1. Rheumatoid Arthritis

Rheumatoid arthritis (RA) is the most common inflammatory arthritis, affecting ~1% of the global population. It is a chronic, symmetric, erosive polyarthritis driven by autoimmune synovial inflammation, with significant systemic and extra-articular manifestations. Early, treat-to-target management has transformed outcomes.

1.1 Epidemiology & Pathogenesis

Epidemiology: Prevalence 0.5–1%; Female:Male = 3:1; Peak onset 40–60 years. Higher prevalence in Native Americans (Pima/Chippewa ~5%). Increased mortality due to cardiovascular disease.

Pathogenesis: Gene–environment interaction: HLA-DRB1 shared epitope (most important genetic risk; OR ~5×); PTPN22, CTLA4. Environmental: smoking (strongest modifiable risk; promotes citrullination via PAD enzymes), periodontitis (P. gingivalis), microbiome dysbiosis.

Citrullinated proteins → anti-CCP (ACPA) → immune complex formation → synovial inflammation → pannus formation → joint destruction.

⚡ Pathogenesis High-Yield

Shared epitope (HLA-DRB1*04:01, *04:04, *01:01) — binds citrullinated peptides, activates CD4+ T cells
TNF-α, IL-1, IL-6, IL-17 → synovial hyperplasia, osteoclast activation → bone erosion
RF = IgM anti-IgG (sensitivity 70–80%, specificity 80%)
Anti-CCP (ACPA) = sensitivity 60–70%, specificity >95% — best specificity marker
ACPA appears up to 10 years before clinical RA (pre-clinical phase)

1.2 Clinical Presentation & Extra-articular Features

Articular: Symmetric polyarthritis — MCP, PIP (sparing DIP), wrists, MTPs. Morning stiffness >1 hour. Boggy synovitis, tenderness, warmth. Fusiform swelling of PIPs.

Joint deformities (late disease):

Swan-neck: PIP hyperextension, DIP flexion
Boutonnière: PIP flexion, DIP hyperextension
Z-deformity thumb: MCP flexion, IP hyperextension
Ulnar deviation at MCPs
Piano-key sign: distal ulna instability

⚡ Extra-articular Manifestations

Rheumatoid nodules — subcutaneous, extensor surfaces; associated with seropositive, active disease; can form in lungs (Caplan syndrome = nodules + pneumoconiosis)
Pulmonary: ILD (UIP pattern most common), pleuritis, bronchiectasis, obliterative bronchiolitis (MTX lung)
Cardiac: Pericarditis, accelerated atherosclerosis, IHD (leading cause of mortality)
Ocular: Keratoconjunctivitis sicca (secondary Sjögren's), episcleritis, scleritis, peripheral ulcerative keratitis (sight-threatening)
Felty syndrome: RA + splenomegaly + neutropenia (HLA-DR4 associated)
Vasculitis: Rare; digital infarcts, mononeuritis multiplex, cutaneous ulcers
Atlantoaxial subluxation (C1-C2): Risk with general anesthesia — screen with flexion/extension X-ray

🔶 Clinical Pearl: RA patients have 2× increased cardiovascular mortality. CVD risk = similar to diabetes mellitus. Screen and manage CV risk factors aggressively. Hydroxychloroquine and methotrexate have cardioprotective effects.

1.3 ACR/EULAR 2010 Classification Criteria

Score-based criteria (apply to patients with ≥1 swollen joint not better explained by another diagnosis). Score ≥6/10 = definite RA.

Domain	Findings	Score
Joint involvement	1 large joint	0
	2–10 large joints	1
	1–3 small joints (with/without large)	2
	4–10 small joints	3
Joint involvement (cont.)	>10 joints (at least 1 small)	5
Serology	Negative RF and ACPA	0
	Low-positive RF or ACPA (<3× ULN)	2
	High-positive RF or ACPA (≥3× ULN)	3
Acute-phase reactants	Normal CRP and ESR	0
Acute-phase reactants	Abnormal CRP or ESR	1
Duration of symptoms	<6 weeks	0
Duration of symptoms	≥6 weeks	1

🔶 Clinical Pearl: The 2010 criteria are classification criteria for research, not diagnostic criteria. Seronegative RA (RF−/ACPA−) can still score ≥6 via joint involvement + APR + symptom duration. Always rule out: septic arthritis, gout, CPPD, OA, psoriatic arthritis, viral arthritis (parvovirus B19, HBV, HCV), SLE.

1.4 Laboratory & Imaging Workup

Serology: RF (IgM anti-IgG) — Sen 70–80%, Spec 80%; Anti-CCP (ACPA) — Sen 60–70%, Spec >95%. Both positive = "double-seropositive" → worse prognosis, more erosive disease.

Acute phase reactants: ESR, CRP (better correlate with disease activity); CBC — normocytic anemia, thrombocytosis in active disease; LFT, renal function (baseline before DMARDs).

Imaging:

X-ray: Fusiform soft tissue swelling → juxta-articular osteopenia → marginal erosions (earliest at radial aspect 2nd/3rd MCP, ulnar styloid) → joint space narrowing
Ultrasound: Detects synovitis (gray-scale) and vascularity (power Doppler) before X-ray changes; guides aspiration
MRI: Most sensitive for bone marrow edema (earliest erosion predictor), tenosynovitis, soft tissue

⚡ Early RA X-ray Sequence (Dr. Paijit)

Fusiform soft tissue swelling → juxta-articular osteopenia → ill-defined marginal erosions (2nd/3rd MCP radial side) → joint space narrowing → severe: subluxation, deformity
Basal joint RA: radio-carpal and intercarpal involvement
DIP joint sparing distinguishes RA from OA and PsA

1.5 Disease Activity Assessment

Index	Components	Remission	Low Activity	High Activity
DAS28-CRP	28 joint counts (tender + swollen) + CRP + VAS global	<2.6	≤3.2	>5.1
SDAI	TJC28 + SJC28 + PGA + EGA + CRP	≤3.3	≤11	>26
CDAI	TJC28 + SJC28 + PGA + EGA (no lab)	≤2.8	≤10	>22
Boolean remission	TJC ≤1 + SJC ≤1 + CRP ≤1 mg/dL + PGA ≤1	All ≤1	—	—

🔶 Clinical Pearl: ACR/EULAR 2019 recommends Boolean or SDAI/CDAI remission as treatment target. DAS28 <2.6 overestimates remission (does not include all relevant joints). For clinical trials, Boolean or SDAI remission is preferred.

1.6 RA Pharmacotherapy — csDMARDs

⚡ ACR 2022 RA Guidelines — Key Recommendations

Methotrexate (MTX) is the anchor drug / first-line csDMARD for all RA patients (unless contraindicated)
Target dose: MTX 15–25 mg/week (oral or SC); SC preferred at higher doses (better bioavailability)
Always co-prescribe folic acid 1 mg/day (or folinic acid) to reduce toxicity
Monitor: CBC, LFT, renal function every 4–8 weeks initially, then every 12 weeks
Contraindications: hepatic disease, renal impairment (CrCl <30), pregnancy, significant lung disease

Drug	Dose	Key Monitoring	Key Toxicities
Methotrexate	7.5–25 mg/week PO/SC	CBC, LFT, Cr q4–8wk	Hepatotoxicity, myelosuppression, ILD (rare), teratogenicity, oral ulcers
Hydroxychloroquine	5 mg/kg/day (≤400 mg/day)	Ophthalmology q1y after 5y	Retinal toxicity (irreversible), GI, rash, QTc prolongation
Sulfasalazine	500 mg → 1,000 mg BID	CBC, LFT q3–6mo	GI, headache, oligospermia, sulfa allergy, agranulocytosis (rare)
Leflunomide	10–20 mg/day	CBC, LFT q4–8wk	Hepatotoxicity, teratogenicity (long half-life — cholestyramine washout), HTN, diarrhea

🔶 HCQ Retinal Toxicity: Deposits in retinal pigment epithelium. Risk factors: dose >5 mg/kg/day, duration >5 years, renal disease, tamoxifen co-use. Screen: annual OCT + visual field after 5 years (Marmor 2016 AAO Guidelines).

1.7 Treat-to-Target (T2T) Strategy

Based on TICORA, BeSt, CAMERA trials. ACR/EULAR 2010 T2T recommendations: target remission or low disease activity; adjust therapy every 1–3 months until target achieved.

⚡ ACR 2022 Treatment Algorithm (Abbreviated)

Step 1: csDMARD monotherapy — MTX preferred; if contraindicated: HCQ, SSZ, or LEF
Step 2 (if Step 1 fails after 3–6 months): Add bDMARD or JAKi OR switch to another csDMARD
bDMARD choices: TNFi (first-line for most), IL-6Ri, CTLA4-Ig (abatacept), anti-CD20 (rituximab — preferred if hx lymphoma, COPD)
JAKi (tsDMARD): Tofacitinib, baricitinib, upadacitinib — FDA/EMA note: prefer bDMARDs first due to safety signals (VTE, CV, malignancy) in ORAL Surveillance
Combination csDMARDs: MTX + HCQ + SSZ (triple therapy) — comparable to MTX + TNFi in TEAR and RACAT

1.8 Biological & Targeted Synthetic DMARDs

Class	Agent	Mechanism	Key Considerations
TNF inhibitors	Etanercept	TNF receptor fusion protein	SC 50 mg/week; no lupus flare risk; preferred in MS
	Adalimumab	Anti-TNF mAb	SC q2wk; available biosimilar
	Infliximab	Anti-TNF chimeric mAb	IV infusion; must use with MTX (anti-drug antibodies)
	Certolizumab pegol	PEGylated Fab fragment	Does not cross placenta — safe in pregnancy
IL-6R inhibitor	Tocilizumab	IL-6 receptor blockade	Can use as monotherapy (no MTX needed); suppresses CRP; watch bowel perforation risk; lipid rise
IL-6 inhibitor	Sarilumab	IL-6 receptor blockade	SC q2wk; similar efficacy to tocilizumab
CTLA4-Ig	Abatacept	T-cell costimulation blockade	Preferred in ILD-RA, seropositive; IV or SC; avoid live vaccines
Anti-CD20	Rituximab	B-cell depletion	IV 1g × 2 (2 weeks apart); preferred in lymphoma hx, hep B carrier; pre-treat check HBsAg/anti-HBc
JAK inhibitors	Tofacitinib	JAK1/3 inhibitor	Oral 5 mg BID or 11 mg XR QD; VTE risk (higher dose); lipid monitoring
	Baricitinib	JAK1/2 inhibitor	Oral 2–4 mg QD; approved RA + COVID-19
	Upadacitinib	JAK1 selective inhibitor	Oral 15 mg QD; highest efficacy among JAKi

🔶 Pre-biologic Screening Checklist: TB screening (TST or IGRA) — treat latent TB before starting; Hepatitis B (HBsAg, anti-HBc, anti-HBs); Hepatitis C; Varicella IgG; Live vaccines (MMR, Varicella, Yellow fever) — complete ≥4 weeks before biologics; CBC, LFT, Cr.

📚 Key References — RA

ACR 2022 RA Guideline — Fraenkel L et al., Arthritis Care Res 2021
EULAR 2022 RA Recommendations — Smolen JS et al., Ann Rheum Dis 2023
ORAL Surveillance — Ytterberg SR et al., NEJM 2022 (JAKi safety)
RACAT — O'Dell JR et al., NEJM 2013 (triple therapy = TNFi+MTX)
BeSt — Goekoop-Ruiterman YP et al., Arthritis Rheum 2005 (T2T)

1.9 Practice Questions

Q1. A 42-year-old woman presents with 3 months of morning stiffness >1 hour, symmetric swelling of bilateral MCPs and PIPs, with positive RF (1:320) and anti-CCP (450 U/mL). CRP is elevated. X-rays show soft tissue swelling and juxta-articular osteopenia. ACR/EULAR 2010 score?

Score = 9/10 → Definite RA

Joint involvement: >10 small joints = 5; Serology: high-positive RF AND anti-CCP (≥3×ULN) = 3; APR: elevated CRP = 1; Duration ≥6 weeks = 1 → but wait, ≥10 joints already scores 5. Re-check: MCPs + PIPs bilateral = small joints >10 → 5 pts. Serology: both RF and anti-CCP high positive = 3 pts. APR: elevated CRP = 1 pt. Duration ≥6 weeks = not stated but implied → assume 1 pt. Total ≥9. Start MTX + folic acid immediately.

Q2. Which bDMARD is preferred in a RA patient with co-existing COPD and previous lymphoma?

Rituximab

Rituximab is preferred in patients with history of lymphoma (lower risk of new malignancy vs TNFi) and in COPD (abatacept also acceptable). TNFi should be avoided in lymphoma history. Certolizumab pegol and etanercept are preferred TNFi in demyelinating disease. Abatacept is preferred in ILD-RA.

2. Systemic Lupus Erythematosus (SLE)

SLE is a chronic, multisystem autoimmune disease characterised by loss of tolerance to nuclear antigens, leading to immune-complex deposition and tissue injury. It predominantly affects women of reproductive age (F:M = 9:1), with higher prevalence and severity in Asian, African-American, and Hispanic populations. The therapeutic landscape has been transformed by EULAR 2023 recommendations, approval of anifrolumab and voclosporin, and breakthrough data from CAR-T cell therapy.

📚 Key 2023–2025 References: EULAR 2023 SLE Recommendations (ARD 2024); TULIP-1 & TULIP-2 (NEJM 2020); AURORA-1 (Lancet 2021); BLISS-LN (NEJM 2020); NOBILITY/REGENCY (NEJM 2025); DORIS 2021; CAR-T NatMed 2022; NEJM case series 2024.

2.1 Epidemiology & Pathogenesis

Global prevalence: 20–150/100,000. Incidence peak: ages 15–45. Higher severity in Asian, African-American, and Hispanic populations. Mortality improved; leading causes of death: infection (early), cardiovascular disease (late), renal failure.

⚡ Pathogenesis — The IFN-α Central Axis

Defective apoptotic clearance → nuclear material (dsDNA, histones, Ro, La) exposed → ANA formation via molecular mimicry and bystander activation
Type I interferon (IFN-α/β) pathway — "interferon signature" present in 75–80% of SLE; driven by plasmacytoid DCs stimulated by nucleic-acid immune complexes via TLR7/TLR9; anifrolumab targets IFNAR1 to block this pathway
Neutrophil extracellular traps (NETs) → release nuclear content → activate pDCs → amplify IFN-α loop; NET components are autoantigens
B-cell overactivity → BLyS/BAFF drives survival and differentiation of autoreactive B-cells; belimumab blocks BLyS/BAFF; obinutuzumab and rituximab deplete CD20+ B-cells
Complement deficiency (C1q, C4A null allele, C2) → defective clearance of apoptotic debris; C3/C4 consumed in active disease
T-cell dysregulation — Th17 excess, Treg deficiency; mTOR pathway hyperactivation; calcineurin inhibitors (tacrolimus, voclosporin) target downstream effectors

Genetic Risk	Function/Association
HLA-DR2, HLA-DR3	Antigen presentation; strongest HLA associations
C4 null allele (esp. C4A)	Defective complement-mediated clearance; very high risk
IRF5, IRF7, STAT4	IFN-α pathway activation
BLK, PTPN22	B-cell signaling dysregulation
TREX1 (DNase III)	Defective DNA degradation → nucleic acid accumulation
FCGR2A/3B	Defective Fc-receptor–mediated IC clearance

🔶 Drug-Induced Lupus (DIL): Causative drugs: hydralazine, procainamide, isoniazid, methyldopa, minocycline, TNF-inhibitors (TNFi-DIL: anti-dsDNA+ but anti-histone−). Features: pleuritis, pericarditis, arthralgia, fever; renal/CNS involvement rare; resolves with drug withdrawal. Anti-histone Ab >95% in classic DIL.

2.2 EULAR/ACR 2019 Classification Criteria

Entry criterion: ANA ≥1:80 (HEp-2 cells) — required. Then additive weighted domains; total score ≥10 = SLE. Sensitivity 96.1%, Specificity 93.4%.

Domain	Criterion	Weight
Constitutional	Fever (>38.3°C, unexplained)	2
Hematologic	Leukopenia (<4,000/mm³)	3
	Thrombocytopenia (<100,000/mm³)	4
	Autoimmune hemolysis (Coombs+)	4
Neuropsychiatric	Delirium	2
	Psychosis	3
	Seizure	5
Mucocutaneous	Non-scarring alopecia	2
	Oral ulcers	2
	Subacute cutaneous or discoid lupus	4
	Acute cutaneous lupus (malar/photosensitive rash)	6
Serosal	Pleural or pericardial effusion	5
Musculoskeletal	Joint involvement (synovitis ≥2 joints or tenderness + morning stiffness ≥30 min)	6
Renal	Proteinuria >0.5 g/24h	4
	Class II or V LN (biopsy-proven)	8
	Class III or IV LN (biopsy-proven)	10
Antiphospholipid Ab	Anti-cardiolipin IgG/IgM or anti-β2GP1 IgG/IgM	2
Antiphospholipid Ab	Lupus anticoagulant positive	3
Complement proteins	Low C3 OR low C4	3
Complement proteins	Low C3 AND low C4	4
SLE-specific Abs	Anti-dsDNA OR anti-Sm (above assay reference range)	6

🔶 SLICC 2012 vs EULAR/ACR 2019: SLICC: 11 clinical + 6 immunologic criteria; ≥4 criteria OR biopsy LN + ANA/anti-dsDNA. Higher sensitivity (97%), better for early/incomplete SLE. EULAR/ACR 2019: higher specificity (93%), preferred for clinical trials and research. In daily practice, both are used. Only count criteria if not better explained by another diagnosis (no "domain exclusion").

