Rheumatology — Autoinflammatory

111. Adult-Onset Still Disease (AOSD)

/AdultOnsetStillDisease · quotidian fever + evanescent salmon rash + arthritis + VERY high ferritin · a diagnosis of exclusion (rule out infection/malignancy) · watch for macrophage activation syndrome · Super Compact

Sx: the classic triad — daily (quotidian) spiking high fevers, an evanescent salmon-pink rash (appears with fever, fades), and arthritis/arthralgia; plus sore throat, lymphadenopathy, hepatosplenomegaly, serositis, myalgia; strikingly high ferritin with low glycosylated fraction; leukocytosis (neutrophilic) · (adult-onset Still disease is a diagnosis of exclusion — infection and malignancy, especially lymphoma, must be ruled out first because they present identically with fever and high ferritin — and the feared complication is macrophage activation syndrome, a hyperinflammatory crisis that can be fatal and which an inpatient Still patient must be monitored for)

Neg: denies infection/malignancy not excluded (Still is a diagnosis of exclusion — rule out sepsis, endocarditis, lymphoma, leukemia first) · denies missed macrophage activation syndrome (sudden cytopenias, very high ferritin, falling ESR/fibrinogen, high triglycerides, hepatic dysfunction — emergency) · denies missed serositis (pericardial/pleural) · denies overlooking sore throat/lymphadenopathy clues · denies myocarditis

SHx: fever pattern/duration, rash timing (with fevers), sore throat, joint symptoms, prior similar episodes, infection exposures, B-symptoms (malignancy concern), medications, recent illness

Etiology: systemic autoinflammatory disorder of unknown cause with innate immune activation and prominent IL-1, IL-6, IL-18 cytokine drive; the same biology that fuels disease can tip into macrophage activation syndrome (secondary HLH); not autoantibody-driven (ANA/RF typically negative)

RF: young-to-middle-aged adults · bimodal age distribution · no clear modifiable risk factors

Data: markedly elevated ferritin (often >1000, sometimes very high; low glycosylated ferritin fraction supports), high CRP/ESR, neutrophilic leukocytosis, elevated LFTs; ANA and RF typically NEGATIVE (helps distinguish from other rheumatic disease); extensive exclusion of infection (cultures, viral serologies, echo for endocarditis) and malignancy (imaging, consider marrow/lymph node biopsy for lymphoma); Yamaguchi criteria used for diagnosis; if deteriorating, MAS/HLH workup (triglycerides, fibrinogen, soluble CD25, marrow for hemophagocytosis)

DDx: AOSD · infection (sepsis, endocarditis, viral — EBV/CMV/HIV) · lymphoma/leukemia · other malignancy · other autoimmune/vasculitis · drug reaction (DRESS) · macrophage activation syndrome · periodic fever syndromes

Home Meds: reconcile; review drugs that could cause DRESS (mimic); plan NSAID/steroid then IL-1 or IL-6 biologic per course; bone/GI/glucose protection with steroids; avoid empiric immunosuppression until infection/malignancy reasonably excluded

Plan

CONSULT: Rheumatology (diagnosis, biologic therapy) · Infectious Disease + Hematology/Oncology (exclude mimics — infection, lymphoma) · ICU if MAS/HLH or organ-threatening

– FIRST exclude infection and malignancy (the diagnosis is one of exclusion): cultures, viral serologies, echocardiogram (endocarditis), cross-sectional imaging, and consider lymph node/bone marrow biopsy to exclude lymphoma before committing to immunosuppression
– ESTABLISH the diagnosis by Yamaguchi criteria (fever, arthralgia, rash, leukocytosis as majors; sore throat, lymphadenopathy/hepatosplenomegaly, LFT abnormality, negative ANA/RF as minors) with exclusions satisfied
– TREAT (escalating):
  • NSAIDs for mild disease/initial symptom control
  • Glucocorticoids — prednisone ~0.5–1 mg/kg/day for significant systemic disease, then taper
  • Biologics for refractory/steroid-dependent/severe: IL-1 inhibitors (anakinra, canakinumab) or IL-6 inhibitor (tocilizumab) — highly effective given the cytokine biology; methotrexate as a steroid-sparing DMARD, per rheumatology
– MONITOR FOR MACROPHAGE ACTIVATION SYNDROME: watch for sudden cytopenias, a rising ferritin with a paradoxically falling ESR and fibrinogen, high triglycerides, hepatic dysfunction, and coagulopathy → if MAS develops, treat urgently as HLH (high-dose steroids ± anakinra ± etoposide-based therapy) with ICU/hematology (see the MAS/HLH approach)
– Adult-onset Still disease is a clinical pattern that screams "look harder before you believe it": daily spiking fevers, a salmon rash that comes and goes with the fever, arthritis, and a ferritin that can be astronomically high. The problem is that infection — sepsis, endocarditis, EBV — and malignancy, especially lymphoma, produce exactly this picture, so Still disease is a diagnosis of exclusion, and the inpatient work is largely the work of ruling those out, sometimes down to a lymph node or marrow biopsy, before you reach for immunosuppression. Once you're confident, the treatment tracks the cytokine biology beautifully — NSAIDs and steroids first, then IL-1 inhibitors like anakinra or the IL-6 inhibitor tocilizumab for anything refractory. The one thing you cannot take your eye off is macrophage activation syndrome: the same hyperinflammation can suddenly tip into a secondary HLH, and the tell is counterintuitive — the ferritin climbs while the ESR and fibrinogen fall, because consumptive coagulopathy is setting in. That's an emergency.
– SUPPORTIVE: manage serositis, monitor for myocarditis, hydration, symptom control
– PT/OT: per joint involvement/deconditioning
– Trend: fever curve, rash, ferritin/CRP/ESR, CBC (cytopenias → MAS), LFTs, fibrinogen/triglycerides (MAS surveillance), response to therapy, exclusion workup results
– Escalation triggers: macrophage activation syndrome (cytopenias + rising ferritin + falling ESR/fibrinogen + high triglycerides + hepatic dysfunction) → ICU + urgent HLH-directed therapy + hematology; myocarditis/tamponade → cardiology + ICU; respiratory/organ failure → ICU; lymphoma identified → oncology
– Discharge checklist: infection + malignancy excluded + diagnosis established; treatment regimen (NSAID/steroid ± IL-1/IL-6 biologic ± methotrexate) + taper; bone/GI/glucose protection; rheumatology follow-up; patient + team educated on MAS warning signs; return precautions (recurrent high fevers, new bruising/bleeding, abdominal pain, breathlessness, confusion)

111. Adult-Onset Still Disease (AOSD)

/AdultOnsetStillDisease · complete reference · quotidian fever + salmon rash + arthritis + very high ferritin · a diagnosis of exclusion, watch for macrophage activation syndrome · Full Card

Symptoms / Associated Sx

• The classic triad — daily (quotidian) spiking high fevers, an evanescent salmon-pink rash (appearing with the fever and fading), and arthritis or arthralgia

• Plus a sore throat, lymphadenopathy, hepatosplenomegaly, serositis, and myalgia; a strikingly high ferritin with a low glycosylated fraction; a neutrophilic leukocytosis

• Adult-onset Still disease is a diagnosis of exclusion — infection and malignancy, especially lymphoma, must be ruled out first because they present identically with fever and a high ferritin — and the feared complication is macrophage activation syndrome, a hyperinflammatory crisis that can be fatal and which an inpatient Still patient must be monitored for

Neg

• Pt denies infection or malignancy not being excluded (Still disease is a diagnosis of exclusion — rule out sepsis, endocarditis, lymphoma, and leukemia first) and a missed macrophage activation syndrome (sudden cytopenias, a very high ferritin, a falling ESR and fibrinogen, high triglycerides, hepatic dysfunction — an emergency).

• Pt denies missed serositis (pericardial or pleural) and overlooking sore throat or lymphadenopathy clues.

• Pt denies myocarditis.

Social History (SHx)

• The fever pattern and duration, the rash timing (with the fevers), and a sore throat.

• Joint symptoms, prior similar episodes, and infection exposures.

• B-symptoms (malignancy concern), medications, and recent illness.

Main Etiology

• A systemic autoinflammatory disorder of unknown cause with innate immune activation and a prominent IL-1, IL-6, and IL-18 cytokine drive

• The same biology that fuels the disease can tip into macrophage activation syndrome (secondary HLH)

• It is not autoantibody-driven (ANA and rheumatoid factor are typically negative)

RF

• Non-modifiable: young-to-middle-aged adults and a bimodal age distribution; there are no clear modifiable risk factors.

Data

• A markedly elevated ferritin (often above 1000, sometimes very high; a low glycosylated ferritin fraction supports it), a high CRP/ESR, a neutrophilic leukocytosis, and elevated LFTs

• ANA and rheumatoid factor are typically negative (which helps distinguish it from other rheumatic disease)

• Extensive exclusion of infection (cultures, viral serologies, an echo for endocarditis) and malignancy (imaging, consider a marrow or lymph node biopsy for lymphoma)

• The Yamaguchi criteria are used for diagnosis; if the patient is deteriorating, a MAS/HLH workup (triglycerides, fibrinogen, soluble CD25, marrow for hemophagocytosis).

DDx

AOSD · infection (sepsis, endocarditis, viral — EBV, CMV, HIV) · lymphoma or leukemia · other malignancy · other autoimmune disease or vasculitis · a drug reaction (DRESS) · macrophage activation syndrome · periodic fever syndromes

Home Meds

• Reconcile medications; review drugs that could cause DRESS (a mimic).

• Plan NSAIDs or steroids then an IL-1 or IL-6 biologic per the course; bone, GI, and glucose protection with steroids.

• Avoid empiric immunosuppression until infection and malignancy are reasonably excluded.

Plan

CONSULT: Rheumatology (diagnosis, biologic therapy) · Infectious Disease and Hematology/Oncology (exclude mimics — infection, lymphoma) · ICU if MAS/HLH or organ-threatening disease

• First exclude infection and malignancy (the diagnosis is one of exclusion): cultures, viral serologies, an echocardiogram (endocarditis), cross-sectional imaging, and consider a lymph node or bone marrow biopsy to exclude lymphoma before committing to immunosuppression.

