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Complete Guide: Arthritis Spectrum, SLE, Thyroid Storm, Wernicke's Encephalopathy & Hospital-Acquired Pneumonia

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1. SERONEGATIVE RHEUMATOID ARTHRITIS

• Does NOT respond as well to B-cell depletion with rituximab
• Does NOT have elevated Tph cells (CD4+ T-cell subtype that helps B cells) in blood or synovial fluid
• The HLA shared epitope association is seen strongly in ACPA-positive RA but NOT in ACPA-negative RA, suggesting different pathogenic mechanisms
• Less likely to develop extra-articular manifestations (nodules, vasculitis, Felty syndrome)
• Generally milder course but this is not universal

• Symmetrical small joint polyarthritis - MCP, PIP, wrists, MTP joints
• Spares DIP joints and spine (early)
• Morning stiffness >1 hour
• Systemic features: fatigue, low-grade fever, weight loss

• Rheumatology, 2-Volume Set (Elsevier, 2022)
• Goldman-Cecil Medicine, International Edition

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2. REACTIVE ARTHRITIS

• GI pathogens: Salmonella typhimurium, Yersinia enterocolitica, Shigella flexneri, Campylobacter jejuni
• GU pathogens: Chlamydia trachomatis (most common overall)

• Follows 2-7% of GI epidemic infections; up to 20% of HLA-B27 positive individuals
• HLA-B27 is the key genetic risk factor - confers risk for onset AND for axial involvement and chronicity
• Genetic variants in TLR-2 implicate innate immunity

• Bacterial antigens can be found in joints by immunofluorescence
• PCR on synovial tissue most consistently positive in post-Chlamydia ReA (viable Chlamydia may persist in joints in metabolically altered state)
• Dactylitis results from inflammation of joint capsule, entheses, periarticular structures, and periosteal bone simultaneously

• Asymmetric oligoarthritis of large joints (knee, ankle, foot most common)
• Sacroiliitis - typically asymmetric (contrast with AS which is symmetric)
• Enthesitis - Achilles tendon, plantar fascia
• Dactylitis - "sausage digit"
• Skin: Keratoderma blennorrhagica (hyperkeratotic skin lesions on palms/soles), circinate balanitis
• Eyes: conjunctivitis, anterior uveitis
• Mucous membranes: painless oral ulcers
• Radiologically: bulky, non-marginal, asymmetric syndesmophytes (contrast with AS's marginal symmetric ones)

• NSAIDs (indomethacin, naproxen) - first line
• Antibiotics: may help in acute post-Chlamydial disease; limited evidence in GI-triggered
• Sulfasalazine for persistent peripheral arthritis
• TNF inhibitors for refractory cases
• Goldman-Cecil Medicine; Firestein & Kelley's Textbook of Rheumatology; Robbins Pathologic Basis of Disease

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3. ENTEROPATHIC (IBD) ARTHRITIS

• Peripheral arthritis: 10-20% in Crohn's, 5-10% in UC
• Axial disease (sacroiliitis/spondylitis): 2-7% in both Crohn's and UC
• HLA-B27 found in 50% of those with axial involvement (not peripheral)
• Extra-articular features more common in Crohn's than UC

• Peripheral arthritis is typically inflammatory, nonerosive, predominantly large joints (knees, ankles, wrists)
• Associated with other extra-enteric features: erythema nodosum, iritis
• Musculoskeletal features may PRECEDE gut symptoms
• Axial disease follows an independent course

• Treat underlying IBD - this often improves peripheral arthritis
• NSAIDs: use cautiously (may exacerbate IBD)
• Sulfasalazine for peripheral disease
• Anti-TNF agents (infliximab, adalimumab): effective for both gut and joint disease - preferred for axial disease
• Goldman-Cecil Medicine; ROSEN's Emergency Medicine

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4. SPONDYLOARTHROPATHY (Spondyloarthritis)

1. Ankylosing spondylitis (AS) - prototype
2. Reactive arthritis
3. Psoriatic arthritis
4. Enteropathic arthritis
5. Undifferentiated spondyloarthritis
6. Juvenile spondyloarthritis

• HLA-B27 association (strongest in AS ~90%)
• Sacroiliitis and/or spondylitis
• Enthesitis (inflammation at tendon/ligament bone insertions)
• Asymmetric peripheral oligoarthritis (large joints)
• Dactylitis
• Extra-articular features (uveitis, skin, bowel, genital lesions)
• Absence of RF and anti-CCP (seronegative)
• Family clustering