2.3 Clinical Manifestations (System Overview)

System	Features	Clinical Pearls
Mucocutaneous (80%)	Malar rash (spares nasolabial folds), photosensitivity, discoid lupus (DLE — scarring), SCLE (anti-Ro/SSA+), bullous lupus, alopecia, oral ulcers (painless)	DLE → permanent scarring/pigmentation; SCLE → no scarring; malar rash differentiator: photodistributed, spares nasolabial folds (vs rosacea)
Musculoskeletal (90%)	Non-erosive arthritis/arthralgia (symmetric, small joints); Jaccoud arthropathy (reducible subluxation, no erosion); avascular necrosis (steroid-related, disease-related — anti-aPL)	Jaccoud = deformity on exam, NO erosions on X-ray. Avascular necrosis most common at femoral head; risk factors: high cumulative CS, APS
Renal (30–60%)	Lupus nephritis (LN) — proteinuria, hematuria, RBC casts, HTN, AKI; asymptomatic until severe	Most important prognostic factor. Biopsy essential for management. Class IV = worst prognosis without treatment
Hematologic (50–85%)	Lymphopenia (most common, >50%), AIHA (Coombs+), ITP, leukopenia, thrombocytopenia; Evans syndrome = AIHA + ITP	Lymphopenia not in EULAR/ACR 2019 weighted criteria but is diagnostic clue. Anti-β2GP1 + thrombocytopenia → APS overlap
Neuropsychiatric (40–70%)	Headache (most common), psychosis, seizure, cerebrovascular disease (anti-aPL → stroke), cognitive dysfunction, mononeuritis multiplex, transverse myelitis (rare)	ACR 1999: 19 NPSLE syndromes. Stroke in young woman → always consider APS. Anti-P ribosomal Ab → NPSLE/psychosis
Cardiovascular	Pericarditis (most common cardiac manifestation), Libman-Sacks endocarditis (sterile verrucous vegetations — mitral/aortic), myocarditis, accelerated atherosclerosis (10× risk vs general population)	Libman-Sacks on mitral valve → regurgitation, embolic source (especially if APS). CAD risk: long-term inflammation + steroids + dyslipidemia
Pulmonary	Pleuritis/effusion, shrinking lung syndrome (diaphragm dysfunction), DAH (emergency), ILD (uncommon), PAH (anti-RNP+)	Shrinking lung = elevated hemidiaphragms on CXR, FVC reduced; responds to immunosuppression. DAH = life-threatening — pulse CS + CYC ± plasmapheresis
GI	Lupus enteritis (mesenteric vasculitis), serositis (ascites, peritonitis), esophageal dysmotility, pancreatitis, hepatitis (lupoid)	Lupus enteritis: abdominal pain, diarrhea; CT abdomen → "target sign" (bowel wall thickening + enhancement), dilated loops; responds to CS
Ophthalmic	Retinal vasculitis, episcleritis, secondary Sjögren's sicca, HCQ retinopathy	HCQ retinopathy: screen with funduscopy + visual field at baseline, then annually after 5 years (or sooner if >5 mg/kg/day)

⚡ High-Yield NPSLE Points

Stroke in SLE → always exclude APS (lupus anticoagulant, anti-cardiolipin, anti-β2GP1)
Seizures in SLE: may be APS-related (thrombosis) or inflammatory; treat accordingly
Transverse myelitis in SLE → APS-related or inflammatory; often anti-aquaporin-4 negative
Cognitive dysfunction ("lupus fog") — most common NPSLE; may persist in remission

2.4 Lupus Nephritis — ISN/RPS 2018 Classification & Treatment

LN occurs in 30–60% of SLE patients. Biopsy is essential for classification and treatment decisions. ISN/RPS 2018 revision introduced NIH Activity Index (AI 0–24) and Chronicity Index (CI 0–12) to replace the A/C subclassification.

Class	Pathology	Clinical Presentation	Treatment Strategy
I	Minimal mesangial LN (normal LM)	Normal UA; incidental finding	Treat underlying SLE only; HCQ always
II	Mesangial proliferative LN	Mild proteinuria (<1g/day), microscopic hematuria	Low-dose CS + HCQ; if heavy proteinuria add MMF 1–2 g/day
III	Focal proliferative LN (<50% glomeruli; endocapillary+/− extracapillary proliferation)	Proteinuria, hematuria, HTN; variable AKI	Induction + Maintenance (see below)
IV	Diffuse proliferative LN (≥50% glomeruli) — most severe; wire-loop lesions, crescents	Nephrotic + nephritic syndrome, HTN, ↑Cr, RBC casts	Induction + Maintenance (see below)
V	Membranous LN (subepithelial immune deposits); may coexist with III/IV	Nephrotic syndrome; AKI uncommon; thrombosis risk (APS)	MMF ± CS (first-line); resistant: CNI (tacrolimus/voclosporin) or rituximab; antithrombotic if nephrotic
VI	Advanced sclerotic LN (>90% globally sclerosed glomeruli)	Chronic renal failure, low-grade proteinuria	Conservative; RAS blockade; prepare for RRT/transplant

⚡ LN Class III/IV — Induction & Maintenance (EULAR 2023 / KDIGO 2024)

Step 0 (all LN): HCQ — continue in ALL LN patients (reduces flares, improves complete renal response); RAS blockade (ACEI/ARB) for proteinuria; monitor BP, lipids
Induction (6 months) — choose anchor drug:
Option A — MMF-based (preferred by EULAR 2023): MMF 2–3 g/day + pulse methylprednisolone 250–1000 mg × 1–3 days → oral prednisone 0.5–1 mg/kg/day, taper to ≤7.5 mg/day by 3–6 months
Option B — CYC-based: Euro-Lupus low-dose CYC (500 mg IV q2wk × 6 doses; total 3 g) OR NIH high-dose CYC (0.5–1 g/m² IV monthly × 6) — preferred in severe crescentic LN or Asian populations
ALMS Trial: MMF = CYC for induction (class III, IV, V); 24-week primary endpoint; similar CR rates (~22% each)
Euro-Lupus Trial: Low-dose CYC non-inferior to high-dose CYC with less toxicity (leukopenia, infection, premature ovarian failure)
ADD-ON Biologics (EULAR 2023 Recommendation):
+ Belimumab IV 10 mg/kg monthly (after 3 loading doses) or SC 200 mg weekly: BLISS-LN — primary renal response 43% vs 32% (p=0.03); ↓ risk of renal events/death by 49%
+ Voclosporin 23.7 mg BID: AURORA-1 — complete renal response at 52 weeks 41% vs 23% (p<0.001); triple therapy = MMF + voclosporin + low-dose CS
Note: Belimumab + CYC = NOT recommended (increased infection risk in pivotal trials)

⚡ LN Maintenance Therapy

MMF 1–2 g/day — preferred maintenance (superior to AZA in MAINTAIN Nephritis Trial)
AZA 2 mg/kg/day — alternative; preferred in pregnancy
Duration: minimum 36 months (EULAR 2023); consider longer if anti-dsDNA remains elevated or C3/C4 persistently low
GC target: ≤5 mg/day prednisone in maintenance; withdraw if possible
Continue voclosporin or belimumab add-on during maintenance if used in induction

Trial	Regimen	Key Result	Year
AURORA-1	Voclosporin 23.7mg BID + MMF + low-dose CS vs MMF + CS	CRR 41% vs 23% at Wk52 (p<0.001); FDA approved Jan 2021	2021
AURORA-2	Voclosporin long-term extension (24 months total)	Sustained renal response maintained; no new safety signals	2022
BLISS-LN	Belimumab 10mg/kg IV + SOC vs SOC; 104 wks	PRR 43% vs 32% (p=0.03); ↓ renal events/death 49%	2020
NOBILITY	Obinutuzumab 1000mg × 2 + MMF + CS; Phase 2	CRR 35% vs 23% (Wk52); 41% vs 23% (Wk104)	2022
REGENCY	Obinutuzumab Phase 3 confirmatory RCT	CRR 46.4% vs 33.1% (Wk76); NEJM 2025	2025
ALMS	MMF 3g/d vs NIH-CYC; 24 wks; n=370 class III-V	MMF = CYC for induction (non-inferior); MMF superior in maintenance	2009
Euro-Lupus	Low-dose CYC 500mg q2wk×6 vs high-dose CYC	Non-inferior efficacy; less toxicity; endorsed by EULAR	2002/2010

🔶 Obinutuzumab vs Rituximab in LN: Obinutuzumab is a next-generation anti-CD20 (type II, glycoengineered) with 35× more potent B-cell depletion than rituximab via ADCC. REGENCY (Phase 3, NEJM 2025): CRR 46.4% vs 33.1% at Wk76 with prednisone tapering. Rituximab remains off-label but widely used for refractory LN; LUNAR trial (2012) was negative, but real-world data supports use. EULAR 2023 allows rituximab for LN refractory to standard treatments.

🔶 ISN/RPS 2018 Key Changes from 2003: (1) Replaced A/C subclasses with modified NIH Activity Index (AI) and Chronicity Index (CI); AI predicts response to therapy, CI predicts long-term renal function loss. (2) Crescents threshold lowered to ≥10% of glomerular circumference. (3) "Lupus podocytopathy" recognized (Class not assigned; minimal change/FSGS pattern; heavy proteinuria without immune deposits → CNI-responsive). (4) Fibrous crescents added to CI.

2.5 SLE Autoantibody Profile

Antibody	Sensitivity	Specificity	Clinical Association / Pearls
ANA	95–99%	57% (low)	Screening test; positive in many non-SLE conditions. ANA ≥1:80 = EULAR/ACR 2019 entry criterion. ≥1:160 more specific
Anti-dsDNA	60–70%	95–99%	Disease activity marker; ↑ titers + ↓ C3/C4 = serologic flare → predict LN flare; Farr radioimmunoassay most specific; ELISA for screening
Anti-Sm	25–30%	~99%	Highly specific for SLE (pathognomonic); does NOT correlate with disease activity. Part of U1-snRNP complex. Positive anti-Sm → high likelihood of SLE diagnosis
Anti-Ro/SSA	25–35%	Moderate	Neonatal lupus (skin rash, CCHB — complete congenital heart block 2–3%); SCLE; secondary Sjögren's; photosensitivity; anti-Ro+ → fetal echo surveillance 18–26 wks gestation
Anti-La/SSB	10–15%	High	Usually with anti-Ro; neonatal lupus; secondary Sjögren's; presence of anti-La without anti-Ro is unusual; lower LN risk
Anti-U1-RNP	25–35%	Moderate	MCTD (very high titer), PAH in SLE/MCTD, Raynaud's; "overlap" serologies
Anti-histone	50–70%	Low	Drug-induced lupus >95%; also in idiopathic SLE (not specific). Test when clinical context suggests DIL
Anti-C1q	30–40%	High for LN	Correlates with active LN and hypocomplementemia; useful to monitor LN activity alongside anti-dsDNA + C3/C4
Anti-P ribosomal	10–20%	~95%	NPSLE (psychosis, cognitive), lupus hepatitis; present in active disease; more common in Asian patients
Anti-β2GP1, aCL, LA	Variable	High (LA most specific)	Antiphospholipid syndrome (APS) — thrombosis, pregnancy morbidity; test all SLE patients; 30–40% SLE have aPL; 10–15% develop APS

⚡ Monitoring SLE Activity with Serology

Anti-dsDNA + C3/C4 = standard activity monitoring panel
↑ anti-dsDNA + ↓ C3 + ↓ C4 = serological flare → anticipate clinical flare in 2–4 weeks
Low C3 and C4 in parallel: Classical pathway consumption (typical of SLE LN); low C3 alone: alternative pathway activation (infections, other)
Anti-Sm and anti-Ro: stable (not activity markers); use for diagnosis and risk stratification only
Periodic aPL re-testing: if initially negative, retest during disease flares as aPL may become detectable

2.6 EULAR 2023 Treatment Principles & Treat-to-Target

📚 Source: Fanouriakis A, et al. EULAR recommendations for the management of SLE: 2023 update. Ann Rheum Dis 2024;83:15–29. (DOI: 10.1136/ard-2023-224762)

⚡ 5 Overarching Principles (EULAR 2023)

1. Treat-to-Target (T2T): Aim for DORIS remission or LLDAS (Lupus Low Disease Activity State) at every clinic visit
2. HCQ universally: Hydroxychloroquine for ALL SLE patients (unless contraindicated — retinopathy, severe renal failure); dose ≤5 mg/kg/day; reduces flares, organ damage accrual, thrombosis, mortality, and improves biologic response
3. GC minimisation: Use GC as bridging therapy; target ≤5 mg prednisone/day for maintenance; withdraw when possible; GC-related damage is a major source of long-term morbidity
4. Early ISD/biologic initiation: Prompt start of immunosuppressives (MTX, AZA, MMF) AND/OR biologics (belimumab, anifrolumab) to control disease and enable GC taper
5. Preventive care: Vaccinations (influenza, pneumococcal, COVID-19; live vaccines avoided if immunocompromised), osteoporosis prophylaxis (Ca+D, bisphosphonates if GC ≥7.5 mg/day >3 months), CV risk reduction, cancer screening

⚡ DORIS Remission & LLDAS Definitions

DORIS Remission (2021): Clinical SLEDAI-2K = 0 (excluding serology items: anti-dsDNA, complement) + Physician's Global Assessment (PGA) <0.5 + Prednisone ≤5 mg/day + stable maintenance IS/biologic dose. If only on HCQ with no IS = "remission off treatment"
LLDAS (Lupus Low Disease Activity State): SLEDAI-2K ≤4 (no major organ involvement) + PGA ≤1 + Prednisone ≤7.5 mg/day + no new disease activity. More attainable than DORIS remission; associated with reduced organ damage accrual
Clinical relevance: Both DORIS and LLDAS are now trial endpoints; achieving LLDAS for ≥50% of follow-up time strongly associated with less organ damage (Lupus Low Disease Activity State Working Group)
Serology without activity: "Serologically active, clinically quiescent" (SACQ) — elevated anti-dsDNA and/or low complement without symptoms → watchful waiting, HCQ optimization, consider belimumab to reduce risk of organ-threatening flare

Disease Manifestation	First-Line Therapy	Escalation / Second-Line
Mild-Moderate (skin, joints, serositis)	HCQ + short-course GC; MTX (skin, joints); Dapsone (bullous lupus)	+ Belimumab or anifrolumab; AZA; MMF (skin)
Active LN (III/IV/V)	MMF 2–3g/day OR Euro-Lupus CYC + pulse methylprednisolone + HCQ	+ Belimumab (BLISS-LN) or voclosporin (AURORA); obinutuzumab (REGENCY)
Neuropsychiatric SLE	If inflammatory: high-dose CS ± CYC; if APS-related: anticoagulation	Rituximab for refractory; plasma exchange for severe (DAH, TTP-like)
Hematologic (severe ITP, AIHA)	High-dose GC ± IVIg; HCQ	Rituximab; splenectomy; AZA; CYC; eltrombopag (ITP)
Refractory/Steroid-dependent	HCQ + IS + biologic (belimumab or anifrolumab)	CAR-T cell therapy (investigational but increasingly used 2024–2025)

🔶 GC Taper Strategy (EULAR 2023): Induction: prednisone 0.5–1 mg/kg/day → taper 10% every 2 weeks once disease controlled → target ≤7.5 mg/day by 3 months → ≤5 mg/day by 6 months → withdraw if possible. Cumulative GC >10g (lifetime) associated with significant organ damage (Sj's damage index); avoid prolonged >7.5 mg/day. Use IS/biologics to enable taper.