• Establish the diagnosis by the Yamaguchi criteria (fever, arthralgia, rash, and leukocytosis as majors; sore throat, lymphadenopathy or hepatosplenomegaly, an LFT abnormality, and a negative ANA and RF as minors) with the exclusions satisfied.

• Treat (escalating):

• • NSAIDs for mild disease or initial symptom control.

• • Glucocorticoids — prednisone ~0.5–1 mg/kg/day for significant systemic disease, then taper.

• • Biologics for refractory, steroid-dependent, or severe disease: IL-1 inhibitors (anakinra, canakinumab) or an IL-6 inhibitor (tocilizumab) — highly effective given the cytokine biology; methotrexate as a steroid-sparing DMARD, per rheumatology.

• Monitor for macrophage activation syndrome: watch for sudden cytopenias, a rising ferritin with a paradoxically falling ESR and fibrinogen, high triglycerides, hepatic dysfunction, and coagulopathy → if MAS develops, treat urgently as HLH (high-dose steroids with possible anakinra and etoposide-based therapy) with ICU and hematology (see the MAS/HLH approach).

• Supportive care: manage serositis, monitor for myocarditis, ensure hydration, and control symptoms.

• PT/OT: per joint involvement or deconditioning.

• Trend: the fever curve, the rash, ferritin, CRP, and ESR, CBC (cytopenias → MAS), LFTs, fibrinogen and triglycerides (MAS surveillance), the response to therapy, and the exclusion workup results.

• Escalation triggers: macrophage activation syndrome (cytopenias with a rising ferritin, a falling ESR and fibrinogen, high triglycerides, and hepatic dysfunction) → ICU, urgent HLH-directed therapy, and hematology; myocarditis or tamponade → cardiology and ICU; respiratory or organ failure → ICU; lymphoma identified → oncology.

• Discharge checklist: infection and malignancy excluded and the diagnosis established; a treatment regimen (NSAIDs or steroids with a possible IL-1 or IL-6 biologic and methotrexate) and a taper; bone, GI, and glucose protection; rheumatology follow-up; the patient and team educated on MAS warning signs; return precautions for recurrent high fevers, new bruising or bleeding, abdominal pain, breathlessness, or confusion.

Red Flags

• Fever with a very high ferritin → could be lymphoma, endocarditis, or sepsis; exclude before calling it Still disease.

• A rising ferritin with a falling ESR and fibrinogen → macrophage activation syndrome; a hyperinflammatory emergency.

• New cytopenias with hepatic dysfunction and high triglycerides → secondary HLH; treat urgently.

• A new murmur or embolic signs → endocarditis mimicking Still disease; echo before immunosuppressing.

• Lymphadenopathy with B-symptoms → exclude lymphoma, often with a node biopsy.

Senior IM Resident Pearls

• It's a diagnosis of exclusion. The fever-rash-ferritin picture is shared by sepsis, endocarditis, and lymphoma — rule those out first.

• The rash is a clue you can time. The salmon rash comes and goes with the fever spikes — ask the nurses to look during a spike.

• Negative ANA and RF help. Their absence nudges away from classic autoimmune disease toward this autoinflammatory one.

• The cytokine biology guides therapy. IL-1 and IL-6 inhibitors work strikingly well in refractory disease.

• Watch for the MAS tell. A climbing ferritin with a falling ESR and fibrinogen is the counterintuitive signature of macrophage activation syndrome.

• Ferritin tracks activity. It's a useful marker to follow the disease and to catch the tip into MAS.

• Common mistake: immunosuppressing the fever as "Still disease" before the lymphoma or endocarditis workup is complete.

Rheumatology — Spondyloarthritis

112. Reactive Arthritis

/ReactiveArthritis · post-infectious (GU or GI) asymmetric oligoarthritis · "can't see, can't pee, can't climb a tree" · HLA-B27-associated · exclude septic arthritis, treat with NSAIDs · Super Compact

Sx: asymmetric oligoarthritis of the lower extremities (knees, ankles) developing days-weeks after a genitourinary (Chlamydia) or gastrointestinal (Salmonella, Shigella, Campylobacter, Yersinia) infection; classic extra-articular triad "can't see, can't pee, can't climb a tree" — conjunctivitis/uveitis, urethritis, arthritis; plus enthesitis (Achilles), dactylitis ("sausage digit"), keratoderma blennorrhagicum, circinate balanitis, low back pain (sacroiliitis) · (an acute warm joint after an infection still has to have septic arthritis excluded by aspiration — reactive arthritis is sterile, the joint inflammation is post-infectious rather than an active joint infection, but you confirm that with the tap rather than assuming it)

Neg: denies missed septic/disseminated gonococcal arthritis (aspirate to exclude active infection) · denies missed ongoing treatable triggering infection (esp Chlamydia — treat it) · denies missing uveitis (needs ophthalmology) · denies missing HIV (can be associated/severe) · denies missing other spondyloarthritis/psoriatic features

SHx: recent GU/GI infection (1–4 weeks prior), sexual history (Chlamydia), diarrheal illness, eye/urinary symptoms, skin/nail changes, back pain, HLA-B27/family history of spondyloarthritis, HIV risk

Etiology: immune-mediated (sterile) arthritis triggered by an antecedent extra-articular infection (enteric or urogenital) in a genetically predisposed host (HLA-B27 association); the joint is inflamed but not infected; part of the spondyloarthritis family

RF: HLA-B27 positivity · preceding GU (Chlamydia) or GI infection · male (slightly) · young adult · HIV

Data: clinical diagnosis (post-infectious pattern + arthritis); arthrocentesis to EXCLUDE septic/crystal arthritis (cell count, Gram stain, culture, crystals — inflammatory, sterile in reactive arthritis); CRP/ESR (elevated), identify/test for triggering infection (Chlamydia NAAT, stool studies if recent diarrhea), HIV testing; HLA-B27 (supportive, not diagnostic); X-rays (enthesitis/sacroiliitis if chronic); ophthalmology if eye symptoms

DDx: reactive arthritis · septic arthritis (incl gonococcal — exclude) · crystal arthritis · psoriatic arthritis/other spondyloarthritis · Lyme arthritis · acute rheumatic fever · viral arthritis · IBD-associated arthritis

Home Meds: reconcile; treat the triggering infection if still active (esp Chlamydia — antibiotics + partner treatment); NSAIDs for arthritis; note antibiotics don't treat the established arthritis itself (treat the infection, not the sterile joint)

Plan

CONSULT: Rheumatology (diagnosis, refractory/chronic disease) · Ophthalmology (uveitis — urgent if eye symptoms) · Infectious Disease/primary care (treat triggering infection, HIV)

– FIRST exclude septic arthritis (including gonococcal): arthrocentesis with cell count, Gram stain, culture, crystals — reactive arthritis is sterile/inflammatory but you confirm by tap (see the septic-vs-inflammatory arthritis approach)
– IDENTIFY + TREAT the triggering infection: Chlamydia → antibiotics (e.g. azithromycin or doxycycline) + treat partners; enteric infections usually self-limited (treat if ongoing/indicated); test for HIV
– TREAT THE ARTHRITIS:
  • NSAIDs are first-line: naproxen 500 mg PO BID or indomethacin (often effective for the arthritis/enthesitis)
  • Intra-articular or short systemic glucocorticoids for inadequate response (after infection excluded)
  • DMARDs (sulfasalazine, methotrexate) for persistent/chronic disease; TNF inhibitors for refractory per rheumatology
– TREAT EXTRA-ARTICULAR FEATURES: uveitis → urgent ophthalmology + topical/systemic therapy; skin/mucosal lesions → topical care
– Reactive arthritis is the joint's delayed protest against an infection that's already happening somewhere else — a urethritis from Chlamydia or a bout of bacterial diarrhea a couple of weeks earlier — and the memorable shorthand, "can't see, can't pee, can't climb a tree," captures the conjunctivitis, urethritis, and arthritis triad. The key conceptual point is that the joint itself is sterile: this is an immune-mediated post-infectious arthritis in an HLA-B27-predisposed host, not an active joint infection. But "sterile" is something you confirm, not assume — you still tap the warm joint to exclude a true septic or gonococcal arthritis, because the consequences of missing those are severe. Treatment then splits cleanly: you treat the triggering infection if it's still live, especially Chlamydia with antibiotics and partner treatment, but antibiotics don't fix the arthritis itself, which responds to NSAIDs first and DMARDs or TNF inhibitors if it turns chronic. Don't forget to test for HIV and to get ophthalmology involved fast if the eye is inflamed.
– PT/OT: maintain mobility, enthesitis management, function
– Trend: joint response, CRP/ESR, eye symptoms, triggering-infection treatment, progression to chronicity
– Escalation triggers: septic arthritis on aspirate → orthopedics + antibiotics; acute anterior uveitis → urgent ophthalmology; severe/refractory or chronic arthritis → DMARD/TNF inhibitor + rheumatology; systemic illness → reconsider diagnosis
– Discharge checklist: septic arthritis excluded + diagnosis established; triggering infection treated (Chlamydia + partners); NSAID regimen; HIV tested; rheumatology + ophthalmology (if uveitis) follow-up; education that most cases resolve over months but some become chronic; return precautions (eye pain/redness/vision change, worsening joints, fever, new urinary/GI symptoms)

112. Reactive Arthritis

/ReactiveArthritis · complete reference · post-GU/GI asymmetric oligoarthritis · HLA-B27, exclude the septic joint, treat the trigger and the arthritis separately · Full Card

Symptoms / Associated Sx

• An asymmetric oligoarthritis of the lower extremities (knees, ankles) developing days to weeks after a genitourinary (Chlamydia) or gastrointestinal (Salmonella, Shigella, Campylobacter, Yersinia) infection

• The classic extra-articular triad "can't see, can't pee, can't climb a tree" — conjunctivitis or uveitis, urethritis, and arthritis; plus enthesitis (Achilles), dactylitis (a "sausage digit"), keratoderma blennorrhagicum, circinate balanitis, and low back pain (sacroiliitis)

• An acute warm joint after an infection still has to have septic arthritis excluded by aspiration — reactive arthritis is sterile, the joint inflammation is post-infectious rather than an active joint infection, but you confirm that with the tap rather than assuming it

Neg

• Pt denies a missed septic or disseminated gonococcal arthritis (aspirate to exclude an active infection) and a missed ongoing treatable triggering infection (especially Chlamydia — treat it).

