, captured narratively; anti-Dsg ELISA is the wired surrogate per Hébert/Joly J Invest Dermatol 2018). Localised/mild → high-potency topical/intralesional + topical oral care; moderate–severe → rituximab-led induction + tapering systemic corticosteroid; refractory → IVIG/immunoadsorption/plasmapheresis/cyclophosphamide/repeat rituximab; paraneoplastic → treat the neoplasm + oncology.
   inputs: body_surface_area_and_severity, mucosal_involvement_extent
   advance: mild/moderate/severe/refractory tier + paraneoplastic status + escalation decision assigned
9. 9TREATMENT
   RITUXIMAB-FIRST evidence-based ladder. WITHDRAW any culprit drug (thiol/ACEi) first. Moderate–severe PV/PF: FIRST-LINE rituximab + a SHORT tapering oral prednisone course (Ritux 3, Joly Lancet 2017 — complete remission off-therapy at 24 mo 89% vs 34% with prednisone alone, p<0.0001, fewer grade 3–4 steroid adverse events; rituximab FDA/EMA-approved for moderate-to-severe PV) — screen HBV/latent-TB + vaccinate before. Steroid-sparing adjuvant or rituximab-ineligible: azathioprine (TPMT-guided) or mycophenolate mofetil (Beissert Arch Dermatol 2006 — equivalent steroid-sparing efficacy). Refractory: IVIG (Amagai JAAD 2009 RCT) / immunoadsorption / plasmapheresis (non_pharm) / cyclophosphamide / repeat-rituximab cycles. Localised/mild: high-potency topical/intralesional corticosteroid + topical oral care (dexamethasone or clobetasol rinse), though most PV needs systemic therapy. Paraneoplastic: treat the underlying neoplasm + oncology. Frailty/pregnancy/TPMT/renal-hepatic + emerging anti-FcRn/BTK note gate agent choice.
   inputs: drug_reconciliation_thiol_acei, tpmt_activity, pregnancy_status, creatinine
   advance: culprit withdrawn if present; severity-appropriate ladder step started (rituximab-first for moderate–severe); HBV/TB screened pre-rituximab; agent gated on TPMT/pregnancy/renal-hepatic
10. 10DISPOSITION
    Mostly outpatient/derm-clinic with rituximab-led induction + monitoring. Admission for: extensive PV with secondary infection/sepsis or large-BSA erosions with fluid/protein loss, severe oral/oesophageal involvement impairing intake (nutrition support), failure to thrive, or a rituximab infection/HBV-reactivation event. Paraneoplastic pemphigus → admit/coordinate oncology for the malignancy workup and treatment. Systemic-therapy initiation/monitoring via dermatology; route SJS/TEN, bullous pemphigoid, erosive OLP and the paraneoplastic neoplasm OUT by engine.
    inputs: secondary_infection_or_sepsis_signs, oral_oesophageal_intake_impairment
    advance: disposition documented; admission only for infection/sepsis, large-BSA fluid loss, intake impairment, failure to thrive or rituximab event; derm follow-up arranged
11. 11MONITORING
    Disease: PDAI/ABSIS activity + new-erosion count + anti-Dsg1/Dsg3 ELISA at follow-up — the ELISA evolution tracks skin disease activity and a rising titre predicts/precedes relapse (Hébert/Joly J Invest Dermatol 2018; informs taper). Drug safety: rituximab → B-cell/immunoglobulin levels, infusion reactions, infection + HBV reactivation vigilance (rare PML); systemic corticosteroid → glucose/BP/bone/GI/infection during induction & taper; azathioprine/MMF/cyclophosphamide → CBC + LFT (TPMT-guided azathioprine); cyclophosphamide → urinalysis (haemorrhagic cystitis). Infection surveillance throughout (leading cause of death). Taper corticosteroid and immunosuppressant guided by remission + anti-Dsg trend.
    inputs: anti_dsg1_dsg3_elisa, glucose_hba1c
    actions: panel.cbc, panel.lft
    advance: activity reassessed (erosions/anti-Dsg titre); drug-class safety labs on schedule; infection + HBV-reactivation surveillance ongoing
12. 12FOLLOWUP
    Chronic relapsing-remitting maintenance: taper corticosteroid/immunosuppressant to the lowest effective dose guided by clinical remission + anti-Dsg ELISA trend, relapse-recognition education (new oral/skin erosions), planned/relapse-triggered repeat-rituximab strategy, periodic immunosuppressant + immunoglobulin + HBV surveillance, infection precautions, oral/dental and nutrition care, and — for drug-induced pemphigus — a permanent culprit-avoidance flag. For confirmed/treated paraneoplastic pemphigus, oncology-led neoplasm surveillance + pulmonary (bronchiolitis obliterans) monitoring. Dermatology continuity for any systemic agent; reassess the diagnosis (repeat biopsy/serology, rat-bladder IIF) if the course is atypical or treatment-refractory.
    inputs: anti_dsg1_dsg3_elisa, drug_reconciliation_thiol_acei
    actions: workup.chronic_pruritus
    advance: taper plan + relapse education + repeat-rituximab strategy + anti-Dsg surveillance + culprit-avoidance flag + paraneoplastic/pulmonary surveillance (if applicable) documented