2.7 Biologic Therapies in SLE — EULAR 2023 Tier

Drug	Target	Indication	Key Trial	Notes
Belimumab (Benlysta)	BLyS/BAFF (soluble; B-cell survival)	Active SLE (non-LN) + active LN (BLISS-LN); IV or SC	BLISS-52, BLISS-76, BLISS-LN	Most effective when anti-dsDNA+, low complement; approved 2011 (SLE), 2020 (LN); SC 200mg/wk or IV 10mg/kg q4wk
Anifrolumab (Saphnelo)	IFNAR1 (type I IFN receptor)	Moderate-severe SLE (non-LN); skin, musculoskeletal disease	TULIP-1, TULIP-2	TULIP-2: BICLA response 47.8% vs 31.5%; approved 2021; IV 300mg q4wk; NOT for LN; herpes zoster ↑ risk (7%)
Voclosporin (Lupkynis)	Calcineurin inhibitor (CNI) — novel modified	Active LN class III/IV/V (add-on to MMF)	AURORA-1, AURORA-2	First oral therapy approved for LN (FDA Jan 2021); CRR 41% vs 23%; does not require dose adjustment for GFR; monitor BP, potassium, drug interactions (CYP3A4)
Rituximab (off-label)	CD20 (B-cell depletion, type I anti-CD20)	Refractory SLE, LN, severe cytopenias, NPSLE	LUNAR (negative), real-world data	LUNAR RCT negative (2012); widely used off-label; EULAR 2023 allows as second-line LN; 375mg/m² ×4 or 1g×2 doses
Obinutuzumab (Gazyva)	CD20 (type II, glycoengineered → ↑↑ B-cell killing)	Active LN (emerging; REGENCY Phase 3 positive)	NOBILITY, REGENCY	35× more potent B-cell depletion than rituximab; REGENCY: CRR 46.4% vs 33.1% (Wk76); not yet FDA approved for LN as of early 2025; likely approval pending

⚡ Anifrolumab — TULIP Trials Key Data

TULIP-1: Primary endpoint SRI-4 — NOT met; BICLA favored anifrolumab; primary endpoint failure due to GC taper rules
TULIP-2: Primary endpoint BICLA — MET; BICLA 47.8% vs 31.5% (difference 16.3%); skin disease ↓ (CLASI-50 response), GC taper success ↑, fewer flares
IFN-high subgroup benefits more (75–80% of SLE patients have IFN signature)
Safety: herpes zoster ↑ (7.2% vs 1.1%); all cutaneous/manageable; influenza ↑ (use with caution); pregnancy contraindicated; live vaccines contraindicated
Subcutaneous formulation (150mg q2wk SC) approved 2024 (Phase 3 positive) — convenience advantage
NOT effective/recommended for LN — LN patients excluded from pivotal trials; IFN-blockade may impair renal immune defense

⚡ Belimumab Practical Pearls

Best responders: anti-dsDNA positive + low complement + high SLEDAI at baseline
Latency: clinical benefit often apparent at 6 months; continue 12+ months for full assessment
SC belimumab 200mg/week = IV efficacy; home self-injection advantage
Reduce flares: 50% reduction in severe SLE flares vs placebo (BLISS-52/76 pooled)
Caution with rituximab combination — not recommended (increased infection in trials)
BLISS-LN long-term: continued renoprotection at 24 months; consider lifelong in high-risk LN

2.8 Emerging Therapies — CAR-T & Beyond (2024–2025)

📚 Landmark References: Mougiakakos D et al. CD19 CAR-T for refractory SLE. NEJM 2021;385:567–9 (case letter); Mackensen A et al. Anti-CD19 CAR-T in refractory SLE. Nature Med 2022;28:2124–32 (n=5); Müller F et al. CD19 CAR-T in autoimmune disease (n=15 incl. SLE). NEJM 2024;390:687–700; Systematic review: 47 SLE patients, LLDAS 81%. REGENCY (obinutuzumab) Phase 3 NEJM 2025.

⚡ Anti-CD19 CAR-T Cell Therapy in Refractory SLE

Rationale: SLE is driven by pathogenic autoreactive B-cells. CAR-T cells engineered to express anti-CD19 chimeric antigen receptor → deep, durable B-cell depletion → "immune reset" → drug-free remission
Mougiakakos/Mackensen group (University of Erlangen), Nature Medicine 2022: 5 patients with refractory SLE (median age 22y, median disease duration 4y, failed multiple IS); all received autologous anti-CD19 CAR-T cells; all 5 achieved drug-free remission at up to 17 months follow-up; serological normalization (anti-dsDNA↓, C3/C4 normalised)
NEJM 2024 (Müller F et al.): Expanded series including SLE, systemic sclerosis, myositis, APS-related; n=15 patients; CAR-T safe (mostly grade 1–2 CRS); all SLE patients achieved DORIS remission; one patient maintained remission off all therapy at 29 months
Systematic review 2024: 47 SLE patients across 10 studies → 81% achieved LLDAS; 80% achieved serological remission; CRS in 87% (mostly grade 1–2); ICANS in 1 patient (mild)
Allogeneic CAR-T (off-the-shelf): Cell Med 2025 — first allogeneic anti-CD19 CAR-T in refractory SLE achieving durable remission; addresses manufacturing time barrier
Current status: Investigational; compassionate use / early Phase 1–2 trials; not standard of care but may be considered for truly refractory SLE (failed ≥2 biologics); active clinical trials ongoing (ClinicalTrials.gov)

Therapy	Target	Stage	Status 2025
Anti-CD19 CAR-T	CD19 (B-cells)	Phase 1–2; compassionate use	Landmark remissions; not standard of care
Obinutuzumab	CD20 (type II)	Phase 3 (REGENCY)	NEJM 2025 positive; FDA approval pending for LN
Dapirolizumab pegol	CD40L (blocks T-B costimulation)	Phase 3 (PHOENYCS GO/FLY)	Positive phase 3 data 2024; regulatory submission
Telitacicept	BLyS + APRIL (dual inhibitor)	Phase 3 (China-approved)	Approved in China 2023; Western trials ongoing
Deucravacitinib	TYK2 inhibitor	Phase 2 (PAISLEY)	PAISLEY Phase 2 positive; Phase 3 enrolling
Ianalumab (VAY736)	BAFF-R (B-cell surface)	Phase 3	Phase 3 trials ongoing; Phase 2 positive in SLE

🔶 CAR-T in SLE — Board Exam Perspective: Know the basic concept (anti-CD19 autologous CAR-T → deep B-cell depletion → drug-free remission) and that it is used for truly refractory SLE. Not standard of care yet. Published in high-impact journals (NEJM, Nature Medicine) 2021–2024. Main concerns: CRS (cytokine release syndrome — managed with tocilizumab), ICANS (neurotoxicity — rare), infection risk during aplasia, manufacturing time (2–4 weeks for autologous). Distinguish from allogeneic (off-the-shelf) which is faster but may have graft-vs-host issues.

2.9 Pregnancy in SLE

SLE pregnancy is high-risk: 2–4× increased risk of preeclampsia, IUGR, prematurity, fetal loss, and neonatal lupus. Optimal conception: ≥6 months of quiescent disease (SLEDAI ≤4, no active LN, prednisolone ≤10 mg/day). Multidisciplinary care (rheumatology + obstetrics + neonatology).

⚡ Drug Safety in SLE Pregnancy

HCQ — ✅ CONTINUE throughout pregnancy; reduces flares during pregnancy by 2–3×; reduces CHB recurrence risk in anti-Ro+ mothers; EULAR 2017 strongly recommends continuation
Prednisone — ✅ Safe ≤20 mg/day; fluorinated steroids (dexamethasone, betamethasone) cross placenta and suppress fetal HPA axis → use only for fetal indications (lung maturity, fetal CHB hydrops)
Azathioprine — ✅ Safe (fetal liver lacks inosinate pyrophosphorylase to convert AZA to active metabolite); preferred steroid-sparing agent in pregnancy; dose ≤2 mg/kg/day
Tacrolimus — ✅ Generally safe (limited data); used for refractory LN in pregnancy; monitor fetal growth, neonatal hypoglycaemia
Low-dose aspirin (LDA) — ✅ From 12 weeks gestation for preeclampsia prevention (especially if prior LN, APS, APLA+)
LMWH — ✅ For APS in pregnancy (aspirin + LMWH throughout pregnancy); do NOT use warfarin in first trimester (teratogenic)
MMF (mycophenolate) — ❌ CONTRAINDICATED; teratogenic (microtia, cleft palate, cardiac malformations — "mycophenolate embryopathy"); stop ≥3 months before conception; switch to AZA
CYC (cyclophosphamide) — ❌ CONTRAINDICATED; teratogenic; if essential (DAH, severe NPSLE), delay until ≥14 weeks; prefer rituximab as alternative
MTX, LEF — ❌ CONTRAINDICATED; folate antagonists (MTX); LEF washout with cholestyramine before conception
Belimumab, Anifrolumab — ❌ Insufficient pregnancy safety data; discontinue before conception; not recommended

⚡ Neonatal Lupus & Congenital Heart Block (CHB)

Risk factor: Anti-Ro/SSA positive mother (anti-La/SSB additional risk)
CHB prevalence: 2–3% of anti-Ro+ pregnancies (incomplete AV block: up to 5%)
Fetal cardiac monitoring: Echocardiogram every 1–2 weeks from weeks 16–26 (highest risk period for PR prolongation → complete CHB)
PR prolongation detected: Start dexamethasone 4 mg/day (fluorinated steroid crosses placenta) — may reverse 1st/2nd degree block; complete (3rd degree) CHB irreversible → pacemaker after birth
Neonatal skin lupus: Transient; disappears by 6–8 months as maternal antibodies clear
HCQ protective: Recent meta-analyses show HCQ continuation during pregnancy reduces CHB risk in anti-Ro+ mothers by ~60%
CHB recurrence risk: 10–20% if prior affected child; consider prophylactic dexamethasone and close surveillance

Risk Factor	Maternal / Fetal Outcome Risk
Active LN at conception	↑↑ Preeclampsia, renal failure, fetal loss, preterm birth
Anti-Ro/SSA positive	CHB 2–3%, neonatal lupus rash (transient)
Antiphospholipid antibodies	Recurrent pregnancy loss, preeclampsia, thrombosis, IUGR
Hypertension pre-pregnancy	Superimposed preeclampsia risk ↑↑
High-dose GC use (>20 mg/day)	Gestational diabetes, preterm PROM, adrenal suppression (fetal)

🔶 When to Conceive — EULAR Guidance: Counsel to plan conception during ≥6 months of clinical remission (SLEDAI-2K ≤4, no active LN, off teratogenic drugs ≥3 months, prednisone ≤10 mg/day). Pregnancy itself can trigger SLE flare (flare rate ~40% during pregnancy), often responds to GC adjustment. High-risk features (prior severe LN, APS, uncontrolled HTN) → defer pregnancy until optimised.

2.10 Practice Questions

Q1. A 28-year-old woman with SLE on HCQ presents with proteinuria 3.5 g/24h, RBC casts, creatinine 1.8 mg/dL. Renal biopsy: diffuse proliferative GN (Class IV) with activity index 14/24, chronicity index 2/12. Which induction therapy combination aligns with EULAR 2023 recommendations for improved renal outcomes?

MMF 2–3 g/day + pulse methylprednisolone 500 mg × 3 days → oral prednisone + Add-on Belimumab (BLISS-LN) OR Voclosporin (AURORA)

EULAR 2023 recommends MMF-based induction (option A) with pulse GC for Class IV LN. Add-on belimumab (BLISS-LN: PRR 43% vs 32%; ↓ renal events/death 49%) or voclosporin (AURORA-1: CRR 41% vs 23%) should be considered for high-risk features (high proteinuria, high activity index). HCQ should be continued throughout. Maintenance: MMF 1–2g/day for ≥36 months with GC taper to ≤5mg/day. Key point: obinutuzumab (REGENCY 2025) is emerging as another add-on option but not yet approved for LN.

Q2. A 32-year-old woman with SLE has persistent skin disease (CLASI score 18) and joint disease despite HCQ and prednisolone. Anti-dsDNA is positive, complement low. She has no renal involvement. Which biologic has the strongest evidence and is FDA-approved for her condition?

Anifrolumab (Saphnelo) — FDA approved 2021 for moderate-severe SLE

Anifrolumab (anti-IFNAR1) is specifically approved for moderate-severe SLE with skin and musculoskeletal disease. TULIP-2: BICLA response 47.8% vs 31.5% (p<0.001); skin response (CLASI-50) significantly better. Particularly effective in IFN-high patients (~75–80% of SLE). Given 300 mg IV q4wk. NOT recommended for lupus nephritis. Belimumab is an alternative (approved for SLE + LN) but anifrolumab shows superior skin disease response. Key side effect: herpes zoster ↑ (prophylactic acyclovir recommended); avoid live vaccines.

Q3. A 25-year-old anti-Ro/SSA positive woman with SLE is 18 weeks pregnant. She is currently on HCQ and prednisolone 5 mg/day. Fetal echocardiogram shows PR interval prolongation (first-degree AV block). What is the most appropriate next step?

Start Dexamethasone 4 mg/day and intensify fetal cardiac monitoring (weekly echo)

First-degree CHB detected in anti-Ro+ pregnancy should prompt fluorinated steroid (dexamethasone) initiation, which can cross the placenta (unlike prednisone) and may reverse 1st/2nd degree block. Complete 3rd degree CHB is irreversible and requires pacemaker after birth. Continue HCQ (reduces CHB risk and flares). Weekly echocardiogram during 16–26 week window (highest risk period). Key distinction: prednisone does NOT cross the placenta (metabolised by placental 11β-HSD2); dexamethasone and betamethasone DO cross → use only for fetal indications.

Q4. According to EULAR 2023, what is the treatment target in SLE, and what are the two main definitions used?

Treat-to-Target: DORIS Remission OR LLDAS (Lupus Low Disease Activity State)

EULAR 2023 establishes treat-to-target (T2T) as a fundamental principle. DORIS Remission (2021 update): Clinical SLEDAI-2K = 0 + PGA <0.5 + prednisone ≤5 mg/day + stable IS/biologic. LLDAS: SLEDAI-2K ≤4 (no major organ activity) + PGA ≤1 + prednisone ≤7.5 mg/day + no new major activity. LLDAS is more attainable; achieving LLDAS ≥50% of follow-up time = significantly less organ damage accrual (Sj's score). Both are now used as primary endpoints in RCTs. GC ≤5 mg/day is the target for long-term maintenance in both definitions.

Q5. A 30-year-old woman with severe refractory SLE (failed HCQ, MMF, AZA, belimumab, rituximab) presents with ongoing disease activity. She read about CAR-T cell therapy for SLE. What is the mechanism, current evidence level, and main safety concern?

Autologous anti-CD19 CAR-T cells → deep B-cell depletion → drug-free remission. Evidence: Phase 1–2 (Nature Medicine 2022, NEJM 2024). Main risk: Cytokine Release Syndrome (CRS).

Mechanism: Patient's T-cells engineered ex vivo with anti-CD19 chimeric antigen receptor → infused after lymphodepletion (fludarabine + cyclophosphamide) → eliminate all CD19+ B-cells (including autoreactive clones) → "immune reset" with B-cell reconstitution of tolerant naive repertoire. Evidence: Mackensen et al. (Nature Medicine 2022) — 5 patients, all achieved drug-free remission up to 17 months; Müller et al. (NEJM 2024) — 15 patients across autoimmune diseases, CAR-T safe. 47-patient systematic review 2024: 81% LLDAS, serological remission in 80%. Safety: CRS in 87% (mostly grade 1–2; managed with tocilizumab); ICANS in 1 patient; infectious risk during aplasia. Status: investigational, not standard of care — compassionate use or clinical trials only.

3. Spondyloarthropathies (SpA)

Spondyloarthropathies are a family of inflammatory arthritides sharing HLA-B27 association, axial and/or peripheral joint involvement, enthesitis, and extra-articular features (uveitis, psoriasis, IBD). Classified as axial SpA (axSpA) or peripheral SpA.

3.1 Classification & SpA Family Overview

Subtype	Key Features	HLA-B27
Ankylosing Spondylitis (AS)	Axial: sacroiliitis + spondylitis; bamboo spine; uveitis (AAU)	90–95%
Psoriatic Arthritis (PsA)	Dactylitis, enthesitis, DIP involvement, asymmetric; psoriasis	40–50%
Reactive Arthritis	Post-infectious (GU: Chlamydia; GI: Salmonella, Shigella, Campylobacter); Reiter triad: urethritis + conjunctivitis + arthritis	60–80%
IBD-associated SpA	Peripheral (correlates with IBD activity) vs axial (independent); UC/CD	25–75%
nr-axSpA	MRI sacroiliac inflammation without X-ray sacroiliitis; predominantly female; good response to biologics	50–70%
DISH	Not true SpA; flowing anterior osteophytes; older males, DM; no inflammatory signs	No assoc.

🔶 HLA-B27 Utility: Prevalence in general population ~8–10% (Thai: ~5%). Sensitivity for AS ~90%; specificity ~90% for AS in low-prevalence group. Positive predictive value depends on clinical context. Not diagnostic alone — always combine with clinical + imaging.

3.2 Ankylosing Spondylitis — Clinical Features & Diagnosis

Classic presentation: Young male (<45 years), insidious back pain >3 months, improved with exercise (not rest), worse in morning (inflammatory back pain). Schober's test <5 cm expansion.

⚡ ASAS 2009 Axial SpA Classification Criteria (for patients with ≥3 months back pain, age onset <45y)

Imaging arm: Sacroiliitis on imaging (X-ray grade ≥2 bilateral or grade 3–4 unilateral; OR MRI active sacroiliitis) + ≥1 SpA feature
Clinical arm: HLA-B27 positive + ≥2 SpA features
SpA features: Inflammatory back pain, arthritis, enthesitis (heel), uveitis, dactylitis, psoriasis, Crohn's/UC, good response to NSAIDs, family history SpA, HLA-B27, elevated CRP

Extra-articular manifestations: Anterior uveitis (AAU) most common (25–40%); acute, unilateral, painful, photophobia; IBD (5–10%); psoriasis; aortic regurgitation (1–4%); apical pulmonary fibrosis (late, rare); cardiac conduction defects.

⚡ AS Radiographic Features (Dr. Paijit — XR Handout)

Sacroiliac joints: Early: pseudo-widening → subchondral sclerosis → erosions → ankylosis (grade 0–4 modified New York)
Romanus lesion: Inflammatory corner erosion at vertebral endplate ("shiny corner" on MRI)
Squaring of vertebral bodies: Loss of anterior concavity → square shape
Syndesmophytes: Thin, vertical, marginal (vs DISH: thick, anterior, non-marginal)
Bamboo spine: Bridging syndesmophytes → "bamboo" appearance on AP view
Dagger sign: Ossification of ALL + interspinous ligaments → single central line on AP view
Trolley track sign: Bilateral facet joint + posterior ligament ossification → 3 lines on AP view

3.3 Psoriatic Arthritis

Occurs in 20–30% of psoriasis patients. Skin precedes arthritis in 75%; simultaneous in 15%; arthritis first in 10%.