• Axial (radiographic AS): Bamboo spine, bilateral symmetric sacroiliitis on X-ray, syndesmophytes
• Non-radiographic axial SpA: Sacroiliac joint inflammation on MRI only, no X-ray changes yet

• Modified New York criteria: sacroiliitis grade ≥2 bilaterally or grade 3-4 unilaterally PLUS at least 1 clinical criterion (low back pain >3 months improved by exercise, limited lumbar flexion, limited chest expansion)
• Schober test assesses lumbar spine mobility
• HLAB27 positive in ~90%
• ESR/CRP often only mildly elevated or normal
• Radiographs: bilateral symmetric sacroiliitis, marginal syndesmophytes ("bamboo spine")
• MRI detects early disease before X-ray changes

• 1 in 4 psoriasis patients develop it
• Patterns: asymmetric oligoarthritis, symmetric RA-like, DIP predominant, psoriatic spondylitis, arthritis mutilans
• Dactylitis in 40-50%; enthesitis in 30-50%
• Nail changes: pitting, onycholysis, oil drop sign, subungual keratosis
• HLA-Cw6 (skin); HLA-B27 (axial disease)
• CASPAR criteria for classification

• NSAIDs (indomethacin, diclofenac, naproxen): first line for axial and peripheral disease. Goal: sufficient relief to allow sustained exercise program
• Physiotherapy and exercise: critical for maintaining posture and spinal mobility in AS
• Sulfasalazine: effective for peripheral arthritis; NOT effective for axial disease
• TNF inhibitors: infliximab 5mg/kg IV q8w, adalimumab 40mg SC q2w, etanercept 50mg SC weekly, golimumab 50mg SC monthly, certolizumab 200mg SC q2w
• IL-17A inhibitors: secukinumab 150mg SC weekly x5 then monthly; ixekizumab 80mg SC q2-4w - highly effective for AS and psoriatic arthritis
• JAK inhibitors: upadacitinib 15mg daily, tofacitinib 5mg twice weekly - approved options for axial SpA
• Intra-articular steroids: sacroiliac joint injection (80% respond); peripheral joints respond less dramatically than in RA
• Systemic steroids: generally NOT recommended for axial disease
• Goldman-Cecil Medicine; Firestein & Kelley's Textbook of Rheumatology

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5. UNDIFFERENTIATED ARTHRITIS

• In the ILAR classification, undifferentiated JIA applies to cases that:
  • Fulfill criteria for NO other JIA category, OR
  • Fulfill criteria for TWO OR MORE other JIA categories
  • ~15% of JIA cases in Scandinavian epidemiologic studies
• Most have oligoarthritis (persistent or extended) or enthesitis-related features
• Main exclusion reason: first-degree relative with psoriasis, or fulfillment of criteria for more than one category

• Inflammatory joint pain and swelling not fitting other diagnoses
• May have low-positive or borderline ANA/RF
• Elevated CRP/ESR
• Monitor for evolution: synovitis on MRI/ultrasound, erosions

• Rheumatology, 2-Volume Set (Elsevier, 2022)

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6. ADULT-ONSET STILL'S DISEASE (AOSD)

• Cytokine storm: markedly elevated TNF, IL-6, IL-8, IL-18, IFN-alpha
• IL-1 plays a central role (anakinra is dramatically effective)
• Th1-dominated cytokine profile
• Hyperferritinemia driven by macrophage activation; <20% of ferritin is glycosylated (key diagnostic marker)
• Macrophage activation syndrome (MAS) overlap: 40% of MAS cases meet AOSD criteria; ferritin >3000 ng/mL has 85% sensitivity for MAS

1. Fever ≥39°C, spiking, daily, for ≥1 week
2. Arthralgia or arthritis ≥2 weeks
3. Non-pruritic salmon-pink macular or maculopapular rash (appears during fever spikes)
4. WBC ≥10,000/mm³ with ≥80% granulocytes

1. Sore throat
2. Lymphadenopathy and/or splenomegaly
3. Liver dysfunction (elevated AST/ALT)
4. Negative RF and ANA

• Serum ferritin: massively elevated (often >10,000 ng/mL) - most characteristic finding
• Glycosylated ferritin <20%: highly specific
• IL-18: extremely elevated, correlated with ferritin and disease severity
• CRP, ESR, PCT: markedly elevated
• WBC: leukocytosis with neutrophilia
• Negative ANA, RF, ACPA
• LFTs: elevated (hepatitis-like picture in severe cases)

1. Monocyclic (self-limited): single episode resolving within 1 year (~20%)
2. Polycyclic (intermittent): recurrent episodes with disease-free intervals (~30%)
3. Chronic (persistent): progressive arthritis, organ damage (~50%)