• Pt denies missing uveitis (needs ophthalmology) and missing HIV (which can be associated and severe).

• Pt denies missing other spondyloarthritis or psoriatic features.

Social History (SHx)

• A recent GU or GI infection (1–4 weeks prior), sexual history (Chlamydia), and a diarrheal illness.

• Eye or urinary symptoms, skin or nail changes, and back pain.

• HLA-B27 or a family history of spondyloarthritis, and HIV risk.

Main Etiology

• An immune-mediated (sterile) arthritis triggered by an antecedent extra-articular infection (enteric or urogenital) in a genetically predisposed host (an HLA-B27 association)

• The joint is inflamed but not infected

• It is part of the spondyloarthritis family

RF

• Modifiable: a preceding GU (Chlamydia) or GI infection and HIV.

• Non-modifiable: HLA-B27 positivity, male sex (slightly), and young adulthood.

Data

• A clinical diagnosis (the post-infectious pattern plus arthritis)

• Arthrocentesis to exclude septic or crystal arthritis (cell count, Gram stain, culture, crystals — inflammatory and sterile in reactive arthritis)

• CRP/ESR (elevated); identify or test for the triggering infection (Chlamydia NAAT, stool studies if recent diarrhea) and HIV testing

• HLA-B27 (supportive, not diagnostic); X-rays (enthesitis or sacroiliitis if chronic); ophthalmology if eye symptoms.

DDx

Reactive arthritis · septic arthritis (including gonococcal — exclude) · crystal arthritis · psoriatic arthritis or other spondyloarthritis · Lyme arthritis · acute rheumatic fever · viral arthritis · IBD-associated arthritis

Home Meds

• Treat the triggering infection if still active (especially Chlamydia — antibiotics plus partner treatment).

• Start NSAIDs for the arthritis; note antibiotics don't treat the established arthritis itself (treat the infection, not the sterile joint).

• Reconcile medications.

Plan

CONSULT: Rheumatology (diagnosis, refractory or chronic disease) · Ophthalmology (uveitis — urgent if eye symptoms) · Infectious Disease or primary care (treat the triggering infection, HIV)

• First exclude septic arthritis (including gonococcal): arthrocentesis with a cell count, Gram stain, culture, and crystals — reactive arthritis is sterile and inflammatory but you confirm by tap (see the septic-versus-inflammatory arthritis approach).

• Identify and treat the triggering infection: Chlamydia → antibiotics (e.g. azithromycin or doxycycline) plus treat partners; enteric infections are usually self-limited (treat if ongoing or indicated); test for HIV.

• Treat the arthritis:

• • NSAIDs are first-line: naproxen 500 mg PO BID or indomethacin (often effective for the arthritis and enthesitis).

• • Intra-articular or short systemic glucocorticoids for an inadequate response (after infection is excluded).

• • DMARDs (sulfasalazine, methotrexate) for persistent or chronic disease; TNF inhibitors for refractory disease per rheumatology.

• Treat extra-articular features: uveitis → urgent ophthalmology and topical or systemic therapy; skin and mucosal lesions → topical care.

• PT/OT: maintain mobility, manage enthesitis, and preserve function.

• Trend: the joint response, CRP/ESR, eye symptoms, the triggering-infection treatment, and progression to chronicity.

• Escalation triggers: septic arthritis on aspirate → orthopedics and antibiotics; acute anterior uveitis → urgent ophthalmology; severe, refractory, or chronic arthritis → a DMARD or TNF inhibitor and rheumatology; systemic illness → reconsider the diagnosis.

• Discharge checklist: septic arthritis excluded and the diagnosis established; the triggering infection treated (Chlamydia and partners); an NSAID regimen; HIV tested; rheumatology and ophthalmology (if uveitis) follow-up; education that most cases resolve over months but some become chronic; return precautions for eye pain, redness, or vision change, worsening joints, fever, or new urinary or GI symptoms.

Red Flags

• An acute warm joint → exclude septic and gonococcal arthritis by aspiration before calling it reactive.

• Eye pain, redness, or vision change → acute anterior uveitis; urgent ophthalmology.

• An active Chlamydia infection → treat it and the partners; antibiotics target the trigger, not the joint.

• Severe or atypical disease → test for HIV, which can be associated and aggressive.

• Persistent arthritis beyond months → chronic disease; escalate to DMARDs or TNF inhibitors.

Senior IM Resident Pearls

• The joint is sterile — but confirm it. Reactive arthritis is post-infectious, not infected, yet you still tap to exclude the septic joint.

• "Can't see, can't pee, can't climb a tree." The conjunctivitis-urethritis-arthritis triad is the classic memory hook.

• Treat the trigger and the joint separately. Antibiotics clear an active Chlamydia infection but don't fix the established arthritis.

• NSAIDs first. They handle most of the arthritis and enthesitis; DMARDs and TNF inhibitors are for chronic disease.

• Test for HIV. It can be associated and produces more severe disease.

• Get ophthalmology fast for the eye. Acute anterior uveitis threatens vision and needs prompt treatment.

• Common mistake: treating it as a simple post-diarrheal arthralgia and missing the active, transmissible Chlamydia infection that needs treating along with the partners.

Rheumatology — Spondyloarthritis

113. Psoriatic Arthritis Flare

/PsoriaticArthritisFlare · skin + joint disease · dactylitis + enthesitis + nail changes · screen infection before escalating immunosuppression · NSAIDs → DMARDs → TNF/IL-17/IL-23 biologics · Super Compact

Sx: inflammatory arthritis in a psoriasis patient — variable patterns (asymmetric oligoarthritis, symmetric polyarthritis, DIP-predominant, spondylitis, arthritis mutilans); characteristic features: dactylitis ("sausage digit"), enthesitis (Achilles/plantar fascia), nail changes (pitting, onycholysis), psoriatic skin plaques; inflammatory back pain if axial; functional decline in a flare · (as with other inflammatory arthritides on immunosuppression, before escalating therapy for a flare you screen for infection, and you aspirate any single joint that's inflamed out of proportion to exclude a septic joint — the biologics these patients are on both raise infection risk and can mask it)

Neg: denies infection masquerading as flare (on immunosuppression/biologics — screen before escalating) · denies missed septic arthritis in a disproportionate joint (aspirate) · denies missed axial/spondylitis involvement · denies missed uveitis/IBD (associated) · denies missing cardiovascular/metabolic comorbidity · denies TB/hepatitis not screened before biologic

SHx: psoriasis duration/severity, PsA duration + pattern + erosions, current DMARDs/biologics + adherence, prior flares, skin/nail status, uveitis/IBD history, metabolic syndrome/cardiovascular risk, infection/TB screening status

Etiology: immune-mediated inflammatory arthritis associated with psoriasis; part of the spondyloarthritis family (TNF, IL-17, IL-23 cytokine axes); enthesitis is a hallmark; flares from medication lapse, infection, stress, undertreated disease; skin and joint disease may or may not correlate

RF: psoriasis (esp nail/scalp) · family history · obesity/metabolic syndrome · established PsA · medication nonadherence

Data: CRP/ESR (may be normal even in active disease), CBC, renal/hepatic function; joint + entheseal + skin/nail exam; aspirate any disproportionately inflamed single joint to exclude septic/crystal arthritis; X-rays (erosions, "pencil-in-cup," periostitis, sacroiliitis); TB/hepatitis screening before biologic initiation/escalation; infection workup if febrile

DDx: psoriatic arthritis flare · septic arthritis (superimposed) · crystal arthritis (coexisting gout) · RA · other spondyloarthritis (reactive, ankylosing) · osteoarthritis (DIP) · medication loss of efficacy

Home Meds: continue DMARDs/biologics unless infection; HOLD biologics if active infection suspected; reconcile; folic acid with methotrexate; screen TB/hepatitis before new biologic; manage cardiovascular/metabolic comorbidity

Plan

CONSULT: Rheumatology (flare management, DMARD/biologic optimization) · Dermatology (skin disease) · Orthopedics (if septic joint) · Ophthalmology (uveitis) · Gastroenterology (IBD)

– FIRST screen for infection (on immunosuppression): cultures + aspirate any disproportionately inflamed single joint to exclude septic arthritis before escalating immunosuppression (see the septic-vs-inflammatory arthritis approach)
– TREAT THE FLARE (once infection addressed) — escalate by disease domain/severity:
  • NSAIDs for mild peripheral/axial symptoms; intra-articular glucocorticoid for limited joints (cautiously — can flare skin); avoid systemic steroid tapers triggering pustular psoriasis rebound where possible
  • Conventional DMARDs (methotrexate, leflunomide, sulfasalazine) for peripheral arthritis — optimize/escalate
  • Biologics/targeted agents: TNF inhibitors, IL-17 inhibitors (secukinumab, ixekizumab), IL-23 inhibitors (guselkumab), or JAK inhibitors for inadequate response or axial/severe disease — per rheumatology (choice considers skin, axial, uveitis, IBD)
– ADDRESS the trigger: restart lapsed meds, treat infection
– TREAT ASSOCIATED FEATURES: skin disease (dermatology), uveitis (ophthalmology), IBD (GI); manage cardiometabolic risk
– Psoriatic arthritis is a disease of domains, and a flare can hit any of them — the peripheral joints, the spine, the entheses where tendons insert, the sausage-swollen digits, and the skin and nails — which is why the treatment is chosen by which domains are active rather than by a single ladder. The inpatient reflex is the same as for any inflammatory arthritis on immunosuppression: screen for infection and tap the joint that's inflamed out of proportion before you escalate, because the biologics these patients take raise infection risk and blunt its signs. A couple of psoriatic-specific wrinkles are worth holding onto. The CRP can be normal even when the joints are genuinely active, so don't let a normal inflammatory marker talk you out of a real flare. And be thoughtful with systemic steroids — tapering them can provoke a rebound pustular psoriasis flare of the skin — so the durable answer usually runs through DMARDs and the TNF, IL-17, and IL-23 biologics, with the agent chosen to cover the patient's particular mix of skin, axial, eye, and bowel involvement.
– PT/OT: joint protection, enthesitis management, function, hand therapy
– Trend: joint/entheseal/skin response, CRP/ESR (caveat: may be normal), functional status, infection markers, medication tolerability (LFTs/CBC), response to optimization
– Escalation triggers: septic arthritis/systemic infection → hold immunosuppression + treat (orthopedics/ID); acute uveitis → urgent ophthalmology; refractory/severe (incl arthritis mutilans, severe axial) → biologic escalation + rheumatology; IBD flare → GI
– Discharge checklist: flare controlled + infection excluded; DMARD/biologic regimen optimized + adherence; folic acid with methotrexate; TB/hepatitis screening if new biologic; rheumatology + dermatology follow-up; cardiometabolic risk addressed; PT/OT; return precautions (fever, new hot single joint, eye symptoms, GI symptoms, skin worsening, functional decline)