CASPAR criteria (2006): Inflammatory joint disease + ≥3 points: psoriasis (current 2pt / hx 1pt / family 1pt); nail changes (1pt); RF negative (1pt); dactylitis (1pt); juxta-articular new bone formation on X-ray (1pt).

⚡ PsA Patterns (5 subtypes — Moll & Wright)

DIP-predominant — associated with nail disease
Asymmetric oligoarthritis — most common; large + small joints; dactylitis (sausage digit)
Symmetric polyarthritis — resembles RA (but RF−, DIP+)
Axial SpA pattern — sacroiliitis, spondylitis; often asymmetric/skip lesions vs AS
Arthritis mutilans — severe; "opera glass" deformity; pencil-in-cup on X-ray

⚡ PsA Radiographic Features (Dr. Paijit)

Pencil-in-cup deformity: Erosion of distal end of proximal phalanx + periosteal reaction of distal phalanx
Mouse-ear osteophytes: Periosteal new bone at DIP margins
Opera glass (main en lorgnette): Severe telescoping of digits due to bone resorption → arthritis mutilans
Periostitis/ankylosis of DIP (distinguishes from RA)
Unilateral/asymmetric sacroiliitis (vs bilateral/symmetric in AS)

3.4 SpA Treatment

Domain	First-Line	Second-Line (bDMARD/tsDMARD)	Notes
Axial SpA (AS/nr-axSpA)	NSAIDs (continuous if active) + physiotherapy	TNFi (adalimumab, etanercept, infliximab, golimumab, certolizumab); IL-17Ai (secukinumab, ixekizumab); JAKi (upadacitinib — approved axSpA)	csDMARDs NOT effective for axial disease; no role for MTX/SSZ in axial
Peripheral SpA / PsA	NSAIDs; csDMARDs (MTX, LEF, SSZ) for peripheral joints only	TNFi, IL-17Ai (ixekizumab preferred for skin + joint), IL-12/23i (ustekinumab), IL-23i (guselkumab, risankizumab), JAKi (upadacitinib, tofacitinib)	IL-17i very effective for skin; TNFi for uveitis; avoid IL-17i in IBD-SpA (worsen IBD)
Reactive Arthritis	NSAIDs; antibiotics only if active infection present	SSZ, MTX; TNFi for refractory	Most self-limiting; chronic in 10–20%

🔶 IL-17 inhibitors in IBD-SpA: Secukinumab and ixekizumab may worsen IBD (new onset or flare). Prefer TNFi (especially infliximab or adalimumab) in patients with SpA + IBD.

📚 Key References — SpA

ASAS/EULAR 2022 axSpA Recommendations — Ramiro S et al., Ann Rheum Dis 2022
ACR/NPF 2018 PsA Guidelines — Singh JA et al., Arthritis Care Res 2019
MEASURE 1 — Secukinumab in AS (NEJM 2015)
SELECT-AXIS 1 — Upadacitinib in nr-axSpA (Lancet 2020)

3.5 Practice Questions

Q1. A 30-year-old man with HLA-B27+, 4 years of morning back stiffness, elevated CRP, and bilateral grade 2 sacroiliitis on X-ray fails 2 different NSAIDs over 12 weeks. Which therapy is next?

TNF inhibitor (e.g., adalimumab, etanercept, certolizumab)

AS with inadequate response to ≥2 NSAIDs over 4 weeks each → eligible for bDMARD. First choice: TNFi. IL-17Ai (secukinumab, ixekizumab) are alternative first-line biologics. csDMARDs (MTX) are NOT effective for axial disease. No need for MTX co-prescription with TNFi in AS.

4. Crystal Arthropathies

Crystal-induced arthropathies include gout (monosodium urate — MSU), pseudogout/CPPD (calcium pyrophosphate dihydrate), and basic calcium phosphate (BCP) deposition disease.

4.1 Gout — Pathogenesis & Epidemiology

Hyperuricemia: SUA >6.8 mg/dL (saturation point). Causes: ↑production (10%) — enzyme defects (HGPRT deficiency: Lesch-Nyhan), high purine diet, myeloproliferative disorders; ↓excretion (90%) — CKD, diuretics (thiazide > loop), low-dose ASA, CsA, pyrazinamide, ethanol.

Epidemiology: M:F = 4:1; peak age males 40–50y; females post-menopause (estrogen uricosuric). Prevalence increasing globally (diet, obesity, diuretics, CKD epidemic).

🔶 Tophus Formation: Monosodium urate crystals deposit in synovium, cartilage, bone, tendons, bursae. Gout stages: asymptomatic hyperuricemia → acute gouty arthritis → intercritical gout → tophaceous gout. Not all hyperuricemia leads to gout.

4.2 Gout — Clinical Presentation & Diagnosis

Acute gout attack: Sudden-onset severe monoarthritis; first MTP (podagra) = 50% first attack, 90% lifetime. Also: ankle, midfoot, knee. Self-limiting 7–14 days. Triggers: alcohol, high-purine meal, dehydration, trauma, illness, rapid urate-lowering (initiation of ULT).

Synovial fluid analysis (gold standard): MSU crystals — needle-shaped, negatively birefringent (yellow under parallel polarizer). WBC 10,000–100,000 (PMN predominant).

⚡ Crystal Comparison

Gout (MSU): Needle-shaped, negatively birefringent (yellow parallel, blue perpendicular to slow ray)
CPPD (Pseudogout): Rhomboid/rod-shaped, positively birefringent (blue parallel, yellow perpendicular)
Mnemonic: "Negative = gNout; Positive = Pseudogout"

ACR 2015 Gout Classification Criteria: Score ≥8 = gout. Domains: pattern of joint/bursa involvement, symptomatic episode characteristics, time course, clinical evidence of tophi, serum urate, synovial fluid analysis, imaging evidence (ultrasound double contour sign, DECT urate, X-ray punched erosion).

4.3 Gout Radiographic Features (Dr. Paijit)

⚡ Gout X-ray Features (ABCDEF-SP)

A (Alignment): Usually preserved; deformity in advanced tophaceous gout
B (Bone density): Normal (preserved bone density — unlike RA)
C (Cartilage/joint space): Preserved until late
E (Erosions): Punched-out lytic lesions with sclerotic margins and overhanging (mushroom) margins — Martel's sign (pathognomonic for gout)
S (Soft tissue): Asymmetric soft tissue swelling; tophaceous deposits (calcified tophi in chronic)
Distinguishing from RA: No juxta-articular osteopenia; no marginal erosions; asymmetric; overhanging margins
Ultrasound: Double contour sign (urate crystals on articular cartilage surface); tophus with acoustic shadowing; power Doppler vascularity in acute attack

4.4 Gout Treatment — ACR 2020 Guidelines

⚡ Acute Gout Attack Management

Colchicine (preferred for most): Low-dose 1.2 mg stat → 0.6 mg 1 hour later (non-inferior to high-dose, less GI toxicity — AGREE trial); reduce dose in renal impairment; avoid with P-gp/CYP3A4 inhibitors (clarithromycin, cyclosporine)
NSAIDs (indomethacin 50 mg TID, naproxen): Effective; avoid in CKD, GI disease, heart failure
Glucocorticoids: Oral prednisone 30–40 mg/day → taper over 7–10 days; intra-articular for mono-/oligoarthritis; IV for severe/polyarticular
Start ULT during acute attack or defer 2–4 weeks (no evidence that starting during attack worsens outcome)

⚡ Urate-Lowering Therapy (ULT) — ACR 2020

Indications (strong): Tophi, ≥2 flares/year, stage ≥2 CKD, renal stones
Target SUA: <6 mg/dL (tophaceous: <5 mg/dL)
Allopurinol (first-line): Start low-dose 50–100 mg/day; titrate by 100 mg every 2–4 weeks; max 800–900 mg. Screen HLA-B*58:01 in Han Chinese, Thai, Korean (risk severe cutaneous reactions — SJS/TEN — prevalence ~8% Thai)
Febuxostat (second-line): 40–80 mg/day; avoid in CV disease (CARES trial: higher CV mortality vs allopurinol); suitable for allopurinol-intolerant or CKD
Probenecid (uricosuric): Second-line; avoid in kidney stones, CrCl <50; check URAT1 SLC22A12
Flare prophylaxis during ULT initiation: Colchicine 0.5–0.6 mg/day or low-dose NSAID for 3–6 months
Pegloticase (IV, recombinant uricase): For refractory tophaceous gout; infusion reactions; check for G6PD deficiency before use

🔶 HLA-B*58:01 Screening (Thai guideline): Before starting allopurinol in Thai, Han Chinese, or Korean patients: screen HLA-B*58:01. Positive (8% Thai) → use febuxostat or benzbromarone instead. If allopurinol must be used, extreme caution. The risk of SJS/TEN in HLA-B*58:01 carriers treated with allopurinol is very high.

4.5 CPPD Disease (Pseudogout)

CPPD (calcium pyrophosphate dihydrate) deposition — affects cartilage, synovium, fibrocartilage. Increases with age (>60y).

Clinical presentations:

Acute CPPD arthritis (pseudogout): Knee most common (vs gout: first MTP); wrist, shoulder; self-limiting; triggers: surgery, illness, trauma, hypercalcemia
Chronic CPPD arthropathy: Resembles OA; can mimic RA (pseudo-RA) or neuropathic arthropathy

Secondary causes of CPPD (younger patients): Hyperparathyroidism (most important), hemochromatosis, hypomagnesemia, hypophosphatasia, hypothyroidism, ochronosis.

X-ray: Chondrocalcinosis — linear calcium deposits in fibrocartilage (menisci, symphysis pubis, triangular fibrocartilage of wrist, labrum) and hyaline cartilage (parallel to subchondral bone).

Synovial fluid: Rhomboid/rod-shaped crystals, positively birefringent.

Treatment: Acute: NSAIDs, colchicine, intra-articular/systemic steroids. Chronic: NSAIDs, HCQ, MTX, IL-1 inhibition (anakinra) for refractory. No disease-modifying agent available.

4.6 Practice Questions

Q1. A 55-year-old Thai male with CKD stage 2 and SUA 9.5 mg/dL has had 3 gout attacks in the past year. You plan to start allopurinol. What must you check first?

HLA-B*58:01 genotype

Thai patients have ~8% prevalence of HLA-B*58:01, which confers very high risk of allopurinol-induced SJS/TEN. Screen before initiating allopurinol. If positive → use febuxostat (40–80 mg/day) or benzbromarone (uricosuric). Also add colchicine 0.5 mg/day prophylaxis for first 3–6 months when starting ULT. Target SUA <6 mg/dL.

Q2. An 80-year-old woman presents with acute swollen, hot knee. Synovial fluid shows 45,000 WBC/mm³ (PMN), rhomboid crystals that are blue under parallel polarized light. What is the diagnosis and what secondary cause should be ruled out?

Acute CPPD arthritis (pseudogout) — Positive birefringence

Blue under parallel polarized light = positively birefringent = CPPD. Always rule out septic arthritis (send culture). In younger patients (<60y) with CPPD, screen for secondary causes: PTH, Ca, Mg, phosphatase, ferritin/transferrin saturation (hemochromatosis), TSH. In elderly, usually primary/age-related. Treatment: NSAID, colchicine, or intra-articular steroid.

5. Connective Tissue Diseases (CTDs)

CTDs include Systemic Sclerosis (SSc), Sjögren's Syndrome, Mixed CTD (MCTD), and Undifferentiated CTD (UCTD). They share ANA positivity, multisystem involvement, and distinctive autoantibody profiles. (Source: Dr. Chayawee Muangchan, Siriraj/Mahidol)

5.1 Systemic Sclerosis (SSc) — Classification & Pathogenesis

SSc is characterized by three hallmarks: vasculopathy, autoimmunity, and fibrosis. F:M = 4:1; peak age 30–50y.

⚡ ACR/EULAR 2013 SSc Classification Criteria

Major criterion: Skin thickening of fingers proximal to MCP = 9 points (sufficient alone)
Skin thickening fingers: puffy/whole finger 4pt, only distal to MCP 2pt
Fingertip lesions: pitting scars 3pt, fingertip ulcers 2pt
Telangiectasia: 2pt
Abnormal NFC: 2pt
Pulmonary arterial HTN or ILD: 2pt each
Raynaud's phenomenon: 3pt
SSc-related Ab (anti-topoisomerase I, anti-centromere, anti-RNA pol III): 3pt
Score ≥9 = definite SSc

Feature	lcSSc (Limited)	dcSSc (Diffuse)
Skin involvement	Distal to elbows/knees + face	Proximal limbs + trunk
Raynaud's	Years before skin changes	Coincides with skin changes
mRSS (modified Rodnan skin score)	Lower (<15)	Higher (15–51)
Key antibodies	Anti-centromere (ACA)	Anti-Scl-70 (anti-topoisomerase I), Anti-RNA pol III
ILD	Less common (5–15%)	Common (20–40%)
PAH	More common (10–15%)	Less common
SRC	Rare	More common (anti-RNA pol III)
CREST syndrome	Calcinosis, Raynaud's, Esophageal dysmotility, Sclerodactyly, Telangiectasia	—

5.2 SSc — Organ Involvement & Complications

System	Features	Screening/Management
Vascular/Raynaud's	Vasospasm → digital ischemia → pitting scars → digital ulcers → amputation. NFC: enlarged/dropout capillaries (scleroderma pattern)	Avoid cold/nicotine; CCB (nifedipine); PDE5i; IV prostacyclins for severe; bosentan for prevention of digital ulcers
Skin	Edematous → indurated → atrophic. Salt-and-pepper, mat telangiectasia, calcinosis	mRSS monitoring; moisturizers; MTX/MMF for rapidly progressive skin
ILD (Pulmonary fibrosis)	NSIP most common pattern (anti-Scl-70); UIP in some. Dry cough, dyspnea, bi-basal crackles	HRCT annually if at risk; PFT (FVC, DLCO); Treat: Nintedanib (SENSCIS trial) or MMF/CYC (SLS II); tocilizumab (fasciitis/ILD subset)
PAH	Progressive exertional dyspnea; RHC required for diagnosis (mPAP ≥20 mmHg + PVR ≥2 WU)	Annual screening: DETECT algorithm (anti-centromere, DLCO%, NT-proBNP, ECG, echo) → RHC if indicated; ERA, PDE5i, prostacyclins
GI	Esophageal dysmotility (90%) → GERD, Barrett's, dysphagia; gastric antral vascular ectasia (GAVE/"watermelon stomach"); colonic hypomotility → constipation, pseudo-obstruction; malabsorption (SIBO)	PPI; prokinetics; endoscopy; rotating antibiotics for SIBO
Cardiac	Pericarditis, myocarditis, arrhythmias, cardiac fibrosis (mRSS correlates). Conduction defects	ECG, echo annually; Holter if symptomatic
Renal (SRC)	Scleroderma Renal Crisis: acute severe HTN + AKI; abrupt onset; MAHA; 80% in dcSSc + anti-RNA pol III. HIGH DOSE STEROID = RISK FACTOR for SRC	ACE inhibitor IMMEDIATELY; monitor BP closely; avoid high-dose steroids if possible

🔶 SSc Disease Evolution (Dr. Chayawee timeline): Raynaud's → (years) → skin thickening → (months–years) → ILD/PAH/cardiac → (years) → atrophy. In dcSSc: rapid skin thickening in first 3–5 years then stabilizes/improves; ILD worst in first 4 years. Anti-RNA pol III+ → higher SRC risk, more malignancy association.

5.3 SSc — Treatment Overview

Manifestation	Treatment	Evidence
Skin (early diffuse)	MTX (early dcSSc) or MMF	Moderate evidence
ILD	MMF (first-line), CYC, Nintedanib	SLS I/II, SENSCIS
PAH	ERA (bosentan, ambrisentan, macitentan), PDE5i (sildenafil), prostacyclins (iloprost)	Established RCT evidence
Raynaud's/Digital ulcers	CCB (nifedipine), PDE5i, IV iloprost, bosentan (prevention)	Multiple trials
SRC	ACE inhibitor STAT (captopril, lisinopril) — do NOT withhold even if AKI	Observational; life-saving
GI (GERD)	PPI; prokinetics (metoclopramide, domperidone)	Symptomatic

5.4 Sjögren's Syndrome

Chronic autoimmune exocrinopathy — predominantly affects exocrine glands (lacrimal, salivary). Primary (1°SS) vs secondary (2°SS in RA, SLE, SSc). F:M = 9:1; peak onset 30–50y.

Clinical: Xerophthalmia (dry eyes — keratoconjunctivitis sicca; Schirmer's test <5mm/5min), xerostomia (dry mouth — unstimulated saliva <1.5 mL/15min), parotid gland enlargement, extraglandular: arthritis, purpura, PNS, renal tubular acidosis, primary biliary cirrhosis overlap.

ACR/EULAR 2016 criteria: Total score ≥4 — lip biopsy focal lymphocytic sialadenitis focus score ≥1 foci/4mm² (3pts), anti-SSA/Ro+ (3pts), ocular staining ≥5 (1pt), Schirmer's ≤5mm/5min (1pt), unstimulated salivary flow ≤0.1mL/min (1pt).

Antibodies: ANA (>90%), anti-Ro/SSA (70%), anti-La/SSB (50%), RF (60–70%). Anti-Ro+ alone can cause primary SS (without SLE).

Complications: Non-Hodgkin lymphoma (MALT type) — 44× increased risk; most important long-term complication. Screen for B-symptoms, lymphadenopathy, parotid enlargement, low C4, cryoglobulins (risk factors).