• Macrophage activation syndrome (MAS) - life-threatening
• Cardiac tamponade, pleuritis
• Hepatic failure (rare but serious)
• DIC

• First line: NSAIDs (aspirin in high doses, or indomethacin)
• Second line: Glucocorticoids (prednisone 0.5-1 mg/kg/day) - effective for systemic features
• Third line (refractory): Methotrexate, hydroxychloroquine, azathioprine
• Biologics for refractory AOSD:
  • IL-1 blockers: Anakinra (rapid, dramatic response) - first choice biologic; canakinumab for sustained response
  • IL-6 blockers: Tocilizumab 5-8 mg/kg IV q2-4 weeks - especially for articular-predominant or when IL-1 fails; marked corticosteroid-sparing effect
  • IL-1 treatment should be tried first before IL-6 unless joint erosion predominates
• Firestein & Kelley's Textbook of Rheumatology; Rheumatology, 2-Volume Set (Elsevier, 2022)

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7. FELTY SYNDROME

1. Rheumatoid Arthritis (seropositive, long-standing, nodular, deforming)
2. Splenomegaly
3. Neutropenia (absolute neutrophil count <2,000/µL)

• Rare (~1% of RA patients); becoming rarer with modern RA treatment
• Occurs after many years of active RA (typically >10 years)
• Almost always RF-positive and ACPA-positive
• HLA-DRB1*0401 (part of shared epitope) - due to linkage disequilibrium
• Paradoxically, active synovitis may be absent at the time Felty syndrome develops

• Lower extremity leg ulcers (indolent)
• Hyperpigmentation of skin
• Positive ANA (~30%)
• Hepatomegaly
• Lymphadenopathy
• Thrombocytopenia
• Hypocomplementemia
• High levels of immune complexes

• Bone marrow is usually normal or hyperplastic (not the problem)
• Proinflammatory cytokines suppress myelopoiesis (inhibitors reduce marrow response)
• Splenic sequestration
• Anti-neutrophil antibodies

• Bacterial infections - major cause of mortality. Risk correlates directly with PMN count <100/µL
• Increased risk of lymphoproliferative malignancy (NHL, large granular lymphocyte leukemia)

• Neutropenia + large granular lymphocytosis in blood and bone marrow
• LGL cells = in vivo-activated clonal cytotoxic T cells
• Low-grade lymphoproliferative disorder
• Rapidly progressive malignancy is unusual

• Methotrexate - first line; often improves neutropenia and joint disease
• Glucocorticoids - short-term
• G-CSF (granulocyte colony-stimulating factor) - for severe neutropenia/infection
• Splenectomy - for refractory cases; improves neutropenia but may not control RA
• Rituximab - second-line biologic for refractory Felty syndrome (B-cell depletion)
• Rheumatology, 2-Volume Set (Elsevier, 2022); Goldman-Cecil Medicine

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8. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

ACR Classification Criteria (≥4 of 11 = SLE)

1. Malar rash - butterfly rash over cheeks/nose, sparing nasolabial folds
2. Discoid rash - erythematous plaques with keratotic scaling; follicular plugging; atrophic scarring
3. Photosensitivity - skin rash after UV exposure
4. Oral ulcers - usually painless (21% of cases)
5. Arthritis - nonerosive, ≥2 peripheral joints with tenderness/swelling/effusion
6. Serositis - pleuritis or pericarditis
7. Renal disorder - proteinuria >0.5g/day OR cellular casts
8. Neurologic disorder - seizures or psychosis (in absence of other cause)
9. Hematologic disorder - hemolytic anemia, OR leukopenia <4000/mm³ on ≥2 occasions, OR lymphopenia <1500/mm³, OR thrombocytopenia <100,000/mm³
10. Immunologic disorder - anti-dsDNA, anti-Sm antibodies, antiphospholipid antibodies (anticardiolipin IgG/IgM, lupus anticoagulant, false-positive VDRL)
11. Positive ANA

SLICC 2012 Criteria (more sensitive):

• Acute cutaneous LE: Butterfly malar rash (begins on malar area and bridge of nose), photosensitive
• Subacute cutaneous LE (SCLE): Photosensitive annular/papulosquamous lesions
• Discoid LE (DLE): Chronic, scarring - may be isolated or part of SLE
• Bullous lupus: Subepidermal blisters
• Oral/palatal ulcers
• Vasculitis: periungual erythema, livedo reticularis, Raynaud's phenomenon
• Hair loss (lupus hair, frontal alopecia)