113. Psoriatic Arthritis Flare

/PsoriaticArthritisFlare · complete reference · skin + joint + enthesitis + dactylitis · screen infection first, treat by domain, biologics chosen to cover the disease mix · Full Card

Symptoms / Associated Sx

• Inflammatory arthritis in a psoriasis patient — variable patterns (asymmetric oligoarthritis, symmetric polyarthritis, DIP-predominant disease, spondylitis, arthritis mutilans)

• Characteristic features: dactylitis (a "sausage digit"), enthesitis (Achilles, plantar fascia), nail changes (pitting, onycholysis), and psoriatic skin plaques; inflammatory back pain if axial; functional decline in a flare

• As with other inflammatory arthritides on immunosuppression, before escalating therapy for a flare you screen for infection, and you aspirate any single joint that's inflamed out of proportion to exclude a septic joint — the biologics these patients are on both raise infection risk and can mask it

Neg

• Pt denies an infection masquerading as a flare (on immunosuppression or biologics — screen before escalating) and a missed septic arthritis in a disproportionate joint (aspirate).

• Pt denies missed axial or spondylitis involvement and missed uveitis or IBD (associated).

• Pt denies missing cardiovascular or metabolic comorbidity and TB or hepatitis not being screened before a biologic.

Social History (SHx)

• Psoriasis duration and severity, and PsA duration, pattern, and erosions.

• Current DMARDs or biologics with adherence, prior flares, and skin and nail status.

• Uveitis or IBD history, metabolic syndrome and cardiovascular risk, and infection and TB screening status.

Main Etiology

• An immune-mediated inflammatory arthritis associated with psoriasis; part of the spondyloarthritis family (the TNF, IL-17, and IL-23 cytokine axes)

• Enthesitis is a hallmark

• Flares arise from a medication lapse, infection, stress, or undertreated disease; skin and joint disease may or may not correlate

RF

• Modifiable: obesity or metabolic syndrome and medication nonadherence.

• Non-modifiable: psoriasis (especially nail or scalp disease), family history, and established PsA.

Data

• CRP/ESR (which may be normal even in active disease), CBC, and renal and hepatic function

• A joint, entheseal, and skin and nail exam; aspirate any disproportionately inflamed single joint to exclude septic or crystal arthritis

• X-rays (erosions, the "pencil-in-cup" deformity, periostitis, sacroiliitis); TB and hepatitis screening before biologic initiation or escalation; an infection workup if febrile.

DDx

Psoriatic arthritis flare · septic arthritis (superimposed) · crystal arthritis (coexisting gout) · RA · other spondyloarthritis (reactive, ankylosing) · osteoarthritis (DIP) · medication loss of efficacy

Home Meds

• Continue DMARDs and biologics unless there is infection; hold biologics if active infection is suspected.

• Screen TB and hepatitis before a new biologic; folic acid with methotrexate.

• Manage cardiovascular and metabolic comorbidity; reconcile.

Plan

CONSULT: Rheumatology (flare management, DMARD/biologic optimization) · Dermatology (skin disease) · Orthopedics (if a septic joint) · Ophthalmology (uveitis) · Gastroenterology (IBD)

• First screen for infection (on immunosuppression): cultures and aspirate any disproportionately inflamed single joint to exclude septic arthritis before escalating immunosuppression (see the septic-versus-inflammatory arthritis approach).

• Treat the flare (once infection is addressed) — escalate by disease domain and severity:

• • NSAIDs for mild peripheral or axial symptoms; an intra-articular glucocorticoid for limited joints (cautiously — it can flare the skin); avoid systemic steroid tapers that trigger a pustular psoriasis rebound where possible.

• • Conventional DMARDs (methotrexate, leflunomide, sulfasalazine) for peripheral arthritis — optimize or escalate.

• • Biologics and targeted agents: TNF inhibitors, IL-17 inhibitors (secukinumab, ixekizumab), IL-23 inhibitors (guselkumab), or JAK inhibitors for an inadequate response or axial or severe disease — per rheumatology (the choice considers skin, axial, uveitis, and IBD involvement).

• Address the trigger: restart lapsed medications and treat infection.

• Treat associated features: skin disease (dermatology), uveitis (ophthalmology), and IBD (GI); manage cardiometabolic risk.

• PT/OT: joint protection, enthesitis management, function, and hand therapy.

• Trend: the joint, entheseal, and skin response, CRP/ESR (with the caveat that it may be normal), functional status, infection markers, medication tolerability (LFTs, CBC), and the response to optimization.

• Escalation triggers: septic arthritis or systemic infection → hold immunosuppression and treat (orthopedics, ID); acute uveitis → urgent ophthalmology; refractory or severe disease (including arthritis mutilans, severe axial disease) → biologic escalation and rheumatology; an IBD flare → GI.

• Discharge checklist: the flare controlled and infection excluded; an optimized DMARD/biologic regimen with adherence; folic acid with methotrexate; TB and hepatitis screening if a new biologic; rheumatology and dermatology follow-up; cardiometabolic risk addressed; PT/OT; return precautions for fever, a new hot single joint, eye symptoms, GI symptoms, skin worsening, or functional decline.

Red Flags

• Fever or a single out-of-proportion joint on a biologic → screen for and exclude a septic joint before escalating.

• A normal CRP doesn't exclude an active flare → psoriatic disease can be active with normal markers.

• Tapering systemic steroids → can trigger a rebound pustular psoriasis flare; prefer DMARD and biologic routes.

• Eye pain or redness → uveitis; urgent ophthalmology.

• New GI symptoms → consider an associated IBD flare and tailor the biologic choice.

Senior IM Resident Pearls

• Treat by domain. Peripheral joints, spine, entheses, dactylitis, skin, and nails each pull the therapy in a direction — match the agent to the active domains.

• Screen and tap before escalating. Biologics raise infection risk and mask it; exclude the septic joint first.

• A normal CRP can lie. Psoriatic disease is often active with normal inflammatory markers — believe the joints.

• Be careful with systemic steroids. Their taper can rebound the skin into pustular psoriasis — lean on DMARDs and biologics.

• Pick the biologic for the whole patient. IL-17 and IL-23 agents handle skin well; TNF inhibitors cover uveitis and IBD; match accordingly.

• Don't forget the cardiometabolic burden. PsA carries excess cardiovascular and metabolic risk worth addressing.

• Common mistake: reaching for a systemic steroid burst in a psoriatic flare and provoking a severe skin rebound on the taper.

Rheumatology — Axial Spondyloarthritis

114. Ankylosing Spondylitis Flare

/AnkylosingSpondylitisFlare · inflammatory back pain · HLA-B27 + sacroiliitis · NSAIDs first-line, TNF/IL-17 biologics, PT essential · beware the rigid spine fracture · Super Compact

Sx: inflammatory back pain (insidious onset before age 45, worse with rest/at night, improves with exercise, prolonged morning stiffness) + sacroiliitis; reduced spinal mobility; can have peripheral arthritis, enthesitis, dactylitis; extra-articular: acute anterior uveitis (common), IBD, psoriasis; advanced: spinal fusion ("bamboo spine"), restrictive lung disease · (in a patient with longstanding fused/ankylosed spine, new or worsening back pain after even minor trauma is a spinal fracture until proven otherwise — the rigid spine fractures easily and unstably, with high risk of spinal cord injury, so this is not simply assumed to be a flare)

Neg: denies spinal fracture mistaken for flare (rigid/fused spine fractures with minor trauma — unstable, cord-injury risk; new focal/post-traumatic pain → image, don't assume flare) · denies missed acute anterior uveitis (urgent ophthalmology) · denies missed cardiac (aortitis/conduction) or pulmonary (restrictive/apical fibrosis) involvement · denies missed cauda equina · denies missed superimposed infection on biologics

SHx: AS duration + spinal involvement/fusion, current NSAIDs/biologics + adherence, uveitis/IBD/psoriasis history, trauma history (fracture risk), smoking, functional/mobility baseline, cardiopulmonary symptoms, TB screening status

Etiology: chronic inflammatory axial spondyloarthritis with sacroiliac and spinal inflammation → new bone formation and ankylosis; strong HLA-B27 association; TNF and IL-17 cytokine drive; flares from undertreated disease/medication lapse; the fused spine becomes brittle (fracture risk)

RF: HLA-B27 · male · young onset · family history · smoking (worse outcomes)

Data: CRP/ESR (may be normal in active disease), CBC; sacroiliac/spine imaging: X-ray (sacroiliitis, syndesmophytes, bamboo spine), MRI (active inflammation/early sacroiliitis); HLA-B27 (supportive); if new/post-traumatic focal pain → CT/MRI spine for fracture (do NOT rely on plain films alone in a fused spine); ophthalmology if eye symptoms; PFTs/echo if cardiopulmonary concern; TB screening before biologics

DDx: AS flare · spinal fracture (in fused spine) · mechanical back pain · other axial spondyloarthritis · infection (discitis/osteomyelitis/epidural abscess) · malignancy · cauda equina · cardiopulmonary complication

Home Meds: continue NSAIDs (first-line, often scheduled) and biologics unless infection; HOLD biologic if active infection; reconcile; screen TB before biologic; smoking cessation; bone health (osteoporosis paradoxically common despite fusion)