⚡ Sjögren's Treatment

Sicca symptoms: artificial tears/saliva, pilocarpine (muscarinic agonist, 5 mg TID), cevimeline
Extraglandular/systemic: HCQ (first-line), MTX, AZA, MMF
Severe/refractory: Rituximab (anti-CD20) — reduces lymphoma risk? trials ongoing
No FDA-approved disease-modifying therapy for primary SS

5.5 MCTD & UCTD

Mixed CTD (MCTD) — Sharp syndrome: Overlap of SLE + SSc + polymyositis features + anti-U1 RNP antibodies (high titer). Raynaud's universal; esophageal dysmotility; PAH major cause of mortality; synovitis; myositis. Treatment: like SLE; PAH management crucial.

Undifferentiated CTD (UCTD): ANA+ with CTD symptoms not fulfilling any specific criteria. ~30% remain UCTD long-term; ~30% evolve to defined CTD (SLE, SSc, SS) over 5 years. HCQ + symptom management; monitor for evolution.

🔶 CTD "Hand Features" Differential (Dr. Chayawee):

RA: MCP/PIP symmetric swelling, DIP sparing, ulnar drift, Z-thumb
SSc: Sclerodactyly, digital pitting scars, periungual telangiectasia, Raynaud's, calcinosis
Sjögren's: Arthritis/arthralgia; mild synovitis; parotid swelling
SLE: Non-erosive; Jaccoud deformity; no true synovitis
DM: Mechanic's hands; Gottron papules on MCPs/PIPs; V-sign; shawl sign

5.6 Practice Questions

Q1. A patient with dcSSc is on prednisone 40 mg/day for rapidly progressive skin thickening. She develops acute severe hypertension (BP 185/110) and creatinine rise from 0.8 to 2.4 mg/dL over 1 week. What is the diagnosis and treatment?

Scleroderma Renal Crisis (SRC) — Start ACE inhibitor immediately

SRC: acute severe HTN + AKI in SSc. Anti-RNA pol III antibody and HIGH-DOSE STEROIDS (≥15 mg/day prednisone) are the main risk factors. Treatment: ACE inhibitor IMMEDIATELY (captopril 25–50 mg TID or lisinopril) — do not withhold even if creatinine is rising. Target: BP normalization within 72h. Avoid ARBs (less evidence). ~30% will still require dialysis short-term but ACEi can lead to recovery of renal function even months later.

6. Inflammatory Myopathies (IIM)

Idiopathic Inflammatory Myopathies (IIM) are a heterogeneous group of systemic autoimmune diseases characterized by skeletal muscle inflammation, autoantibodies, and multisystem involvement. (Source: Dr. Chayawee Muangchan, Siriraj/Mahidol)

6.1 IIM Classification — 5 Major Subtypes

Subtype	Key Features	Key Antibodies	Malignancy Risk
Dermatomyositis (DM)	Proximal muscle weakness + characteristic skin rashes (heliotrope, Gottron's); ILD common	Anti-Mi-2, anti-TIF1γ, anti-NXP2, anti-MDA5, anti-SAE	High (esp. anti-TIF1γ, anti-NXP2 in adults)
Polymyositis (PM)	Proximal muscle weakness without skin; less common than DM; now considered overlap/IMNM	Anti-Jo-1 and other anti-synthetase	Slightly elevated
Immune-mediated Necrotizing Myopathy (IMNM)	Severe proximal weakness; minimal inflammation on biopsy; necrosis + regeneration; statin-associated	Anti-SRP, anti-HMGCR	Elevated (anti-SRP)
Inclusion Body Myositis (IBM)	Distal + proximal weakness (asymmetric); >50y; m>f; dysphagia; RESISTANT to treatment	Anti-cN1A (not diagnostic)	Not elevated
Juvenile DM (JDM)	Children; vasculopathy prominent; calcinosis; no malignancy risk	Anti-MDA5, anti-NXP2, anti-TIF1γ	None

🔶 IBM Pearls: Most common inflammatory myopathy in patients >50y. Characteristic: finger flexor + quadriceps weakness (distal + proximal asymmetric). Dysphagia in ~50%. Does NOT respond to steroids or immunosuppressants. No proven disease-modifying treatment.

6.2 Myositis-Specific & Myositis-Associated Antibodies (MSA/MAA)

Antibody	Target	Clinical Syndrome
Myositis-Specific Antibodies (MSA)
Anti-Jo-1	Histidyl-tRNA synthetase	Antisynthetase syndrome: ILD + myositis + arthritis + mechanic's hands + Raynaud's + fever. Most common MSA (~25%)
Anti-PL-7, -12, -EJ, -OJ, -KS	Other aminoacyl-tRNA synthetases	Antisynthetase syndrome (ILD more prominent than muscle in some)
Anti-MDA5	MDA5 (melanoma differentiation antigen 5)	Clinically amyopathic DM (CADM); rapidly progressive ILD; skin ulcers; palmar papules; HIGH mortality (RP-ILD)
Anti-TIF1γ	TIF1-gamma (transcription intermediary factor)	Adult DM + high malignancy risk; classic DM rashes; photosensitivity
Anti-NXP2	Nuclear matrix protein NXP2	Adult DM + malignancy; calcinosis; edema; JDM
Anti-Mi-2	Nucleosome remodeling	Classic DM rashes (V-sign, shawl sign, Gottron's); good prognosis; responds well to steroids
Anti-SRP	Signal recognition particle	IMNM; severe acute proximal weakness; cardiac involvement; statin-independent
Anti-HMGCR	HMG-CoA reductase	IMNM; statin-associated (but also statin-naïve); slower onset
Anti-SAE	Small ubiquitin-like modifier activating enzyme	DM with dysphagia; skin-predominant initially; European cohorts
Myositis-Associated Antibodies (MAA)
Anti-PM/Scl (Anti-PM-75/100)	Exosome complex	SSc-PM overlap; ILD; "mechanic's hands"; good prognosis
Anti-Ku	DNA-PK subunit	PM/SSc overlap; ILD; PAH; arthritis
Anti-U1 RNP	U1 snRNP	MCTD; Raynaud's; myositis; SSc features

6.3 Dermatomyositis — Skin Features & Anti-MDA5

⚡ DM Pathognomonic & Characteristic Skin Rashes

Gottron's papules — violaceous papules over dorsal MCPs/PIPs/DIPs (pathognomonic)
Gottron's sign — erythematous/violaceous macular rash over extensor surfaces (elbows, knees)
Heliotrope rash — violaceous periorbital edema/erythema (pathognomonic)
V-sign — photosensitive erythema in V-neck distribution (anterior chest/neck)
Shawl sign — erythema over posterior shoulders/upper back
Holster sign — erythema over lateral thighs
Mechanic's hands — hyperkeratotic, cracked skin on lateral fingers (associated with antisynthetase syndrome)
Flagellate erythema — linear whip-like streaks on trunk
Calcinosis — calcium deposits in skin/subcutaneous tissue (esp. JDM, anti-NXP2)
Periungual telangiectasia — dilated capillaries at nail fold (NFC: irregular, dilated loops)

🔶 Anti-MDA5 DM (Clinically Amyopathic DM / CADM): Minimal or no muscle weakness; distinctive skin features — palmar papules (Gottron's over palms), skin ulcers, mucosal ulcers, painful palmar pitting. Rapidly progressive ILD (RP-ILD) is the key danger — mortality up to 50% within 6 months without aggressive treatment. TX: high-dose steroids + calcineurin inhibitors (tacrolimus/cyclosporine) + MMF or CYC; consider rituximab early.

6.4 IIM Workup & Diagnosis

Muscle enzymes: CK (most sensitive — may be markedly elevated in PM/IMNM, mildly elevated or normal in DM/CADM/IBM), aldolase, LDH, AST, ALT. CK normal in ~20% DM.

EMG: Myopathic pattern — short-duration, low-amplitude, polyphasic MUAPs; spontaneous activity (fibrillations, PSW); useful to guide biopsy site.

MRI (STIR/T2): Muscle edema = active inflammation; guides biopsy site; monitors treatment response.

Muscle biopsy: Gold standard. DM: perifascicular atrophy + perivascular/perimysial inflammation; PM: endomysial inflammation + CD8+ T cell invasion of non-necrotic fibers; IMNM: necrosis + regeneration + minimal inflammation; IBM: rimmed vacuoles + 15–18nm tubulofilamentous inclusions.

MSA panel: Essential for subtype diagnosis, prognosis, and ILD screening strategy.

Malignancy screening: All adult DM/IMNM (especially anti-TIF1γ, anti-NXP2, anti-SRP): CT chest/abdomen/pelvis, mammography, PAP smear, PET-CT if suspicious. Screen at diagnosis and annually ×3 years.

ILD screening: HRCT + PFT (FVC, DLCO) at baseline — especially anti-Jo-1, anti-MDA5, anti-PL-7/12.

6.5 IIM Treatment

⚡ IIM Treatment Algorithm (Dr. Chayawee)

First-line: Prednisolone 1 mg/kg/day (max 60–80 mg/day); severe: IV pulse methylprednisolone 500–1000 mg × 3 days
Early steroid-sparing agent (start simultaneously or within 4–8 weeks):
— Methotrexate 15–25 mg/week (preferred for skin/muscle; avoid if ILD)
— Azathioprine 2–3 mg/kg/day (preferred if ILD; slower onset)
— MMF 2–3 g/day (preferred for ILD and DM skin)
Refractory disease: IVIg 2 g/kg/month (especially DM; FDA-approved for DM — ProDERM trial); Rituximab (RIM trial — anti-Jo-1 and anti-Mi-2 best predictors of response)
Anti-MDA5 RP-ILD: Triple therapy — high-dose steroids + tacrolimus/cyclosporine + CYC; early rituximab
IMNM (anti-HMGCR/SRP): High-dose steroids + IVIG + RTX; stop statin if applicable
IBM: No proven treatment; PT/OT; dysphagia management; trial of IVIg for dysphagia

📚 Key References — IIM

EULAR/ACR 2017 IIM Classification Criteria — Lundberg IE et al., Ann Rheum Dis 2017
ProDERM — IVIg for DM (NEJM 2022)
RIM trial — Rituximab in Myositis (Arthritis Rheum 2013)
BSR/BHPR 2017 IIM Guidelines — Oldroyd A et al.

6.6 Practice Questions

Q1. A 45-year-old woman has Gottron's papules, V-sign rash, and proximal muscle weakness. CK is 3,200 U/L. Anti-MDA5 is positive. She develops progressive dyspnea and HRCT shows bilateral ground-glass opacities with consolidation. What is the key concern and management?

Rapidly Progressive ILD (RP-ILD) in Anti-MDA5 DM — requires aggressive treatment

Anti-MDA5+ DM with RP-ILD is a rheumatologic emergency. Mortality >50% without aggressive therapy. Treatment: pulse methylprednisolone + tacrolimus (or cyclosporine) + IV cyclophosphamide. Consider early rituximab. Tofacitinib has emerging evidence for anti-MDA5 RP-ILD. ICU-level monitoring for respiratory failure; consider early intubation if needed. Anti-MDA5 patients may have minimal muscle weakness (CADM) despite severe systemic disease.

Q2. A 68-year-old man has 1 year of progressive weakness affecting finger flexors and quadriceps, more in the right side. CK is 450 U/L. EMG shows myopathic changes. Muscle biopsy shows rimmed vacuoles. What is the diagnosis and treatment?

Inclusion Body Myositis (IBM) — No proven disease-modifying treatment

IBM clues: >50 years, male, distal+proximal asymmetric weakness (finger flexors + quadriceps), rimmed vacuoles + 15–18nm inclusions on biopsy. IBM does NOT respond to steroids, MTX, or AZA. Management: PT/OT, fall prevention, dysphagia evaluation (videofluoroscopy), PEG if severe dysphagia. Anti-cN1A antibody seen in ~50% (not diagnostic alone). IVIg may temporarily improve dysphagia.

7. Systemic Vasculitis

Vasculitides are inflammatory disorders of blood vessel walls, classified by predominant vessel size (Chapel Hill Consensus Conference 2012). Recognition requires clinical pattern + ANCA + biopsy/imaging. This section incorporates EULAR 2022, ACR/VF 2021, and ACR/EULAR 2022 Classification Criteria with landmark trial evidence through 2024.

7.1 Chapel Hill 2012 Classification & ACR/EULAR 2022 Criteria

Category	Entities	Key Vessel	ANCA
Large Vessel	Takayasu arteritis (TAK), Giant cell arteritis (GCA)	Aorta + major branches	Negative
Medium Vessel	Polyarteritis nodosa (PAN), Kawasaki disease	Muscular arteries (no glomerulonephritis)	Negative
Small Vessel — ANCA+	GPA, MPA, EGPA	Capillaries, venules, arterioles; glomeruli	Positive
Small Vessel — IC-mediated	IgAV (HSP), Cryoglobulinemic, Anti-GBM (Goodpasture)	Capillaries, venules; IC deposits on IF	Negative
Variable Vessel	Behçet's disease, Cogan's syndrome	Any vessel size	Negative

⚡ ACR/EULAR 2022 Classification Criteria — AAV (Ann Rheum Dis 2022)

New point-based scoring system; requires confirmation of vasculitis by biopsy/imaging AND exclusion of mimics
GPA (10 items): Upper airway (+3), bloody nasal discharge/nasal ulcers/sinusitis (+3), cartilage involvement (+2), hearing loss (+1), lung nodule/mass/cavitation (+2), granulomatous inflammation on biopsy (+3), PR3-ANCA positive (+5), MPO-ANCA negative (+1) — Threshold ≥5 (Sens 92.5%, Spec 93.8%)
MPA (6 items): Pauci-immune GN on biopsy (+5), fibrosis on HRCT (+3), MPO-ANCA positive (+6), PR3-ANCA negative (+1), no upper airway (+3), no granuloma (+3) — Threshold ≥5 (Sens 91.1%, Spec 93.9%)
EGPA (7 items): Obstructive airway disease (+3), nasal polyps (+3), eosinophilia ≥1×10⁹/L (+5), extravascular eosinophils on biopsy (+2), granulomatous inflammation (+1), MPO-ANCA/PR3-ANCA positive (−3), no hematuria (−1) — Threshold ≥5 (Sens 84.9%, Spec 99.1%)

🔶 ANCA Testing: c-ANCA/PR3 specificity for GPA; p-ANCA/MPO for MPA & EGPA. Both indirect IF (ANCA pattern) AND antigen-specific ELISA (PR3/MPO) should be performed (ACR/EULAR 2022). PR3-ANCA = higher relapse rate, benefits more from extended RTX. MPO-ANCA = more likely MPA, associated with ILD, more fibrotic/less inflammatory phenotype.

7.2 Large Vessel Vasculitis — GCA & TAK (ACR/VF 2021, EULAR 2018, ACR/EULAR 2022 Criteria)

Feature	GCA (Giant Cell Arteritis)	TAK (Takayasu Arteritis)
Age	>50 years (mean 72y); increases with age	<50 years (mostly 10–40y)
Sex	F:M = 3:1	F:M = 8:1 (Asian women)
Ethnicity	Northern European predominance	Asian, Middle Eastern, Latin American
Vessels	External carotid branches (temporal, ophthalmic); extracranial aorta branches; thoracic aorta in LVV-GCA variant	Aorta & all major branches: subclavian (most common), carotid, renal, celiac, mesenteric; pulmonary arteries (PAH)
Key Symptoms	New temporal headache; scalp tenderness; jaw claudication; vision loss (AION); diplopia; PMR features (40–60%); constitutional	Early: fever, myalgia, arthralgia, elevated APR. Late: absent pulses, BP discrepancy >10 mmHg arms, claudication, bruits, HTN (renal artery), angina (coronary)
Lab	ESR >50 mm/hr; CRP markedly elevated; normocytic anemia; thrombocytosis; ANCA negative	ESR/CRP elevated; ANCA negative; IL-6 elevated
Diagnosis	TAB (gold standard; ≥1 cm; bilateral if first negative); Temporal artery US (halo sign); MRA/CTA/PET-CT for LVV-GCA	MRA/CTA (aorta + branches): stenosis/occlusion/dilation/aneurysm; PET-CT: vessel wall FDG uptake (active inflammation); Angiography: gold standard for stenosis
Pathology	Granulomatous inflammation: giant cells, lymphocytes in media; fragmented internal elastic lamina; skip lesions (30–40%)	Granulomatous panarteritis; transmural inflammation; adventitial fibrosis

⚡ ACR/EULAR 2022 GCA Classification Criteria — Score-Based (Threshold ≥6)

Positive TAB or temporal artery halo sign on US: +5 (most weighted item)
ESR ≥50 mm/hr or CRP ≥10 mg/L: +3
Sudden visual loss: +3
Morning stiffness in shoulders or neck: +2
Jaw or tongue claudication: +2
New temporal headache: +2
Scalp tenderness: +2
Temporal artery abnormality on exam: +2
Bilateral axillary involvement on imaging: +2
FDG-PET activity throughout aorta: +2
Sensitivity 87.0%, Specificity 94.8% (Ponte et al., Arthritis Rheumatol 2022)