• Hydroxychloroquine (HCQ): cornerstone therapy for ALL patients with SLE (reduces flares, organ damage, mortality, thrombosis)
• NSAIDs: for arthritis, serositis (with caution re: renal function)
• Low-dose steroids for mild-moderate disease; pulse methylprednisolone for severe flares
• Azathioprine, mycophenolate mofetil (MMF): steroid-sparing maintenance; MMF preferred for nephritis maintenance
• Cyclophosphamide: severe nephritis (class III/IV), CNS lupus, severe vasculitis
• Belimumab (anti-BLyS): FDA-approved biologic; reduces flares and steroid dose
• Anifrolumab (anti-IFN receptor): newer biologic for moderate-severe non-renal SLE
• Voclosporin + MMF: approved for lupus nephritis
• Andrews' Diseases of the Skin; Goldman-Cecil Medicine; Bradley & Daroff's Neurology

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9. THYROID STORM

• Surgery (thyroid or non-thyroid)
• Trauma
• Infection/sepsis
• Iodine load (contrast, amiodarone)
• Parturition/labor
• Acute MI, pulmonary embolism
• Hyperemesis gravidarum, preeclampsia
• Diabetic ketoacidosis
• Stopping antithyroid drugs abruptly

• Marked pyrexia: 104-106°F (40-41°C)
• Extreme tachycardia (often disproportionate to fever level)
• Altered mental status: agitation, delirium, psychosis, coma
• Cardiovascular collapse: CHF, hypotension, AF and other supraventricular arrhythmias, Takotsubo cardiomyopathy
• GI symptoms: nausea, vomiting, diarrhea, abdominal pain
• Hepatic failure: cholestatic jaundice (poor prognosis)
• Background hyperthyroid signs: goiter, exophthalmos, lid lag, stare, tremor, ophthalmopathy

• Propylthiouracil (PTU) 200-250 mg q4h PO/NG - preferred over methimazole in storm because it also blocks peripheral T4→T3 conversion
• OR Methimazole 20-30mg q4-6h

• Potassium iodide (SSKI) or Lugol's solution - blocks Wolff-Chaikoff effect; must be given AFTER PTU/MMI to prevent using iodide as hormone substrate

• Beta-blockers: Propranolol (IV/PO) - blocks adrenergic symptoms AND inhibits T4→T3 conversion; use esmolol (short-acting) for titration in unstable patients; use cautiously in severe heart failure (may worsen)
• Glucocorticoids (hydrocortisone 100mg IV q8h or dexamethasone) - block T4→T3 conversion, treat relative adrenal insufficiency, may have immunologic benefit

• IV fluids for volume depletion
• Cooling measures for hyperthermia (cooling blankets, acetaminophen - NOT aspirin: displaces T4 from TBG)
• Treat precipitating cause (antibiotics if infection)
• Rate control for AF (digoxin in failure setting; avoid calcium channel blockers if possible)
• Bile acid sequestrants (cholestyramine) to block enterohepatic recirculation of thyroid hormones
• ROSEN's Emergency Medicine; Braunwald's Heart Disease; Cummings Otolaryngology

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10. WERNICKE'S ENCEPHALOPATHY

• Alcoholism (most common - poor intake + malabsorption)
• Prolonged fasting/starvation
• Malabsorption syndromes (Crohn's, celiac, bariatric surgery)
• Hyperemesis gravidarum
• Glucose infusion without thiamine in depleted patients (CLASSIC trigger - IV glucose without thiamine replacement precipitates/worsens WE)
• Hemodialysis (thiamine is water-soluble, lost in dialysis - 33% prevalence of thiamine deficiency in dialysis encephalopathy patients)
• Cancer/chemotherapy
• AIDS
• Digitalis poisoning

1. Ocular dysfunction - nystagmus, conjugate gaze palsy, lateral rectus palsy (CN VI), complete ophthalmoplegia
2. Cerebellar ataxia - gait ataxia predominantly
3. Confusion/encephalopathy - global confusional state, disorientation, inattention

• Mamillary bodies (most characteristic)
• Periaqueductal gray matter
• Medial thalami
• Third ventricular walls
• Pons and medulla
• Basal ganglia
• Rarely: cortex (worst prognosis)

• T2/FLAIR hyperintensity bilaterally and symmetrically in:
  • Medial thalami (most frequently involved)
  • Periventricular regions of third ventricle
  • Mamillary bodies (highly specific)
  • Periaqueductal region
  • Dorsal medulla
• DWI may show restricted diffusion in acute phase
• Mamillary body atrophy on follow-up MRI