Plan

CONSULT: Rheumatology (flare management, biologic optimization) · Spine surgery/Neurosurgery (URGENT if fracture/neuro deficit in fused spine) · Ophthalmology (uveitis) · PT (essential) · Gastroenterology (IBD)

– FIRST exclude spinal fracture + serious mimics if new, focal, or post-traumatic pain or any neuro deficit: CT/MRI spine (a fused/ankylosed spine fractures unstably with minor trauma — do not assume "flare"); exclude infection (discitis, epidural abscess) and cauda equina
– TREAT THE FLARE (inflammatory, no fracture/red flag):
  • NSAIDs are first-line and cornerstone: e.g. naproxen 500 mg PO BID or other NSAID, often scheduled/continuous for active disease (most effective for axial symptoms)
  • Biologics for inadequate NSAID response: TNF inhibitors (adalimumab, etanercept, infliximab) or IL-17 inhibitors (secukinumab, ixekizumab); JAK inhibitors as another option — per rheumatology (choice considers uveitis, IBD, psoriasis)
  • Conventional DMANDs (sulfasalazine) only help peripheral, NOT axial disease; systemic steroids are NOT very effective for axial AS (limited role; local injection for peripheral/SI)
– PHYSICAL THERAPY + EXERCISE is essential (maintains mobility/posture, reduces stiffness — a core treatment, not adjunct)
– TREAT EXTRA-ARTICULAR/COMPLICATIONS: acute anterior uveitis → urgent ophthalmology; IBD → GI; monitor cardiac (aortic regurgitation, conduction) and pulmonary (restrictive, apical fibrosis); bone health (fracture/osteoporosis risk)
– Ankylosing spondylitis is one of the few arthritides where exercise is as much a treatment as the drugs, and where the drug ladder is genuinely different from rheumatoid arthritis: NSAIDs are the cornerstone, often taken continuously, and when they fail you go straight to a TNF or IL-17 biologic — the conventional DMARDs and systemic steroids that anchor RA do little for axial disease here. But the single most important inpatient instinct is about the spine itself. A patient whose spine has fused over years has a rigid, brittle column that fractures with trivial trauma, and those fractures are unstable and threaten the cord. So when an AS patient presents with new, focal, or post-traumatic back pain — or any neurologic change — you do not shrug it off as a flare; you image with CT or MRI, because plain films routinely miss these fractures in a fused spine, and a missed unstable fracture can paralyze. The same vigilance covers the other serious mimics: discitis, epidural abscess, and cauda equina.
– Trend: back pain/stiffness/mobility, CRP/ESR (caveat: may be normal), response to NSAID/biologic, neuro status (if any concern), eye/GI/cardiopulmonary symptoms
– Escalation triggers: spinal fracture or neuro deficit in a fused spine → urgent CT/MRI + spine surgery/neurosurgery + spinal precautions; epidural abscess/discitis → urgent imaging + ID + surgery; cauda equina → emergent surgery; acute uveitis → urgent ophthalmology; cardiac conduction/aortic disease → cardiology
– Discharge checklist: fracture/serious mimic excluded + flare controlled; NSAID regimen (scheduled if active); biologic optimized if needed; TB screening if new biologic; PT/exercise program; rheumatology + (ophthalmology/GI as needed) follow-up; smoking cessation; bone health; patient educated that new/post-trauma back pain needs evaluation (fracture risk); return precautions (new focal/post-traumatic back pain, neuro symptoms, eye symptoms, chest symptoms)

114. Ankylosing Spondylitis Flare

/AnkylosingSpondylitisFlare · complete reference · inflammatory back pain + sacroiliitis · NSAIDs first-line, biologics for failure, PT essential, exclude the fused-spine fracture · Full Card

Symptoms / Associated Sx

• Inflammatory back pain (insidious onset before age 45, worse with rest and at night, improving with exercise, with prolonged morning stiffness) plus sacroiliitis

• Reduced spinal mobility; possible peripheral arthritis, enthesitis, and dactylitis; extra-articular features: acute anterior uveitis (common), IBD, and psoriasis; advanced disease: spinal fusion ("bamboo spine") and restrictive lung disease

• In a patient with a longstanding fused or ankylosed spine, new or worsening back pain after even minor trauma is a spinal fracture until proven otherwise — the rigid spine fractures easily and unstably, with a high risk of spinal cord injury, so this is not simply assumed to be a flare

Neg

• Pt denies a spinal fracture mistaken for a flare (a rigid or fused spine fractures with minor trauma — unstable, with cord-injury risk; new focal or post-traumatic pain → image, don't assume a flare) and missed acute anterior uveitis (urgent ophthalmology).

• Pt denies missed cardiac (aortitis, conduction) or pulmonary (restrictive, apical fibrosis) involvement and a missed cauda equina.

• Pt denies a missed superimposed infection on biologics.

Social History (SHx)

• AS duration with spinal involvement or fusion, and current NSAIDs or biologics with adherence.

• Uveitis, IBD, or psoriasis history, trauma history (fracture risk), and smoking.

• Functional and mobility baseline, cardiopulmonary symptoms, and TB screening status.

Main Etiology

• A chronic inflammatory axial spondyloarthritis with sacroiliac and spinal inflammation leading to new bone formation and ankylosis

• A strong HLA-B27 association; a TNF and IL-17 cytokine drive; flares arise from undertreated disease or a medication lapse

• The fused spine becomes brittle (fracture risk)

RF

• Modifiable: smoking (worse outcomes).

• Non-modifiable: HLA-B27, male sex, young onset, and family history.

Data

• CRP/ESR (which may be normal in active disease) and CBC

• Sacroiliac and spine imaging: X-ray (sacroiliitis, syndesmophytes, bamboo spine), MRI (active inflammation or early sacroiliitis); HLA-B27 (supportive)

• If new or post-traumatic focal pain → CT or MRI spine for fracture (do not rely on plain films alone in a fused spine)

• Ophthalmology if eye symptoms; PFTs and echo if there is cardiopulmonary concern; TB screening before biologics.

DDx

AS flare · spinal fracture (in a fused spine) · mechanical back pain · other axial spondyloarthritis · infection (discitis, osteomyelitis, epidural abscess) · malignancy · cauda equina · a cardiopulmonary complication

Home Meds

• Continue NSAIDs (first-line, often scheduled) and biologics unless there is infection; hold the biologic if active infection.

• Screen TB before a biologic; encourage smoking cessation.

• Attend to bone health (osteoporosis is paradoxically common despite fusion); reconcile.

Plan

CONSULT: Rheumatology (flare management, biologic optimization) · Spine surgery or Neurosurgery (urgent if fracture or neuro deficit in a fused spine) · Ophthalmology (uveitis) · PT (essential) · Gastroenterology (IBD)

• First exclude a spinal fracture and serious mimics if there is new, focal, or post-traumatic pain or any neuro deficit: CT or MRI spine (a fused or ankylosed spine fractures unstably with minor trauma — do not assume a "flare"); exclude infection (discitis, epidural abscess) and cauda equina.

• Treat the flare (inflammatory, no fracture or red flag):

• • NSAIDs are first-line and the cornerstone: e.g. naproxen 500 mg PO BID or another NSAID, often scheduled or continuous for active disease (most effective for axial symptoms).

• • Biologics for an inadequate NSAID response: TNF inhibitors (adalimumab, etanercept, infliximab) or IL-17 inhibitors (secukinumab, ixekizumab); JAK inhibitors as another option — per rheumatology (the choice considers uveitis, IBD, and psoriasis).

• • Conventional DMARDs (sulfasalazine) only help peripheral, not axial, disease; systemic steroids are not very effective for axial AS (a limited role; local injection for peripheral or sacroiliac disease).

• Physical therapy and exercise are essential (maintaining mobility and posture, reducing stiffness — a core treatment, not an adjunct).

• Treat extra-articular features and complications: acute anterior uveitis → urgent ophthalmology; IBD → GI; monitor cardiac (aortic regurgitation, conduction) and pulmonary (restrictive disease, apical fibrosis); attend to bone health (fracture and osteoporosis risk).

• Trend: back pain, stiffness, and mobility, CRP/ESR (with the caveat that it may be normal), the response to the NSAID or biologic, neuro status (if any concern), and eye, GI, and cardiopulmonary symptoms.

• Escalation triggers: a spinal fracture or neuro deficit in a fused spine → urgent CT or MRI, spine surgery or neurosurgery, and spinal precautions; an epidural abscess or discitis → urgent imaging, ID, and surgery; cauda equina → emergent surgery; acute uveitis → urgent ophthalmology; cardiac conduction or aortic disease → cardiology.

• Discharge checklist: a fracture and serious mimic excluded and the flare controlled; an NSAID regimen (scheduled if active); an optimized biologic if needed; TB screening if a new biologic; a PT and exercise program; rheumatology and (ophthalmology or GI as needed) follow-up; smoking cessation; bone health; the patient educated that new or post-trauma back pain needs evaluation (fracture risk); return precautions for new focal or post-traumatic back pain, neuro symptoms, eye symptoms, or chest symptoms.

Red Flags

• New, focal, or post-traumatic back pain in a fused spine → an unstable fracture until imaged; CT or MRI, not plain films alone.

• Any new neurologic deficit → cord compromise from a fracture, epidural abscess, or cauda equina; emergent evaluation.

• Eye pain, redness, or photophobia → acute anterior uveitis; urgent ophthalmology.

• Fever with back pain → discitis or epidural abscess; image and culture, don't assume a flare.

• New murmur, syncope, or dyspnea → aortic regurgitation, conduction disease, or restrictive lung disease.

Senior IM Resident Pearls

• Exercise is treatment. A structured PT and exercise program is core therapy in AS, not an optional add-on.

• The drug ladder differs from RA. NSAIDs are the cornerstone, then straight to TNF or IL-17 biologics — conventional DMARDs and systemic steroids do little for axial disease.

• The fused spine is brittle. New or post-traumatic pain is an unstable fracture until imaged — and plain films miss it.

• Image with CT or MRI. A fracture through ankylosed bone is easy to overlook on radiographs and catastrophic to miss.

• Uveitis is common and urgent. A red, painful eye in an AS patient goes to ophthalmology fast.

• Bones are weak despite the fusion. Osteoporosis is paradoxically common — attend to bone health.