⚡ GCA Treatment — ACR/VF 2021 & EULAR 2018 Recommendations

IMMEDIATE GC (do NOT delay for biopsy):
— Cranial GCA without visual symptoms: Prednisolone 40–60 mg/day oral
— Cranial ischemia / visual threat: IV methylprednisolone 500–1000 mg × 3 days THEN oral
— LVV-GCA / isolated aortitis: 40–60 mg/day oral (IV pulse less indicated)
Tocilizumab (IL-6Ri) — ACR 2021: Conditional recommendation to ADD TCZ to GC for all newly diagnosed GCA
— SC 162 mg/week OR IV 8 mg/kg q4wk (GiACTA trial, NEJM 2017)
— Sustained GC-free remission at 52 weeks: 56% TCZ-weekly vs 14% placebo/26-wk taper vs 18% placebo/52-wk taper
— Enables 26-week GC taper (shorter duration), markedly reduces cumulative GC dose
— Long-term extension: substantial drug-free remission maintenance after TCZ cessation (GiACTA open-label extension, 2024)
— TCZ added for: relapsing GCA, high GC toxicity risk, or as early combination (ACR 2021 conditional)
Methotrexate 15–25 mg/week: alternative steroid-sparer if TCZ unavailable/contraindicated (EULAR 2018)
Low-dose aspirin: No longer routinely recommended (EULAR 2018); use only if another cardiovascular indication exists
Taper GC slowly: prednisolone should not reach <5 mg before ≥12 months

⚡ TAK Treatment — ACR/VF 2021 & EULAR 2018

All TAK patients: GC + non-biologic IS simultaneously (EULAR 2018 — unlike GCA where GC alone initially acceptable)
Initial GC: Prednisolone 1 mg/kg/day (max 60 mg) → taper over 6–12 months
Non-biologic IS (add at diagnosis): MTX 15–25 mg/wk (preferred, ACR 2021), AZA 2 mg/kg/day, or MMF 2 g/day
Refractory/relapsing TAK (biologics):
— TNFi first (ACR 2021 preferred): Infliximab 5 mg/kg IV q6-8wk or Adalimumab SC q2wk; substantial evidence from case series and registry data
— Tocilizumab: ACR 2021 recommends TCZ only for TAK refractory to other agents (limited RCT data); EULAR 2018 lists as option
— Abatacept: emerging evidence (CTLA4-Ig)
Revascularization (PTA/stenting/bypass): only in inactive disease (remission ≥3 months preferred); risk of restenosis in active disease
Disease activity monitoring: PET-CT (most sensitive for active inflammation); MRA for structural changes; CRP/ESR (may be normal in active TAK — "silent TAK")

🔶 GCA Visual Emergency Protocol: Any GCA with visual symptoms (amaurosis fugax, AION, diplopia) → IV methylprednisolone 500–1000 mg × 3 days BEFORE any delay. Do NOT wait for TAB — biopsy remains valid for ≥2 weeks on steroids (giant cells persist). Add aspirin 75–100 mg/day for ischemic risk reduction. Ophthalmology consultation same day. Temporal artery ultrasound (halo sign: hypoechoic wall thickening, non-compressible) can confirm diagnosis rapidly even in emergency setting.

7.3 ANCA-Associated Vasculitis (AAV) — EULAR 2022 & ACR/VF 2021

Feature	GPA (Wegener's)	MPA	EGPA (Churg-Strauss)
ANCA (IF/ELISA)	c-ANCA/PR3 80–90%	p-ANCA/MPO 70–80%	p-ANCA/MPO ~40% (ANCA− in 60%)
ENT	Bloody nasal discharge, septal perforation, saddle nose, otitis, subglottic stenosis, oral ulcers	Minimal ENT (key distinguishing point)	Allergic rhinitis, chronic sinusitis, nasal polyps
Pulmonary	Pulmonary nodules (often cavitating, bilateral), DAH, infiltrates	DAH (commonest pulmonary cause of death), pulmonary fibrosis (MPO/MPA — UIP pattern)	Asthma (required); eosinophilic pneumonia; migratory infiltrates
Renal	Pauci-immune RPGN (80%); necrotizing/crescentic GN	Pauci-immune RPGN (90%); most severe renal involvement of AAV	Focal segmental GN (30%); rarely severe
Eosinophilia	Absent	Absent	>10% or >1500/mm³ required
Granulomas	Granulomatous (necrotizing) — upper + lower airways	Absent (pauci-immune only)	Eosinophilic infiltration + granulomas
Other	Orbital pseudotumor; episcleritis/scleritis; mononeuritis multiplex; skin purpura	Mononeuritis multiplex; purpura; skin ulcers	Mononeuritis multiplex (most common cause); eosinophilic myocarditis (leading cause of death); skin nodules; GI ischemia
Relapse risk	HIGH (PR3+, granulomatous): 50–70% at 5 years	MODERATE: 30–40%	MODERATE–HIGH: 30–70%

⚡ AAV Induction Therapy — EULAR 2022 (Hellmich et al., Ann Rheum Dis 2023)

Severe/Organ-threatening AAV (GPA/MPA) — Remission Induction:
→ Rituximab (375 mg/m² × 4 weeks OR 2× 1000 mg 2 weeks apart) + high-dose GC — Preferred for GPA (PR3+), relapsing disease, childbearing age, bladder/gonadal toxicity concern
→ OR IV Cyclophosphamide (pulse: 15 mg/kg q2–3wk × 6; or 500 mg IV q2wk × 6 — Euro-Lupus-adapted) + high-dose GC
→ RAVE (NEJM 2010): RTX = CYC for induction; RTX superior for relapsing disease
→ RITUXVAS (NEJM 2010): RTX + 2 doses CYC = CYC for RPGN
Avacopan (C5aR1 inhibitor) — EULAR 2022 NEW:
→ Avacopan 30 mg BID PO + RTX or CYC — to substantially reduce GC exposure (not as GC replacement entirely)
→ ADVOCATE trial (NEJM 2021, Jayne et al.): Avacopan non-inferior for remission at 26 weeks (72.3% vs 70.1%) and superior for sustained remission at 52 weeks (65.7% vs 54.9%, p=0.007)
→ Superior renal recovery (eGFR improvement), less GC-related toxicity, improved quality of life
→ FDA-approved Oct 2021 for GPA/MPA; EULAR 2022 conditional recommendation
GC Tapering (EULAR 2022): Target ≤5 mg/day prednisolone within 4–5 months (supported by PEXIVAS reduced-dose GC arm)
Non-severe/Limited GPA: MTX 20–25 mg/week + GC (no CYC/RTX needed); trimethoprim-sulfamethoxazole for maintenance of upper airway GPA (reduces ENT relapses)

⚡ PEXIVAS Trial (NEJM 2020) — Practice-Changing Results

PEXIVAS (Walsh M et al., NEJM 2020): N=704 patients, severe AAV (eGFR <50 OR DAH), 16 countries
Plasma exchange (PLEX) arm: PLEX did NOT reduce death or ESKD at 2.9 years (HR 0.86; 95% CI 0.65–1.13; p=0.27)
→ PLEX no longer recommended as standard induction for severe AAV — even with severe renal failure or DAH
Glucocorticoid arm: Reduced-dose GC protocol non-inferior to standard-dose for death/ESKD AND resulted in significantly fewer serious infections at 1 year (27.3% vs 33.0%)
→ Supports early aggressive GC tapering strategy (EULAR 2022 recommendation)
Note: Very small subgroup with anti-GBM disease co-existing + DAH may still benefit from PLEX — clinical judgement required

⚡ AAV Maintenance Therapy — EULAR 2022

After RTX induction: Rituximab maintenance preferred (over AZA)
→ RTX 500 mg IV q6 months × 2 years: MAINRITSAN (Ann Int Med 2014): RTX > AZA for relapse prevention
→ MAINRITSAN2 (Lancet 2016): tailored RTX (CD19 or ANCA-guided redosing) — non-inferior to fixed schedule, fewer doses
→ MAINRITSAN3 (Ann Int Med 2020): Extended RTX maintenance (additional 18 months) vs placebo after first maintenance course — relapse-free survival 96% vs 74% at 28 months; benefit especially in PR3-ANCA+
→ RITAZAREM (NEJM-published 2023, PMC): RTX 1000 mg q4m vs AZA after relapse — RTX superior (relapse 13% vs 38%; HR 0.36; p<0.001)
After CYC induction: AZA 2 mg/kg/day OR RTX 500 mg q6 months (RTX preferred if relapse history or PR3-ANCA+)
Duration of maintenance: Minimum 24 months after achieving remission; consider extended (up to 4–5 years) in PR3-ANCA+, relapsing disease
TMP-SMX 960 mg 3×/week for Pneumocystis prophylaxis during induction (EULAR 2022)
Monitor B-cell counts and ANCA to guide RTX re-dosing

⚡ EGPA Treatment — ACR/VF 2021 & MIRRA/MANDARA Trials

Remission induction (severe/organ-threatening EGPA): High-dose GC + CYC or RTX (same approach as GPA/MPA); mepolizumab not adequate for severe manifestations
Non-severe/Relapsing EGPA — Biologic Anti-IL-5 therapy:
→ Mepolizumab 300 mg SC q4wk: FDA-approved for relapsing/refractory EGPA; MIRRA trial (NEJM 2017): ≥24 weeks remission 28% vs 3% placebo; annual relapse rate halved; GC-sparing (median OCS 10→5 mg/day)
→ Benralizumab 30 mg SC q4wk (anti-IL-5Rα): Non-inferior to mepolizumab (MANDARA trial, NEJM 2024): remission 59% vs 56% (95% CI −13 to 18); superior GC discontinuation (41% vs 26%); approved FDA 2024 for EGPA
→ Benralizumab advantage: more complete eosinophil depletion (IL-5Rα vs IL-5 blockade); SC given q4wk (after first 3 monthly doses → q8wk in asthma, but q4wk in EGPA trial)
→ Choose mepolizumab or benralizumab based on patient preference/availability/cardiac safety profile
Cardiac EGPA (eosinophilic myocarditis): MRI cardiac + troponin; high-dose GC + CYC; echocardiography for thrombus; ICU monitoring
Mononeuritis multiplex in EGPA: high-dose GC ± CYC; may need RTX for refractory

7.4 Immune Complex Vasculitis, PAN & Behçet's Disease

Entity	Key Features	Diagnosis	Treatment
IgA Vasculitis (HSP)	Children (peak 4–6y); palpable purpura lower limbs/buttocks; colicky abdominal pain (GI bleeding); arthralgia; IgA nephropathy (hematuria ± proteinuria)	Skin/renal biopsy: IgA deposits by IF. Clinical diagnosis in classic presentation	Supportive; NSAIDs for arthralgia; GC for severe abdominal/renal (GN); cyclophosphamide for severe nephritis. Usually self-limiting
Cryoglobulinemic Vasculitis	Type II/III (mixed): palpable purpura, peripheral neuropathy (mononeuritis), membranoproliferative GN; low C4, RF+, cryoglobulins+. 90% due to HCV	Serum cryoglobulins (collect warm); C4↓, C3 normal; HCV serology/PCR; skin biopsy: leukocytoclastic vasculitis + IC	Treat HCV with DAAs (first-line, removes antigenic drive); RTX for severe/non-HCV cryo-vasculitis; steroids + PLEX for rapidly progressive GN; low-dose GC for mild
Polyarteritis Nodosa (PAN)	ANCA-negative medium vessel; segmental transmural inflammation; aneurysms/occlusions; mononeuritis multiplex; renal involvement (renal artery aneurysms, HTN) but NO GN; skin (livedo, ulcers, nodules); orchitis; GI ischemia	Angiography (gold standard): microaneurysms (5–10 mm) in hepatic/renal/mesenteric vessels. Biopsy: fibrinoid necrosis. Hepatitis B in 30%	HBV-associated: antiviral (tenofovir) + short GC + PLEX (to clear IC). Non-HBV: GC ± CYC for severe disease
Behçet's Disease	Recurrent oral ulcers ≥3/year (required) + ≥2 of: genital ulcers, eye lesions (uveitis — sight-threatening), skin (EN, pseudofolliculitis), pathergy positive. DVT, arterial aneurysms, CNS involvement, GI ulcers	ICBD 2014 criteria: oral ulcers (2pt) + genital ulcers (2pt) + eye lesions (2pt) + skin (1pt) + pathergy (1pt) + neurological (1pt) + vascular (1pt) — score ≥4. HLA-B51 associated	Mucocutaneous: colchicine (first-line), apremilast (RELIEF trial); Ocular: AZA + GC, TNFi (infliximab for refractory uveitis); Vascular thrombosis: IS (AZA/CsA) ± anticoagulation (NO anticoag if arterial aneurysm); Severe: GC + AZA or CYC; TNFi for refractory/severe

🔶 Behçet's Vascular Paradox: Venous thrombosis in Behçet's is driven by vessel wall inflammation, not hypercoagulability. Treatment priority = immunosuppression (AZA, GC) first; add anticoagulation only if no concomitant arterial aneurysm (rupture risk). Anticoagulation alone without IS is inadequate. Pathergy reaction: positive in 30–50% (highest in Japan/Turkey; less reliable in Southeast Asia, European cohorts).

7.5 AAV Disease Monitoring, Relapse Prediction & Special Situations

⚡ ANCA as Biomarker — Clinical Interpretation

Rising PR3-ANCA: Strong predictor of impending relapse → consider pre-emptive RTX redosing or increase monitoring
Rising MPO-ANCA: Weaker predictor of relapse — decisions should integrate clinical assessment
Persistent ANCA positivity: Common during maintenance; alone does NOT warrant treatment escalation (EULAR 2022)
ANCA-negative AAV: Usually MPO-ANCA−/PR3-ANCA− MPA or GPA; use clinical criteria + biopsy; lower relapse rate
Monitor CD19+ B cells to guide RTX redosing: B-cell repopulation often precedes ANCA rise and relapse

⚡ Vasculitis Disease Activity & Damage Scores

BVAS (Birmingham Vasculitis Activity Score): Gold-standard activity assessment; validated in clinical trials (RAVE, ADVOCATE); BVAS = 0 = remission
VDI (Vasculitis Damage Index): Accumulated irreversible damage; distinguishes active disease from damage
EUVAS/BVAS-WG: GPA-specific version; 33-item tool

Clinical Scenario	Management (EULAR 2022 / ACR 2021)
Severe relapse (organ-threatening)	Repeat RTX induction (preferred) OR CYC if RTX was induction drug; pulse GC; reassess maintenance duration
Limited/minor relapse (constitutional, minor ENT/skin)	Increase GC temporarily; add/switch to MTX for GPA; TMP-SMX for upper airway GPA; re-evaluate maintenance
Subglottic stenosis (GPA)	Often NOT active vasculitis (fibrosis); intralesional GC injection + dilation; MTX as adjunct; avoid systemic IS escalation if isolated
Pregnancy in AAV	RTX: discontinue ≥6 months before conception; AZA preferred IS in pregnancy; GC acceptable; monitor ANCA + renal function closely
CKD/ESRD with AAV	Dose-adjust CYC; RTX preferred (no renal dose adjustment); avacopan dose reduction in severe renal impairment
Refractory AAV	Consider: switch RTX↔CYC; avacopan; IVIg; plasma exchange (DAH); IV methylprednisolone pulse; bortezomib (plasma cell-directed, emerging)

7.6 Practice Questions

Q1. A 36-year-old woman presents with 3 months of bloody nasal discharge, saddle-nose deformity, hemoptysis, creatinine 2.9 mg/dL rising, RBC casts on UA, bilateral cavitating lung nodules on CT. c-ANCA/PR3 positive at high titer. She has never received immunosuppression. What is the preferred induction regimen and should you add plasma exchange?

GPA with severe renal + pulmonary involvement — Rituximab + pulse GC; NO plasma exchange (PEXIVAS)

Classic GPA: ENT (saddle nose, bloody discharge) + pulmonary (cavitating nodules) + RPGN (creatinine rising + RBC casts) + PR3-ANCA+. Preferred induction: Rituximab 375 mg/m² × 4 weekly + IV methylprednisolone 500 mg × 3 days then pred 1 mg/kg/day tapering to ≤5 mg by month 4–5. PR3-ANCA+ / first presentation → RTX preferred over CYC (RAVE 2010). Add avacopan 30 mg BID if available to reduce GC exposure (ADVOCATE 2021; EULAR 2022 conditional recommendation). Plasma exchange: PEXIVAS 2020 showed NO benefit for death/ESKD even in severe renal failure — do NOT add routinely. TMP-SMX prophylaxis for PCP. Maintenance: RTX 500 mg q6 months × ≥2 years after remission; PR3+ → consider extended maintenance (MAINRITSAN3).

Q2. A 72-year-old woman with 3 weeks of temporal headache and jaw claudication. ESR 92 mm/hr, CRP 68 mg/L. She develops sudden painless right visual loss. What is the immediate management?

GCA with visual threat — IV methylprednisolone 1000 mg × 3 days STAT, then high-dose oral prednisolone

Do NOT wait for temporal artery biopsy. Start IV methylprednisolone 500–1000 mg/day × 3 days immediately. Then oral prednisolone 60 mg/day. TAB should be done within 2 weeks (histology remains valid — steroid effect on giant cells minimal in early days). Temporal artery US (halo sign) can confirm rapidly. ACR/EULAR 2022 GCA criteria score: new headache (+2) + jaw claudication (+2) + ESR ≥50 (+3) + CRP ≥10 (+3) = 10 points ≥6 threshold. Add tocilizumab SC weekly (ACR 2021: conditionally recommended for newly diagnosed GCA, especially with visual involvement, to reduce relapse and enable GC taper). Urgently refer to ophthalmology for AION evaluation. Aspirin 75–100 mg/day (not routinely for vasculitis per EULAR 2018, but consider for ischemic stroke/AION risk in this patient).