• Irreversible amnestic syndrome
• Anterograde amnesia (inability to form new memories) - most prominent
• Retrograde amnesia (loss of old memories)
• Confabulation (fabrication of false memories)
• Relatively preserved other cognitive functions
• Wernicke-Korsakoff syndrome = the continuum

• Thiamine IV/IM 500mg three times daily x 3 days, then 250mg daily x 5 days (Pabrinex/B-vitamin complex high-dose)
• Always give thiamine BEFORE glucose (IV glucose in thiamine-depleted state can precipitate/worsen WE)
• Oral supplementation insufficient for established WE
• Treatment reverses ocular findings rapidly (within hours-days); ataxia recovers over weeks; confusion over days-weeks; amnesia may not fully recover

• Grainger & Allison's Diagnostic Radiology; Bradley & Daroff's Neurology; Goldman-Cecil Medicine

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11. HOSPITAL-ACQUIRED PNEUMONIA (HAP)

• Most common hospital-acquired infection in the ICU
• Increases ICU stay by 4-13 days
• Mortality: 20-50% for VAP; lower for non-ventilated HAP
• Blood cultures positive in <15% of cases

• Aspiration of oropharyngeal secretions (most common route) - colonized with hospital organisms
• Microaspiration around endotracheal tube cuff (VAP)
• Hematogenous seeding (rare)
• Impaired mucociliary clearance, cough reflex, and immune defenses in hospitalized patients
• Gram-negative colonization of oropharynx within 48-72 hours of hospitalization

• Prior IV antibiotics in past 90 days
• Septic shock at time of VAP
• ARDS before VAP
• ≥5 days of hospitalization before pneumonia
• Acute renal replacement therapy
• Local ICU antibiogram showing >10-20% MRSA or >10% Gram-negative resistance

• New or progressive pulmonary infiltrate on chest X-ray/CT
• PLUS at least two of: fever >38°C, leukocytosis or leukopenia, purulent secretions
• Clinical Pulmonary Infection Score (CPIS): Incorporates fever, WBC, secretions, oxygenation, X-ray, culture

• ATS/IDSA 2016 guidelines recommend noninvasive sampling with semiquantitative cultures (sputum, endotracheal aspirate) rather than invasive BAL/protected brush sampling
• Obtain cultures BEFORE starting antibiotics if possible
• Blood cultures (low yield, <15% positive)
• Legionella and pneumococcal urinary antigens
• Procalcitonin helps guide antibiotic duration (target <0.5 ng/mL for stopping)

• Ceftriaxone, OR
• Ampicillin-sulbactam, OR
• Ertapenem, OR
• Levofloxacin/moxifloxacin
• (Penicillin allergy: quinolone, or clindamycin + aztreonam)

• Antipseudomonal beta-lactam: piperacillin-tazobactam, cefepime, ceftazidime, imipenem, meropenem, ceftolozane-tazobactam, ceftazidime-avibactam
• PLUS antipseudomonal quinolone (ciprofloxacin, high-dose levofloxacin) OR aminoglycoside
• PLUS (if MRSA risk ≥10-20%): linezolid OR vancomycin

• After 48-72 hours, review cultures and clinical response
• Switch to monotherapy targeting identified organism
• Use narrowest effective spectrum
• Antibiogram-guided de-escalation reduces resistance and side effects
• Pseudomonas: can stop aminoglycoside after 5 days, continue with single sensitive agent
• Duration: generally 7-8 days (vs. longer courses previously used)

• Each ICU should have a local antibiogram guiding empiric choices
• Use different antibiotic class from what patient received in past 2 weeks
• Pharmacokinetic/pharmacodynamic dosing (weight-based, extended infusions for beta-lactams)
• Anaerobic coverage generally not needed in VAP (unlike non-ventilated HAP with macroaspiration)
• Non-ventilated HAP has lower MDR pathogen frequency and better host immunity → monotherapy often sufficient
• Harrison's Principles of Internal Medicine (2025); Fishman's Pulmonary Diseases; Robbins Pathologic Basis of Disease

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Quick Comparison Summary

All content sourced from: Rheumatology 2-Volume Set (Elsevier 2022), Goldman-Cecil Medicine, Firestein & Kelley's Textbook of Rheumatology, Andrews' Diseases of the Skin, ROSEN's Emergency Medicine, Braunwald's Heart Disease, Grainger & Allison's Diagnostic Radiology, Bradley & Daroff's Neurology in Clinical Practice, Harrison's Principles of Internal Medicine (22e, 2025), Fishman's Pulmonary Diseases and Disorders.