• Common mistake: attributing new back pain in a long-standing fused-spine patient to a flare and missing the unstable fracture.

Rheumatology — Autoimmune

115. Sjögren Syndrome Complications

/SjogrenComplications · sicca (dry eyes/mouth) + systemic features · renal tubular acidosis, neuropathy, ILD · watch the lymphoma risk · Super Compact

Sx: sicca — dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia), parotid gland enlargement; systemic/extraglandular complications: arthralgia, renal (distal renal tubular acidosis → hypokalemia, interstitial nephritis), neuropathy (sensory/small-fiber, cranial), interstitial lung disease, cutaneous vasculitis, cytopenias; profound fatigue · (the complication that defines long-term risk in Sjögren is B-cell non-Hodgkin lymphoma, for which these patients carry a markedly elevated risk — so persistent parotid swelling, a new mass, lymphadenopathy, or unexplained cytopenias should prompt evaluation for lymphoma rather than being dismissed as part of the disease)

Neg: denies missed lymphoma (markedly increased risk — persistent/firm parotid mass, lymphadenopathy, new cytopenias, low C4, cryoglobulins → evaluate) · denies missed distal RTA/hypokalemia (can cause weakness/paralysis/stones) · denies missed neuropathy/CNS involvement · denies missed ILD · denies missed associated/secondary autoimmune disease (RA, SLE)

SHx: sicca duration, parotid swelling history, prior Sjögren complications, associated autoimmune disease, medications causing dryness (anticholinergics), neuropathy/renal/pulmonary symptoms, B-symptoms (lymphoma)

Etiology: autoimmune lymphocytic infiltration of exocrine glands (lacrimal, salivary) → glandular dysfunction (sicca); extraglandular immune-mediated involvement of kidneys, nerves, lung, skin, blood; chronic B-cell activation underlies the lymphoma predisposition; primary or secondary (with another CTD)

RF: female (strongly) · middle age · other autoimmune disease (secondary) · anti-Ro/La positivity · low complement/cryoglobulins/persistent parotid enlargement (lymphoma risk markers)

Data: anti-Ro (SSA)/anti-La (SSB), ANA, RF; objective sicca testing (Schirmer, ocular staining, salivary flow); labile salivary gland biopsy (focal lymphocytic sialadenitis) if needed; complication workup: electrolytes/ABG/urine pH (distal RTA), creatinine/UA (interstitial nephritis), nerve studies (neuropathy), HRCT/PFTs (ILD), CBC; lymphoma evaluation if red flags: complement (low C4), cryoglobulins, serum protein electrophoresis, imaging, tissue biopsy of persistent mass/node

DDx: primary Sjögren · secondary Sjögren (RA/SLE/scleroderma) · sicca from medications/age/radiation · IgG4-related disease · sarcoidosis · HIV/HCV (sicca mimic) · lymphoma (the key complication)

Home Meds: reconcile; review/limit drying agents (anticholinergics); replace potassium + alkali for distal RTA; symptomatic sicca care; immunosuppression for significant extraglandular disease per rheumatology

Plan

CONSULT: Rheumatology (diagnosis, systemic disease) · Hematology/Oncology (if lymphoma suspected) · Nephrology (RTA/interstitial nephritis) · Neurology (neuropathy/CNS) · Pulmonology (ILD) · Ophthalmology/Dentistry (glandular)

– EVALUATE FOR LYMPHOMA if red flags (persistent/firm parotid or nodal enlargement, new cytopenias, low C4, cryoglobulinemia, monoclonal protein): imaging + tissue biopsy + hematology — do not attribute these to "just Sjögren"
– TREAT THE SPECIFIC COMPLICATION:
  • Distal renal tubular acidosis: potassium replacement + oral alkali (sodium bicarbonate or potassium citrate); treat hypokalemia (can cause weakness/paralysis); evaluate nephrocalcinosis/stones
  • Interstitial nephritis / significant renal disease: glucocorticoids ± immunosuppression per nephrology/rheumatology
  • Neuropathy / CNS / vasculitis / ILD: immunosuppression (glucocorticoids ± steroid-sparing/rituximab) per specialist for significant organ involvement
  • Severe systemic disease: rituximab/other immunosuppression per rheumatology
– SICCA + SYMPTOMATIC CARE: artificial tears/ocular lubricants, saliva substitutes, secretagogues (pilocarpine, cevimeline), meticulous dental/eye care, humidification, hydration
– HYDROXYCHLOROQUINE often used for arthralgia/fatigue/glandular symptoms per rheumatology
– Most people know Sjögren as the dry-eyes-and-dry-mouth disease, but the inpatient reasons to care are the systemic complications and the one long shadow over it all — lymphoma. Sjögren patients carry a markedly elevated lifetime risk of B-cell non-Hodgkin lymphoma, so the persistent firm parotid swelling, the new lymphadenopathy, the unexplained cytopenias, the low C4 and cryoglobulins are not "just the Sjögren acting up" — they're the signals to image and biopsy and call hematology. The other complications are scattered across organ systems and each has its own fix: a distal renal tubular acidosis that drops the potassium dangerously and needs alkali and potassium repletion, an interstitial nephritis, a small-fiber or cranial neuropathy, an interstitial lung disease, cutaneous vasculitis — the significant organ involvement gets immunosuppression, often including rituximab. The sicca itself is managed symptomatically with lubricants and secretagogues and scrupulous dental care, while hydroxychloroquine helps the fatigue and arthralgia.
– PT/OT: per neuropathy/functional impact
– Trend: potassium/acid-base (RTA), renal function, neuro/pulmonary status, complement/cryoglobulins (lymphoma markers), CBC, response to therapy, lymphoma workup if pursued
– Escalation triggers: lymphoma confirmed/suspected → hematology/oncology; severe hypokalemia from RTA (weakness/arrhythmia) → urgent repletion + monitoring; rapidly progressive ILD → pulmonology ± ICU; severe neuropathy/CNS/vasculitis → immunosuppression + specialist; renal failure → nephrology
– Discharge checklist: complication(s) characterized + lymphoma excluded/evaluated if indicated; RTA managed (potassium + alkali); organ-specific immunosuppression if needed; sicca care; hydroxychloroquine if used; rheumatology + relevant specialist follow-up; education on lymphoma warning signs (persistent gland swelling, lumps, weight loss/night sweats); return precautions (new mass/lymphadenopathy, weakness, breathlessness, neuro symptoms, B-symptoms)

115. Sjögren Syndrome Complications

/SjogrenComplications · complete reference · sicca + systemic complications (RTA, neuropathy, ILD) · the defining long-term risk is lymphoma · Full Card

Symptoms / Associated Sx

• Sicca — dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia), with parotid gland enlargement

• Systemic and extraglandular complications: arthralgia, renal disease (distal renal tubular acidosis → hypokalemia, interstitial nephritis), neuropathy (sensory or small-fiber, cranial), interstitial lung disease, cutaneous vasculitis, and cytopenias; profound fatigue

• The complication that defines long-term risk in Sjögren is B-cell non-Hodgkin lymphoma, for which these patients carry a markedly elevated risk — so persistent parotid swelling, a new mass, lymphadenopathy, or unexplained cytopenias should prompt evaluation for lymphoma rather than being dismissed as part of the disease

Neg

• Pt denies a missed lymphoma (a markedly increased risk — a persistent or firm parotid mass, lymphadenopathy, new cytopenias, a low C4, or cryoglobulins → evaluate) and a missed distal RTA or hypokalemia (which can cause weakness, paralysis, or stones).

• Pt denies a missed neuropathy or CNS involvement and missed ILD.

• Pt denies a missed associated or secondary autoimmune disease (RA, SLE).

Social History (SHx)

• Sicca duration, parotid swelling history, and prior Sjögren complications.

• Associated autoimmune disease and medications causing dryness (anticholinergics).

• Neuropathy, renal, or pulmonary symptoms, and B-symptoms (lymphoma).

Main Etiology

• Autoimmune lymphocytic infiltration of the exocrine glands (lacrimal, salivary) causing glandular dysfunction (sicca)

• Extraglandular immune-mediated involvement of the kidneys, nerves, lung, skin, and blood; chronic B-cell activation underlies the lymphoma predisposition

• Primary or secondary (with another connective tissue disease)

RF

• Non-modifiable: female sex (strongly), middle age, other autoimmune disease (secondary), anti-Ro/La positivity, and low complement, cryoglobulins, or persistent parotid enlargement (lymphoma risk markers).

Data

• Anti-Ro (SSA) and anti-La (SSB), ANA, and rheumatoid factor; objective sicca testing (Schirmer test, ocular staining, salivary flow); a labial salivary gland biopsy (focal lymphocytic sialadenitis) if needed

• Complication workup: electrolytes, ABG, and urine pH (distal RTA), creatinine and urinalysis (interstitial nephritis), nerve studies (neuropathy), HRCT and PFTs (ILD), and CBC

• Lymphoma evaluation if red flags: complement (low C4), cryoglobulins, serum protein electrophoresis, imaging, and a tissue biopsy of a persistent mass or node

DDx

Primary Sjögren · secondary Sjögren (RA, SLE, scleroderma) · sicca from medications, age, or radiation · IgG4-related disease · sarcoidosis · HIV or HCV (a sicca mimic) · lymphoma (the key complication)

Home Meds

• Review and limit drying agents (anticholinergics); reconcile.

• Replace potassium and alkali for distal RTA; provide symptomatic sicca care.

• Use immunosuppression for significant extraglandular disease per rheumatology.

Plan

CONSULT: Rheumatology (diagnosis, systemic disease) · Hematology/Oncology (if lymphoma suspected) · Nephrology (RTA, interstitial nephritis) · Neurology (neuropathy, CNS) · Pulmonology (ILD) · Ophthalmology and Dentistry (glandular care)

• Evaluate for lymphoma if red flags (persistent or firm parotid or nodal enlargement, new cytopenias, low C4, cryoglobulinemia, a monoclonal protein): imaging, a tissue biopsy, and hematology — do not attribute these to "just Sjögren."

• Treat the specific complication:

• • Distal renal tubular acidosis: potassium replacement and oral alkali (sodium bicarbonate or potassium citrate); treat hypokalemia (which can cause weakness or paralysis); evaluate for nephrocalcinosis or stones.