Q3. A 45-year-old woman with known asthma develops progressive dyspnea, bilateral leg numbness (foot drop), eosinophil count 4,800/mm³, bilateral infiltrates on CXR, p-ANCA/MPO weakly positive. What is the diagnosis and what biologic is now FDA-approved for this condition?

EGPA (Churg-Strauss) — Mepolizumab (MIRRA) OR Benralizumab (MANDARA 2024) for relapsing/refractory disease

EGPA diagnosis: asthma (required) + eosinophilia >1500/mm³ + mononeuritis multiplex (foot drop) + eosinophilic pneumonia + p-ANCA/MPO+. ACR/EULAR 2022 EGPA criteria: asthma score + eosinophilia + MPO-ANCA. For induction of severe disease (mononeuritis multiplex): high-dose GC + CYC or RTX. For relapsing/non-severe EGPA: Mepolizumab 300 mg SC q4wk (anti-IL-5; MIRRA trial: halved relapse rate, GC-sparing) OR Benralizumab 30 mg SC q4wk (anti-IL-5Rα; MANDARA trial NEJM 2024: non-inferior to mepolizumab, superior OCS discontinuation 41% vs 26%). Both FDA-approved. Cardiac evaluation essential (echo, troponin, MRI) — eosinophilic myocarditis is the main cause of EGPA death.

📚 Key References — Systemic Vasculitis (High-Impact)

EULAR 2022 AAV Recommendations — Hellmich B et al., Ann Rheum Dis 2023; 82(8):1071–1082
ACR/VF 2021 Guideline — AAV — Chung SA et al., Arthritis Care Res 2021;73(8):1064–1082
ACR/VF 2021 Guideline — GCA & TAK — Maz M et al., Arthritis Care Res 2021;73(8):1071–1082
EULAR 2018 LVV Recommendations — Hellmich B et al., Ann Rheum Dis 2020;79(1):19–30
ACR/EULAR 2022 Classification Criteria — GPA/MPA/EGPA — Robson JC et al., Ann Rheum Dis 2022
ACR/EULAR 2022 Classification Criteria — GCA — Ponte C et al., Arthritis Rheumatol 2022;74(12):1881–1889
ADVOCATE — Jayne DRW et al. (Avacopan in AAV). NEJM 2021;384(7):599–609
PEXIVAS — Walsh M et al. (Plasma exchange in AAV). NEJM 2020;382(7):622–631
GiACTA — Stone JH et al. (Tocilizumab in GCA). NEJM 2017;377(4):317–328
RAVE — Stone JH et al. (RTX vs CYC in AAV). NEJM 2010;363(3):221–232
MAINRITSAN3 — Charles P et al. (Extended RTX maintenance). Ann Int Med 2020;173(3):179–187
RITAZAREM — Smith RM et al. (RTX vs AZA after relapse). Ann Rheum Dis 2023
MIRRA — Wechsler ME et al. (Mepolizumab in EGPA). NEJM 2017;376(20):1921–1932
MANDARA — Wechsler ME et al. (Benralizumab vs Mepolizumab in EGPA). NEJM 2024;390(10):911–921

8. Antiphospholipid Syndrome (APS)

APS is an acquired thrombophilia caused by antiphospholipid antibodies (aPL) — persistent, causing vascular thrombosis and/or pregnancy morbidity. May be primary (no underlying disease) or secondary (most often with SLE).

8.1 Sapporo/Sydney Classification Criteria (2006)

Requires ≥1 clinical criterion AND ≥1 laboratory criterion (antibodies confirmed on ≥2 occasions, ≥12 weeks apart).

⚡ APS Classification Criteria

Clinical criteria:
1. Vascular thrombosis: ≥1 arterial, venous, or small vessel thrombosis in any tissue/organ
2. Pregnancy morbidity:
- ≥1 unexplained fetal death ≥10 weeks gestation
- ≥1 premature birth ≤34 weeks (severe preeclampsia/eclampsia or placental insufficiency)
- ≥3 consecutive unexplained pregnancy losses <10 weeks
Laboratory criteria (must be positive ×2, ≥12 weeks apart):
— Lupus anticoagulant (LA) — strongest thrombotic risk
— Anti-cardiolipin IgG or IgM (≥40 GPL/MPL or >99th percentile)
— Anti-β₂ glycoprotein I IgG or IgM (>99th percentile)

🔶 aPL Risk Stratification: High-risk profile = "Triple positive" (LA + aCL + anti-β₂GPI) → highest thrombosis/pregnancy risk. LA alone is the single strongest predictor of thrombosis. aCL IgG > IgM in significance. Isolated low-positive aCL or anti-β₂GPI = low risk; clinical context essential.

8.2 Clinical Manifestations

System	Manifestations
Venous thrombosis	DVT (most common), PE; Budd-Chiari, portal vein, renal vein thrombosis; cerebral venous sinus thrombosis
Arterial thrombosis	Stroke (young patient), TIA, MI, peripheral arterial occlusion, retinal artery occlusion
Obstetric	Recurrent pregnancy loss, IUFD, IUGR, preeclampsia, placental abruption
Cardiac	Libman-Sacks endocarditis (valvular vegetations, usually mitral/aortic regurgitation); valve thickening
Hematologic	Thrombocytopenia (immune-mediated; usually mild 100–150k; paradoxically associated with thrombosis not bleeding)
Skin	Livedo reticularis (classic "lace-like" pattern), skin ulcers, digital gangrene, superficial thrombophlebitis
Renal	APS nephropathy: small vessel thrombosis → fibrous intimal hyperplasia → CKD, HTN
CNS	Stroke, TIA, cognitive dysfunction, chorea, seizures, transverse myelitis

8.3 APS Treatment

⚡ APS Treatment Algorithm (EULAR 2019)

Thrombotic APS — first venous thrombosis: Warfarin INR 2–3; indefinite anticoagulation (high recurrence without treatment)
Thrombotic APS — arterial thrombosis: Warfarin INR 2–3 (some experts: INR 3–4); add aspirin 75–100 mg/day controversial
DOACs in APS: NOT recommended for high-risk aPL profile (triple positive, arterial events) — TRAPS trial (rivaroxaban vs warfarin): higher thrombotic events in triple-positive patients on rivaroxaban; DOACs may be used in low-risk single aPL, venous-only APS if warfarin not tolerated
Obstetric APS: LDA (low-dose aspirin 75–100 mg from pre-conception/5–6 weeks) + LMWH (prophylactic/therapeutic dose depending on history); continue LMWH 6 weeks postpartum
Asymptomatic aPL carriers: LDA if high-risk profile; hydroxychloroquine (SLE-APS)
HCQ as adjunct in SLE-APS — reduces thrombosis risk

8.4 Catastrophic APS (CAPS)

CAPS = rapidly progressive multi-organ thrombosis (≥3 organs in <1 week) in the setting of aPL. Mortality 30–50% despite treatment.

Triggers: Infection (most common), surgery, anticoagulation withdrawal, pregnancy, malignancy.

Clinical: Renal failure, pulmonary (ARDS, PE), CNS (stroke, encephalopathy), cardiac, skin (livedo, gangrene), adrenal infarction.

Treatment ("Triple therapy"):

Anticoagulation (IV heparin/UFH) — immediate
Corticosteroids (IV methylprednisolone pulse) — treat underlying inflammation
Plasma exchange (PLEX) ± IVIg — remove circulating aPL and cytokines
Eculizumab (anti-C5) for refractory CAPS — complement-mediated microangiopathy
Rituximab for refractory cases

📚 Key References — APS

EULAR 2019 APS Recommendations — Tektonidou MG et al., Ann Rheum Dis 2019
TRAPS trial — Pengo V et al., NEJM 2018 (DOACs inferior in triple-positive APS)
WOAPS — Obstetric APS management

8.5 Practice Questions

Q1. A 32-year-old woman with SLE has had 2 first-trimester losses and 1 stillbirth at 28 weeks. She is planning another pregnancy. aPL: LA positive ×2, anti-β₂GPI IgG positive ×2. What is the treatment plan?

Obstetric APS — LDA + prophylactic LMWH throughout pregnancy

She meets Sapporo criteria: obstetric (≥3 losses <10wk OR ≥1 fetal loss ≥10wk) + aPL lab criteria (LA+ ×2 ≥12 weeks apart; anti-β₂GPI+ ×2). Treatment: low-dose aspirin (100 mg/day) start before conception or at 5–6 weeks + prophylactic LMWH (e.g., enoxaparin 40 mg/day) from positive pregnancy test throughout pregnancy + 6 weeks postpartum. Continue HCQ (she has SLE). Monitor closely: fetal surveillance, Doppler, preeclampsia screening.

9. Osteoarthritis & Metabolic Bone Disease

OA is the most prevalent joint disease worldwide — a disorder of whole-joint failure, not merely "wear and tear." Metabolic bone disease (osteoporosis, osteomalacia, Paget's) is common in the rheumatology patient population.

9.1 OA Pathogenesis & Classification

Pathogenesis: Cartilage matrix degradation (MMP, ADAMTS) + subchondral bone remodeling + synovitis + osteophyte formation. Risk factors: age, obesity, female, prior joint injury, genetic factors, repetitive loading.

Type	Features	Examples
Primary OA	Idiopathic; aging + genetic; DIP, PIP, 1st CMC (thumb base), knee, hip, spine	Nodal OA (Heberden's + Bouchard's nodes)
Secondary OA	Underlying cause: prior injury, developmental (DDH), metabolic (hemochromatosis, ochronosis, acromegaly), inflammatory, neuropathic	Post-traumatic knee OA; hemochromatosis MCP OA
Erosive/Inflammatory OA	Aggressive OA variant; DIP/PIP erosions; episodes of inflammation; "gull-wing" sign on X-ray; F>M; menopausal	Inflammatory OA of hands

🔶 OA vs RA Hand Features: OA: DIP + 1st CMC involvement, hard bony swelling (Heberden/Bouchard nodes), no morning stiffness >30 min, no systemic features. RA: MCP/PIP involvement, DIP sparing, soft synovitis, prolonged morning stiffness, RF/ACPA+, systemic.

9.2 OA Radiographic Features & Grading

⚡ OA X-ray Features (ABCDEF-SP — Dr. Paijit)

A (Alignment): Varus (medial compartment OA) or valgus deformity of knee
B (Bone density): Normal or increased (subchondral sclerosis)
C (Cartilage/joint space): Asymmetric joint space narrowing (medial > lateral in knee)
D (Deformity): Subchondral cysts (geodes), subchondral sclerosis
E (Erosions): Usually absent (erosive OA: central erosion — "gull-wing" sign)
S (Soft tissue): No significant swelling; bony enlargement
Osteophytes: Marginal (key feature) — "buttress osteophytes" at DIP/PIP; "traction osteophytes" at entheses
Gull-wing sign (erosive OA): Central erosion + marginal osteophyte at DIP → resembles seagull wing

Grade	Kellgren-Lawrence (Knee)	Iwano (Hip)
0	Normal	Normal (>4mm)
I	Possible osteophyte; no JSN	Narrowing 2–4mm
II	Definite osteophyte; possible JSN	Narrowing 1–2mm
III	Definite osteophyte + JSN; sclerosis; possible cysts	Narrowing <1mm; no bone contact
IV	Large osteophytes; severe JSN; sclerosis + cysts; deformity	Bone contact (stage IVa/b/c)

9.3 OA Management

⚡ OARSI 2019 / EULAR 2019 OA Recommendations

Non-pharmacologic (first-line, always): Exercise (aerobic + strengthening + flexibility), weight loss (≥5% body weight), physiotherapy, occupational therapy, assistive devices, patient education
Pharmacologic:
— Topical NSAIDs (diclofenac gel): first choice for hand/knee OA; good efficacy, less systemic toxicity
— Oral NSAIDs: effective; use lowest dose/shortest duration; use PPI if GI risk; avoid in CKD, CVD, elderly
— Intra-articular corticosteroids: short-term (6–12 weeks) pain relief; max 3–4/year per joint; no long-term cartilage benefit
— Duloxetine: central sensitization; knee OA with central pain component; FDA-approved
— Tramadol: when NSAIDs contraindicated/insufficient; avoid strong opioids
— Intra-articular hyaluronic acid: controversial; some evidence for knee OA
Surgical: Total joint replacement (TJR) for refractory severe OA (K-L grade III–IV + functional limitation)
NOT recommended: Glucosamine/chondroitin (insufficient evidence); arthroscopic lavage/debridement

9.4 Osteoporosis — Diagnosis & Treatment

Diagnosis: DXA BMD T-score ≤ −2.5 at lumbar spine or femoral neck (WHO). Osteopenia: T-score −1.0 to −2.5. Normal: T-score ≥ −1.0. FRAX tool: 10-year probability of major osteoporotic fracture (MOF) — integrates BMD + clinical risk factors.

Glucocorticoid-induced osteoporosis (GIO): Most common secondary cause in rheumatology. Any prednisolone dose ≥5 mg/day for ≥3 months → start prophylaxis. ACR 2017 GIO guidelines: stratify by FRAX/BMD → calcium + vitamin D + bisphosphonate (oral or IV).

⚡ Osteoporosis Treatment Summary

Calcium 1000–1200 mg/day + Vitamin D 800–1000 IU/day (all patients)
Bisphosphonates (first-line antiresorptive): Alendronate 70 mg/week PO, Risedronate 35 mg/week PO, Zoledronic acid 5 mg/year IV — prevent vertebral + hip fractures; ONJ risk (especially IV, dental procedures); AFF risk (>5 years use)
Denosumab (anti-RANKL): SC q6 months; effective, no renal dose adjustment; rebound vertebral fractures if stopped abruptly → transition to bisphosphonate
Teriparatide (PTH 1-34 analog): anabolic; SC daily; for severe/multiple fractures; max 2 years; expensive
Romosozumab (anti-sclerostin): dual anabolic + antiresorptive; SC monthly × 12 months; most effective for very high-risk fractures; CV risk concern (black box warning)
Raloxifene (SERM): reduces vertebral fractures only (not hip); premenopausal women; increases VTE risk

9.5 Practice Questions

Q1. A 58-year-old woman with SLE on prednisolone 10 mg/day for 2 years. DXA shows T-score −2.1 lumbar spine, −2.3 femoral neck. No prior fractures. What is the most appropriate management?

Calcium + Vitamin D + bisphosphonate (glucocorticoid-induced osteoporosis)

T-score −2.3 with chronic steroid use (≥5 mg/day ≥3 months) = high-risk GIO. ACR 2017: start oral bisphosphonate (alendronate 70 mg/week) + calcium 1000–1200 mg/day + Vitamin D 800–1000 IU/day. Minimize steroid dose (use steroid-sparing agents for SLE). Monitor DXA every 1–2 years. If unable to take oral bisphosphonate or CrCl <30 → IV zoledronic acid 5 mg/year or denosumab.

10. Autoinflammatory & Miscellaneous Rheumatic Diseases

A diverse group including adult-onset Still's disease, periodic fever syndromes, IgG4-RD, polymyalgia rheumatica, relapsing polychondritis, and reactive arthritis — often presenting diagnostic challenges in the general internal medicine setting.

10.1 Adult-Onset Still's Disease (AOSD)

AOSD is a rare systemic inflammatory disorder: quotidian fever + evanescent salmon-colored rash + arthritis. Now considered part of the hyperferritinemic syndrome spectrum.

⚡ Yamaguchi Criteria for AOSD (≥5 criteria, ≥2 major, exclude infections/malignancy/CTD)

Major: Fever ≥39°C lasting ≥1 week; arthralgia/arthritis ≥2 weeks; evanescent salmon-colored rash; WBC ≥10,000/mm³ (≥80% PMN)
Minor: Sore throat; lymphadenopathy/splenomegaly; LFT abnormal; RF and ANA negative

Key biomarker: Serum ferritin markedly elevated (>5× ULN); glycosylated ferritin <20% (normal 50–80%) highly specific. Monitor for MAS (ferritin suddenly very high + cytopenias + coagulopathy = trigger MAS workup).

Treatment: NSAIDs (mild); Prednisolone 0.5–1 mg/kg/day (moderate-severe); MTX (steroid-sparing); Biologics for refractory: Anakinra (IL-1 inhibitor, excellent for systemic disease), Canakinumab, Tocilizumab (IL-6R, better for articular). MAS complication: IL-1/IL-18 pathway → treat with anakinra + high-dose steroids ± CsA.

10.2 Polymyalgia Rheumatica (PMR)

PMR: bilateral shoulder and pelvic girdle aching + stiffness, age >50y (peak 70–75y), markedly elevated ESR/CRP, normal CK (distinguishes from myositis). Dramatic response to low-dose steroids (diagnostic!). Associated with GCA in 15–20%.

ACR/EULAR 2012 PMR Classification Criteria: Age ≥50 + bilateral shoulder aching + ESR/CRP elevated + score ≥4 (without ultrasound) or ≥5 (with ultrasound). Points: morning stiffness >45 min (2), hip pain/limitation (1), absent RF/ACPA (2), absence of peripheral synovitis (1), ultrasound: subdeltoid bursitis/glenohumeral synovitis/biceps tenosynovitis (1/2 pts).