• • Interstitial nephritis or significant renal disease: glucocorticoids with possible immunosuppression per nephrology and rheumatology.

• • Neuropathy, CNS disease, vasculitis, or ILD: immunosuppression (glucocorticoids with a possible steroid-sparing agent or rituximab) per specialist for significant organ involvement.

• • Severe systemic disease: rituximab or other immunosuppression per rheumatology.

• Sicca and symptomatic care: artificial tears and ocular lubricants, saliva substitutes, secretagogues (pilocarpine, cevimeline), meticulous dental and eye care, humidification, and hydration.

• Hydroxychloroquine is often used for arthralgia, fatigue, and glandular symptoms per rheumatology.

• PT/OT: per neuropathy or functional impact.

• Trend: potassium and acid-base status (RTA), renal function, neuro and pulmonary status, complement and cryoglobulins (lymphoma markers), CBC, the response to therapy, and the lymphoma workup if pursued.

• Escalation triggers: lymphoma confirmed or suspected → hematology and oncology; severe hypokalemia from RTA (weakness, arrhythmia) → urgent repletion and monitoring; rapidly progressive ILD → pulmonology with possible ICU; severe neuropathy, CNS disease, or vasculitis → immunosuppression and the specialist; renal failure → nephrology.

• Discharge checklist: the complications characterized and lymphoma excluded or evaluated if indicated; RTA managed (potassium and alkali); organ-specific immunosuppression if needed; sicca care; hydroxychloroquine if used; rheumatology and relevant specialist follow-up; education on lymphoma warning signs (persistent gland swelling, lumps, weight loss, night sweats); return precautions for a new mass or lymphadenopathy, weakness, breathlessness, neuro symptoms, or B-symptoms.

Red Flags

• Persistent firm parotid swelling, new lymphadenopathy, or unexplained cytopenias → evaluate for lymphoma, not a disease flare.

• A low C4, cryoglobulins, or a monoclonal protein → lymphoma risk markers; pursue the workup.

• Profound hypokalemia with weakness → distal renal tubular acidosis; replete potassium and give alkali.

• Progressive dyspnea → interstitial lung disease; HRCT and PFTs.

• New sensory or cranial neuropathy → extraglandular nervous system involvement; consider immunosuppression.

Senior IM Resident Pearls

• The lymphoma risk defines the disease. Sjögren patients have a markedly elevated B-cell lymphoma risk — persistent gland swelling or new cytopenias earn a workup.

• Know the lymphoma risk markers. A low C4, cryoglobulins, persistent parotid enlargement, and a monoclonal protein raise the concern.

• The RTA can be dangerous. A distal renal tubular acidosis can drop the potassium to paralytic levels — replete potassium and give alkali.

• It's a multi-organ disease. Kidneys, nerves, lungs, skin, and blood can all be involved beyond the dryness.

• Significant organ disease gets immunosuppression. Rituximab and steroids are used for serious extraglandular involvement.

• Hydroxychloroquine helps the constitutional symptoms. Fatigue and arthralgia often respond.

• Common mistake: dismissing a persistent firm parotid mass as glandular Sjögren and missing the lymphoma growing in it.

Rheumatology — Connective Tissue Disease

116. Systemic Sclerosis (Scleroderma)

/SystemicSclerosis · skin thickening + Raynaud + organ fibrosis · SCLERODERMA RENAL CRISIS = ACE inhibitor (NOT steroids) · pulmonary ILD + PAH drive mortality · Super Compact

Sx: skin thickening/sclerosis (sclerodactyly, distal-to-proximal), Raynaud phenomenon (often early), digital ulcers/pitting, telangiectasias, calcinosis; organ involvement: GI (dysmotility, reflux, GAVE), pulmonary (interstitial lung disease + pulmonary arterial hypertension — leading causes of death), cardiac, renal (scleroderma renal crisis); diffuse vs limited (CREST) subtypes · (two emergencies define inpatient scleroderma. Scleroderma renal crisis presents as abrupt severe hypertension with acute kidney injury and a microangiopathic picture — the treatment is an ACE inhibitor, and crucially, high-dose corticosteroids can PRECIPITATE it and should be avoided. And pulmonary involvement — ILD and pulmonary arterial hypertension — is the main driver of mortality and must be actively screened for.)

Neg: denies scleroderma renal crisis missed/mismanaged (abrupt HTN + AKI + MAHA → ACE inhibitor immediately; AVOID high-dose steroids which precipitate it) · denies steroid use that could trigger renal crisis (esp diffuse/early, anti-RNA polymerase III) · denies missed ILD or pulmonary arterial hypertension (screen — leading mortality) · denies missed GI (GAVE bleeding, dysmotility, malnutrition) · denies missed cardiac involvement · denies digital ischemia/critical ulcers

SHx: Raynaud onset, skin changes extent/progression, subtype (diffuse vs limited), disease duration (renal crisis risk highest early diffuse), antibody profile, GI/pulmonary/cardiac symptoms, recent steroid exposure, BP history, digital ulcers

Etiology: autoimmune connective tissue disease with vasculopathy + fibrosis + immune activation → skin and internal organ fibrosis and small-vessel disease; scleroderma renal crisis from severe renin-driven hypertensive small-vessel injury; subtypes by skin extent + antibodies (anti-Scl70/topoisomerase → diffuse/ILD; anti-centromere → limited/PAH; anti-RNA pol III → renal crisis)

RF: diffuse cutaneous subtype + early disease (renal crisis) · anti-RNA polymerase III (renal crisis) · high-dose steroids (renal crisis trigger) · anti-Scl70 (ILD) · anti-centromere (PAH) · female

Data: BP + renal function + urinalysis (renal crisis: severe HTN, rising creatinine, MAHA — schistocytes, low platelets, low haptoglobin); autoantibodies (ANA, anti-Scl70, anti-centromere, anti-RNA pol III); pulmonary screening: HRCT chest + PFTs (ILD), echocardiogram + consider right heart catheterization (PAH); cardiac eval (ECG/echo/troponin); GI evaluation as indicated (endoscopy for GAVE/reflux); nailfold capillaroscopy

DDx: systemic sclerosis (diffuse/limited) · scleroderma renal crisis vs other TMA/malignant HTN · other connective tissue disease/overlap · localized scleroderma · nephrogenic systemic fibrosis · eosinophilic fasciitis · other ILD/PAH causes

Home Meds: ACE inhibitor is the treatment for renal crisis (continue even as creatinine rises); AVOID high-dose corticosteroids (precipitate renal crisis) — use lowest necessary dose if required; proton pump inhibitor (reflux), Raynaud/digital therapy (calcium channel blocker, etc.); reconcile; organ-specific therapy per disease

Plan

CONSULT: Rheumatology (overall management) · Nephrology (URGENT for renal crisis) · Pulmonology (ILD/PAH) · Cardiology (PAH/cardiac) · Gastroenterology (GI/GAVE) · ICU if renal crisis/severe organ involvement

– SCLERODERMA RENAL CRISIS (EMERGENCY): abrupt severe hypertension + AKI ± microangiopathic hemolysis →
  • START an ACE inhibitor IMMEDIATELY (e.g. captopril, titrate aggressively to control BP) — this is the specific life- and kidney-saving treatment; CONTINUE it even as creatinine rises
  • AVOID high-dose corticosteroids (a known precipitant); minimize/avoid other nephrotoxins
  • Supportive: dialysis if needed (some recover renal function over months), ICU-level BP management; nephrology urgently
– PULMONARY (leading mortality — screen + treat):
  • ILD: immunosuppression (mycophenolate mofetil first-line; cyclophosphamide; consider antifibrotic nintedanib; tocilizumab) per pulmonology/rheumatology
  • Pulmonary arterial hypertension: confirm by right heart catheterization → PAH-specific therapy (endothelin antagonists, PDE5 inhibitors, prostacyclins) per PAH specialist
– OTHER ORGAN-SPECIFIC: GI — PPI for reflux, prokinetics for dysmotility, manage GAVE (endoscopic) and malnutrition; Raynaud/digital ulcers — calcium channel blockers, PDE5 inhibitors, prostacyclin/endothelin antagonists for severe; treat digital ischemia; cardiac — manage per involvement
– SKIN/DISEASE-MODIFYING: immunosuppression (mycophenolate, methotrexate) for progressive skin/ILD per rheumatology
– Scleroderma's inpatient danger lives in two organs, and the renal one carries a counterintuitive rule that you must know cold. Scleroderma renal crisis is an abrupt malignant hypertension with acute kidney injury and a microangiopathic blood picture, and its treatment is an ACE inhibitor — captopril, titrated hard — which you continue even as the creatinine climbs, because it's the renin-angiotensin system driving the injury. The trap is steroids: high-dose corticosteroids actually precipitate renal crisis, so in a scleroderma patient, especially early diffuse disease with anti-RNA polymerase III antibodies, you avoid them or use the smallest possible dose, which is the opposite of your instinct in most rheumatic emergencies. The second danger is the lungs — interstitial lung disease and pulmonary arterial hypertension are the leading causes of death in scleroderma, so you actively screen with HRCT, PFTs, and an echo rather than waiting for symptoms, treating the ILD with mycophenolate and the PAH, once confirmed by right heart catheterization, with pulmonary vasodilators.
– PT/OT: hand function, contracture prevention, skin care
– Trend: BP + creatinine (renal crisis — daily/frequent), hemolysis markers, oxygenation/PFTs/echo (pulmonary), GI/nutrition, digital perfusion, response to therapy
– Escalation triggers: scleroderma renal crisis → ICU + immediate ACE inhibitor + nephrology ± dialysis; respiratory failure/severe PAH → ICU + pulmonology/PAH; GI bleeding (GAVE) → endoscopy; critical digital ischemia → urgent vasodilator/vascular; cardiac decompensation → cardiology
– Discharge checklist: renal crisis treated (ACE inhibitor, BP controlled) or excluded; pulmonary screening (HRCT/PFTs/echo) done + ILD/PAH therapy if present; steroids minimized/avoided (renal crisis risk); PPI; Raynaud/digital therapy; rheumatology + relevant organ specialists follow-up; patient educated on renal crisis (home BP monitoring) + that steroids carry renal-crisis risk; return precautions (rising BP, decreased urine, breathlessness, GI bleeding, worsening digital ulcers/ischemia)

116. Systemic Sclerosis (Scleroderma)

/SystemicSclerosis · complete reference · skin + organ fibrosis · renal crisis treated with ACE inhibitors and worsened by steroids, ILD and PAH drive mortality · Full Card

Symptoms / Associated Sx

• Skin thickening and sclerosis (sclerodactyly, distal-to-proximal), Raynaud phenomenon (often early), digital ulcers and pitting, telangiectasias, and calcinosis

• Organ involvement: GI (dysmotility, reflux, GAVE), pulmonary (interstitial lung disease and pulmonary arterial hypertension — leading causes of death), cardiac, and renal (scleroderma renal crisis); diffuse versus limited (CREST) subtypes

• Two emergencies define inpatient scleroderma. Scleroderma renal crisis presents as abrupt severe hypertension with acute kidney injury and a microangiopathic picture — the treatment is an ACE inhibitor, and crucially, high-dose corticosteroids can precipitate it and should be avoided. And pulmonary involvement — ILD and pulmonary arterial hypertension — is the main driver of mortality and must be actively screened for.