⚡ PMR Treatment

Initial: Prednisolone 12.5–25 mg/day (not high-dose) — dramatic response within 48–72h (if not → reconsider diagnosis)
Slow taper: reduce by 1 mg/month once clinical response achieved; total duration 12–24 months
Relapse common (30–50%); increase dose back to last effective dose
Tocilizumab (PMR-SPARE trial) — steroid-sparing benefit in relapsing PMR; approved
Screen for GCA: if headache, jaw claudication, visual symptoms → urgent temporal artery evaluation

10.3 IgG4-Related Disease (IgG4-RD)

IgG4-RD is a fibro-inflammatory condition causing tumefactive lesions with IgG4-positive plasma cell infiltration and storiform fibrosis. Mimics malignancy, lymphoma, and many inflammatory conditions.

Common manifestations: Autoimmune pancreatitis (type 1, "sausage pancreas" on CT), IgG4-related sclerosing cholangitis, IgG4 orbital disease (pseudotumor), Riedel thyroiditis, IgG4 tubulointerstitial nephritis, retroperitoneal fibrosis, aortitis, submandibular gland swelling (Mikulicz).

Diagnosis: Serum IgG4 >135 mg/dL (elevated in 70%; not sensitive); biopsy essential: lymphoplasmacytic infiltration + storiform fibrosis + obliterative phlebitis + IgG4+ plasma cells >10/HPF with IgG4:IgG ratio >40%.

Treatment: Prednisolone 0.5–0.6 mg/kg/day → dramatic response; taper over 3–6 months; high relapse rate off steroids. Steroid-sparing: AZA, MTX. Rituximab (anti-CD20) excellent for relapsing/refractory — depletes IgG4-producing B cells.

10.4 Relapsing Polychondritis (RPC)

Episodic inflammatory destruction of cartilaginous structures. McAdam criteria: ≥3 of — auricular chondritis (bilateral; spares earlobes), non-erosive seronegative arthritis, nasal chondritis (saddle nose), ocular inflammation (episcleritis, scleritis), respiratory tract chondritis (larynx/trachea — most dangerous), audiovestibular dysfunction.

Key danger: Tracheobronchial involvement → dynamic airway collapse, stridor, respiratory failure. ENT evaluation mandatory. CT airway: "tracheomalacia."

Treatment: NSAIDs + dapsone (mild); Prednisolone (moderate-severe); MTX/AZA/CsA; biologics (TNFi, IL-6Ri, tocilizumab) for refractory. Airway stenting for severe tracheal collapse.

10.5 Practice Questions

Q1. A 72-year-old man presents with 3 weeks of bilateral shoulder and hip girdle aching, morning stiffness 2 hours, ESR 95 mm/hr. CK is normal. ANA and RF are negative. He responds dramatically to prednisone 20 mg/day. What should you also screen for in this patient?

Polymyalgia Rheumatica — Screen for Giant Cell Arteritis

Classic PMR: bilateral girdle aching + elevated ESR + age >50 + normal CK + dramatic response to low-dose steroids. Must screen for GCA (co-occurs in 15–20%): ask about headache (temporal), scalp tenderness, jaw claudication, visual symptoms. If any GCA symptoms → urgent temporal artery biopsy/ultrasound + high-dose steroids (40–60 mg/day). Temporal artery tenderness or pulse loss on exam = urgent investigation. Maintain vigilance throughout PMR course as GCA can develop later.

11. Rheumatologic Emergencies

Life-threatening complications of rheumatic diseases require rapid recognition and treatment. Key emergencies: MAS/HLH, Scleroderma Renal Crisis, Diffuse Alveolar Hemorrhage, CAPS, and acute monoarthritis.

11.1 Macrophage Activation Syndrome (MAS) / Secondary HLH

MAS is a life-threatening hyperinflammatory syndrome (secondary HLH) occurring in rheumatic diseases — especially AOSD, SLE, Kawasaki disease, other CTDs. Uncontrolled macrophage activation + cytokine storm (IL-18, IFN-γ).

⚡ MAS Diagnosis — 2016 Classification Criteria (Ravelli)

Fever + Ferritin ≥684 ng/mL + any 2 of:
— Platelet ≤181×10⁹/L
— AST >48 U/L
— Triglycerides ≥156 mg/dL
— Fibrinogen ≤360 mg/dL

Clinical red flags: Sudden ferritin spike (>10,000 = very suspicious; >500,000 = near-diagnostic), cytopenias in setting of inflammatory disease, consumptive coagulopathy (↓fibrinogen, ↑D-dimer), hepatosplenomegaly, encephalopathy, hemophagocytosis on bone marrow biopsy.

Treatment:

Dexamethasone (high-dose IV) or methylprednisolone pulse — first-line
Cyclosporine A (CsA) 2–7 mg/kg/day — rapid effect; first-line for MAS in sJIA/AOSD
Etoposide (VP-16): if refractory, HLH-94 protocol — CD8+ T cell/macrophage cytotoxicity
Anakinra (IL-1 inhibitor): effective for MAS in AOSD; rapid response; off-label but widely used
Ruxolitinib (JAK1/2 inhibitor): emerging evidence for refractory MAS/sHLH
Treat underlying trigger (infection, SLE flare, AOSD)

🔶 MAS vs Disease Flare (SLE/AOSD): Paradoxical worsening despite treatment + sudden ferritin spike + cytopenias + falling ESR (fibrinogen consumed) + rising LDH/AST = think MAS. ESR falls while CRP stays high = consumptive hypofibrinogenemia → clue to MAS.

11.2 Scleroderma Renal Crisis (SRC)

Acute severe hypertension (often >150/90 or new HTN) + AKI in SSc patient — typically dcSSc in first 5 years. Anti-RNA pol III antibody + high-dose corticosteroids are key risk factors.

Pathophysiology: Renal arteriolar vasospasm + intimal proliferation → MAHA (schistocytes, ↑LDH, ↓haptoglobin, Coombs−) + thrombocytopenia (TMA picture).

Treatment:

ACE inhibitor IMMEDIATELY (captopril 6.25–25 mg q8h titrating up; or lisinopril) — life-saving even if creatinine rising
Target: normalize BP within 72h
Avoid ARBs (less evidence); avoid CCBs as sole therapy
~30–50% still require dialysis short-term; ~30% can recover renal function months later with ACEi
Continue ACEi even on dialysis — may allow renal recovery
Prevention: minimize steroids in SSc; if steroids needed, keep <15 mg/day; monitor BP closely

11.3 Diffuse Alveolar Hemorrhage (DAH)

DAH = alveolar flooding with red blood cells — not always accompanied by hemoptysis (can be "silent"). Rheumatic causes: SLE (lupus pneumonitis/DAH), AAV (GPA, MPA), anti-GBM disease (Goodpasture), APS, mixed.

Clinical triad: Hemoptysis (absent in 33%) + bilateral infiltrates on CXR/CT + falling hemoglobin.

BAL (bronchoalveolar lavage): Gold standard — progressively bloodier returns from serial lavage; hemosiderin-laden macrophages (>20% = chronic); if present → confirms DAH and excludes other diagnoses.

Treatment:

IV methylprednisolone 500–1000 mg/day × 3 days (pulse) — all causes
Add Cyclophosphamide IV for AAV, severe SLE-DAH
Add Rituximab for AAV-DAH (if CYC contraindicated or PR3-ANCA)
Plasma exchange (PLEX): anti-GBM disease + SLE-DAH + CAPS-related
Mechanical ventilation (ARDS protocol if needed); packed RBC transfusion for severe anemia

🔶 SLE-DAH Emergency: New respiratory failure + bilateral infiltrates in known SLE or at SLE diagnosis → urgent BAL. Mortality 50–90% without treatment. Start pulse steroids immediately; add CYC; consider PLEX. Check ANCA + anti-GBM to rule out overlap.

11.4 Acute Monoarthritis — Approach

Always rule out septic arthritis first — it is the most dangerous cause and requires urgent drainage + antibiotics.

Condition	WBC (cells/mm³)	PMN%	Crystals	Culture
Normal	<200	<25%	—	Negative
Non-inflammatory (OA, trauma)	200–2,000	<25%	—	Negative
Inflammatory (RA, SpA, reactive)	2,000–50,000	50–75%	—	Negative
Crystal arthropathy (Gout/CPPD)	5,000–100,000	>75%	Present	Negative
Septic arthritis	>50,000 (can overlap)	>90%	—	Positive (~50%)

🔶 Key Principle: Crystals DO NOT rule out septic arthritis — they can coexist. Always send culture. WBC >100,000/mm³ = septic until proven otherwise. Most common organisms: S. aureus (any age), N. gonorrhoeae (young sexually active adults), Gram-negative bacilli (elderly, immunocompromised). Treatment: urgent arthrocentesis (therapeutic drainage) + IV antibiotics (empiric: vancomycin ± ceftriaxone); surgical washout for refractory/hip/shoulder.

11.5 Practice Questions

Q1. A 28-year-old woman with AOSD develops high spiking fever, new pancytopenia (Hb 7.2, PLT 58k, WBC 2.1k), ferritin 85,000 ng/mL, AST 210 U/L, fibrinogen 180 mg/dL. What is the complication and management?

Macrophage Activation Syndrome (MAS) — Triple therapy: steroids + cyclosporine ± anakinra

MAS complicating AOSD: ferritin >684 + PLT ≤181k + AST >48 + fibrinogen ≤360 = meets 2016 criteria. Ferritin 85,000 is extremely high → near-diagnostic. Management: (1) IV dexamethasone or pulse methylprednisolone; (2) Cyclosporine A 3–5 mg/kg/day (most evidence in AOSD-MAS); (3) Anakinra (IL-1i) — rapid response for AOSD-MAS; may add to CsA. Rule out and treat infectious trigger. Bone marrow biopsy if diagnosis uncertain. ICU-level care for severe cases. Ferritin, CBC, LFT, coagulation daily monitoring.

12. Radiology in Rheumatic Diseases

Systematic radiographic interpretation is essential for rheumatologic diagnosis. Based on Dr. Paijit Asavatanabodee's ABCDEF-SP framework (Phramongkutklao Hospital, 34th IMBR, April 2026) — the gold-standard systematic approach for rheumatology plain films.

12.1 ABCDEF-SP Systematic Approach

⚡ ABCDEF-SP Mnemonic (Dr. Paijit)

A — Alignment: Subluxation, dislocation, deformity (varus/valgus/swan-neck/ulnar drift)
B — Bone density: Diffuse (osteoporosis) vs juxta-articular (RA early); normal/increased (OA, gout)
C — Cartilage/Joint space: Symmetric (RA, SpA) vs asymmetric (OA, septic); chondrocalcinosis (CPPD)
D — Deformity of bone: Subchondral cysts/sclerosis (OA); bone destruction (septic); intraosseous tophi
E — Erosions: Marginal (RA); central gull-wing (erosive OA); punched-out overhanging (Gout = Martel's sign); pencil-in-cup (PsA)
F — Foreign bodies: Prosthesis, surgical implants, calcified tophi, soft tissue calcification
S — Soft tissue: Swelling pattern (fusiform = RA; asymmetric = gout/septic); tophi; calcinosis (SSc, DM)
P — Periosteal reaction: New bone formation; periostitis (PsA, reactive arthritis); syndesmophytes (AS); "whiskers" (diffuse idiopathic skeletal hyperostosis)

12.2 Comparative Radiographic Features — RA vs PsA vs OA vs Gout

Feature	RA	PsA	OA	Gout
Distribution	MCP, PIP, wrist; symmetric; DIP spared	DIP + any joint; asymmetric; "ray" pattern	DIP, PIP, 1st CMC, knee, hip; asymmetric	1st MTP, midfoot, ankle, knee; asymmetric
Bone density	Juxta-articular osteopenia (early sign)	Normal or increased	Normal or increased (subchondral sclerosis)	Normal (preserved — key finding)
Joint space	Symmetric narrowing	Variable; ankylosis in DIP	Asymmetric narrowing (weight-bearing)	Preserved until late
Erosions	Marginal (barebone area); ill-defined; juxta-articular	Pencil-in-cup (DIP); mouse-ear osteophytes	Absent (or central in erosive OA — gull-wing)	Punched-out lytic ± sclerotic margin; overhanging margin (Martel)
New bone	Absent	Periostitis, ankylosis, enthesophytes	Osteophytes (marginal)	Rarely in tophi area
Soft tissue	Fusiform symmetric swelling	Dactylitis ("sausage digit")	Bony enlargement	Eccentric tophaceous swelling; asymmetric
Special sign	Boutonnière/swan-neck/ulnar drift; carpal crowding	Opera glass; pencil-in-cup; ankylosis	Gull-wing (erosive); K-L grading; buttress osteophytes	Martel's sign (overhanging margin)

12.3 AS Spine vs DISH vs Spondylodiscitis vs OVCF

Feature	AS	DISH	Infective Spondylodiscitis	OVCF
Osteophytes/Ossification	Thin, vertical, marginal syndesmophytes; ALL, ISL ossification	Thick, flowing anterior osteophytes ≥4 vertebrae; non-marginal; right-sided	—	—
Disc space	Preserved early; obliterated late	Preserved; lucency between osteophyte and vertebral body	Disc destruction (both endplates)	Anterior wedge; height loss; no disc destruction
Sacroiliac joint	Bilateral sacroiliitis → ankylosis	Normal	Normal (unless pyogenic SIJ)	Normal
Posterior elements	Facet ankylosis; dagger + trolley track signs	Normal	May be involved (epidural abscess)	May fracture in severe
MRI key findings	Romanus lesion (corner erosion); fatty change; bone marrow edema (STIR)	—	Disc + endplate signal change (T2↑, T1↓); epidural/paraspinal abscess; enhancement	Vertebral edema (T1↓, T2↑/STIR); marrow replacement
CRP/ESR	Elevated (active disease)	Normal	Markedly elevated; fever	Normal or mildly elevated

🔶 Spondylodiscitis MRI vs OVCF (Dr. Paijit): Spondylodiscitis: disc involved (T2 bright disc + endplate erosion) + paraspinal/epidural abscess + strong enhancement. OVCF: disc preserved; marrow edema of vertebral body; no soft tissue mass; vacuum disc sign favors chronic/benign OVCF. Key: if disc is destroyed = infection until proven otherwise. Biopsy if diagnosis uncertain (CT-guided).

12.4 Advanced Imaging in Rheumatology

Modality	Best Use in Rheumatology	Key Finding
Musculoskeletal Ultrasound (MSUS)	Synovitis (gray-scale + PD), tenosynovitis, enthesitis, crystal deposition (gout: double contour; CPPD: chondrocalcinosis), guided injection/aspiration	PD signal = active synovitis; double contour sign = MSU crystals on cartilage
MRI	Early RA (bone marrow edema, tenosynovitis), sacroiliitis (axSpA), myositis (STIR for active inflammation), AVN, spondylodiscitis, soft tissue masses	STIR sequence: bone marrow edema/inflammation; Romanus lesion in AS
DECT (Dual-Energy CT)	Gout: urate crystal deposition (color-coded green); differentiates urate from calcium; tophi mapping; difficult joints (spine, hip)	Urate = green on DECT; calcium = blue
PET-CT (¹⁸F-FDG)	Large vessel vasculitis (TAK, GCA — aortic uptake); FUO workup; paraneoplastic/malignancy search in myositis	Aortic wall uptake = LVV activity; standardized uptake value (SUV) for quantification
Nailfold Capillaroscopy (NFC)	SSc/CTD screening; Raynaud's evaluation; early SSc pattern: giant/enlarged loops; late: avascular areas + branching/bushy loops	Scleroderma pattern: enlarged + dropout capillaries; vs normal: regular, horseshoe-shaped

12.5 Practice Questions

Q1. A 70-year-old man with known gout has a plain X-ray of his right foot showing: normal bone density, preserved joint spaces, a punched-out lytic lesion at the 1st MTP with a sclerotic margin and overhanging cortical margin. What is the name of this specific sign and what does it confirm?

Martel's sign (overhanging margin) — pathognomonic for chronic tophaceous gout

Martel's sign = punched-out lytic erosion with overhanging (mushroom-shaped / rat-bite) cortical margin due to tophus eroding bone from outside. Preserved bone density distinguishes gout from RA (where juxta-articular osteopenia is early). Preserved joint space until late distinguishes from OA. Asymmetric, eccentric soft tissue swelling from tophi. Normal/high bone density + preserved joint space + Martel's sign = classic tophaceous gout triad.

Q2. On AP X-ray of the spine, you see three vertical lines: a central line from ALL + interspinous ligament ossification, and two paravertebral lines from bilateral facet ankylosis. What are these signs called and what is the diagnosis?

Dagger sign (central) + Trolley track sign (3 lines) — Ankylosing Spondylitis

Dagger sign = single central dense line on AP view = ossification of supraspinous/interspinous ligaments + ALL. Trolley track sign = 3 parallel lines on AP view = dagger sign (centre) + bilateral facet joint/paravertebral muscle ossification (outer 2 lines). Also look for: bamboo spine (bridging syndesmophytes), squaring of vertebral bodies, bilateral sacroiliitis. These signs indicate advanced AS with complete spinal ankylosis. Distinguish from DISH: DISH = thick flowing right-sided osteophytes, no sacroiliitis, disc spaces preserved.

📚 Key References — Radiology in Rheumatology

Dr. Paijit Asavatanabodee — "Radiology in Rheumatology," 34th IMBR, PMK Hospital, April 6, 2026
EULAR Recommendations for MSUS in RA — Colebatch AN et al., Ann Rheum Dis 2013
ACR/EULAR 2022 axSpA Imaging Guidelines — Ramiro S et al., Ann Rheum Dis 2022
OMERACT Ultrasound Group — Standardized US definitions for synovitis scoring