Neg

• Pt denies a scleroderma renal crisis missed or mismanaged (abrupt HTN with AKI and MAHA → ACE inhibitor immediately; avoid high-dose steroids, which precipitate it) and steroid use that could trigger renal crisis (especially diffuse or early disease, anti-RNA polymerase III).

• Pt denies missed ILD or pulmonary arterial hypertension (screen — leading mortality) and missed GI disease (GAVE bleeding, dysmotility, malnutrition).

• Pt denies missed cardiac involvement and digital ischemia or critical ulcers.

Social History (SHx)

• Raynaud onset, the extent and progression of skin changes, and the subtype (diffuse versus limited).

• Disease duration (renal crisis risk is highest in early diffuse disease), the antibody profile, and GI, pulmonary, and cardiac symptoms.

• Recent steroid exposure, BP history, and digital ulcers.

Main Etiology

• An autoimmune connective tissue disease with vasculopathy, fibrosis, and immune activation leading to skin and internal organ fibrosis and small-vessel disease

• Scleroderma renal crisis arises from severe renin-driven hypertensive small-vessel injury

• Subtypes are defined by skin extent and antibodies (anti-Scl70/topoisomerase → diffuse disease and ILD; anti-centromere → limited disease and PAH; anti-RNA polymerase III → renal crisis)

RF

• Modifiable: high-dose steroids (a renal crisis trigger).

• Non-modifiable: the diffuse cutaneous subtype with early disease and anti-RNA polymerase III (renal crisis), anti-Scl70 (ILD), anti-centromere (PAH), and female sex.

Data

• BP, renal function, and urinalysis (renal crisis: severe HTN, a rising creatinine, MAHA — schistocytes, low platelets, low haptoglobin)

• Autoantibodies (ANA, anti-Scl70, anti-centromere, anti-RNA polymerase III)

• Pulmonary screening: HRCT chest and PFTs (ILD), an echocardiogram and consider right heart catheterization (PAH); cardiac evaluation (ECG, echo, troponin)

• GI evaluation as indicated (endoscopy for GAVE or reflux); nailfold capillaroscopy.

DDx

Systemic sclerosis (diffuse or limited) · scleroderma renal crisis versus other thrombotic microangiopathy or malignant hypertension · other connective tissue disease or overlap · localized scleroderma · nephrogenic systemic fibrosis · eosinophilic fasciitis · other causes of ILD or PAH

Home Meds

• An ACE inhibitor is the treatment for renal crisis (continue even as the creatinine rises).

• Avoid high-dose corticosteroids (they precipitate renal crisis) — use the lowest necessary dose if required.

• A proton pump inhibitor (reflux) and Raynaud and digital therapy (a calcium channel blocker); reconcile; organ-specific therapy per disease.

Plan

CONSULT: Rheumatology (overall management) · Nephrology (urgent for renal crisis) · Pulmonology (ILD, PAH) · Cardiology (PAH, cardiac disease) · Gastroenterology (GI, GAVE) · ICU if renal crisis or severe organ involvement

• Scleroderma renal crisis (emergency): abrupt severe hypertension with AKI and possible microangiopathic hemolysis →

• • Start an ACE inhibitor immediately (e.g. captopril, titrated aggressively to control BP) — this is the specific life- and kidney-saving treatment; continue it even as the creatinine rises.

• • Avoid high-dose corticosteroids (a known precipitant); minimize or avoid other nephrotoxins.

• • Supportive: dialysis if needed (some recover renal function over months), ICU-level BP management, and nephrology urgently.

• Pulmonary (leading mortality — screen and treat):

• • ILD: immunosuppression (mycophenolate mofetil first-line; cyclophosphamide; consider the antifibrotic nintedanib; tocilizumab) per pulmonology and rheumatology.

• • Pulmonary arterial hypertension: confirm by right heart catheterization → PAH-specific therapy (endothelin antagonists, PDE5 inhibitors, prostacyclins) per a PAH specialist.

• Other organ-specific care: GI — a PPI for reflux, prokinetics for dysmotility, manage GAVE (endoscopic) and malnutrition; Raynaud and digital ulcers — calcium channel blockers, PDE5 inhibitors, and prostacyclin or endothelin antagonists for severe disease; treat digital ischemia; cardiac — manage per involvement.

• Skin and disease-modifying therapy: immunosuppression (mycophenolate, methotrexate) for progressive skin disease or ILD per rheumatology.

• PT/OT: hand function, contracture prevention, and skin care.

• Trend: BP and creatinine (renal crisis — daily or frequent), hemolysis markers, oxygenation, PFTs, and echo (pulmonary), GI and nutrition, digital perfusion, and the response to therapy.

• Escalation triggers: scleroderma renal crisis → ICU, immediate ACE inhibitor, nephrology, and possible dialysis; respiratory failure or severe PAH → ICU and pulmonology or PAH service; GI bleeding (GAVE) → endoscopy; critical digital ischemia → urgent vasodilator and vascular service; cardiac decompensation → cardiology.

• Discharge checklist: renal crisis treated (ACE inhibitor, BP controlled) or excluded; pulmonary screening (HRCT, PFTs, echo) done with ILD or PAH therapy if present; steroids minimized or avoided (renal crisis risk); a PPI; Raynaud and digital therapy; rheumatology and relevant organ specialist follow-up; the patient educated on renal crisis (home BP monitoring) and that steroids carry renal-crisis risk; return precautions for rising BP, decreased urine, breathlessness, GI bleeding, or worsening digital ulcers or ischemia.

Red Flags

• Abrupt severe hypertension with a rising creatinine → scleroderma renal crisis; start an ACE inhibitor immediately.

• High-dose steroids in a scleroderma patient → can precipitate renal crisis; avoid or minimize, especially in early diffuse disease.

• Progressive dyspnea → interstitial lung disease or pulmonary arterial hypertension, the leading causes of death; screen and treat.

• GI bleeding → gastric antral vascular ectasia (GAVE); endoscopic management.

• A cold, dusky, ulcerating digit → critical digital ischemia; urgent vasodilation.

Senior IM Resident Pearls

• Renal crisis is treated with an ACE inhibitor — and you keep it on. Continue captopril even as the creatinine climbs; the renin-angiotensin system is driving the injury.

• Steroids precipitate renal crisis. The opposite of your usual rheumatic-emergency instinct — avoid or minimize high-dose steroids in scleroderma.

• The lungs kill. ILD and PAH are the leading causes of death — screen with HRCT, PFTs, and echo rather than waiting for symptoms.

• Confirm PAH before treating it. A right heart catheterization establishes the diagnosis before pulmonary vasodilators.

• Antibodies forecast the organ. Anti-Scl70 leans ILD, anti-centromere leans PAH, anti-RNA polymerase III leans renal crisis.

• Mind the gut. Reflux, dysmotility, GAVE bleeding, and malnutrition are common and manageable.

• Common mistake: giving high-dose steroids to a scleroderma patient for skin or joint symptoms and triggering a renal crisis.

Rheumatology — Vasculitis

117. Cryoglobulinemic Vasculitis

/CryoglobulinemicVasculitis · palpable purpura + arthralgia + neuropathy + GN · low C4 · usually HCV-associated — treat the underlying cause · Super Compact

Sx: small-vessel vasculitis from cryoglobulins (immunoglobulins that precipitate in cold) — classic triad palpable purpura (lower extremities), arthralgia, and weakness; plus peripheral neuropathy, glomerulonephritis (membranoproliferative), skin ulcers, Raynaud; constitutional symptoms; most commonly associated with hepatitis C (type II/III mixed) · (the central principle is that cryoglobulinemic vasculitis is usually secondary — most often to hepatitis C, sometimes to other infection, autoimmune disease, or a hematologic/lymphoproliferative disorder — so identifying and treating the underlying cause, especially curing the hepatitis C, is the foundation of treatment, not just immunosuppression)

Neg: denies missed underlying cause (hepatitis C most common — must test/treat; also other infection, autoimmune, lymphoproliferative) · denies missed glomerulonephritis/renal involvement (urinalysis/creatinine) · denies missed severe/organ-threatening disease (RPGN, progressive neuropathy, GI ischemia, pulmonary) · denies missed underlying lymphoma · denies misattributing purpura to other cause

SHx: hepatitis C status/risk, other infections, autoimmune disease, lymphoproliferative history, purpura/neuropathy/renal symptoms, cold sensitivity, prior cryoglobulin testing

Etiology: immune-complex small-vessel vasculitis driven by cryoglobulins (cold-precipitable immunoglobulins); type I (monoclonal — lymphoproliferative/myeloma), types II/III mixed (often HCV-driven, also other infection/autoimmune); complement-consuming immune-complex deposition → vessel inflammation

RF: hepatitis C infection (dominant) · other chronic infection · autoimmune disease (Sjögren, SLE) · lymphoproliferative disorder/B-cell lymphoma

Data: serum cryoglobulins (collect + transport warm — false negatives if mishandled), low complement (especially LOW C4), rheumatoid factor (often positive); hepatitis C testing (and HBV/HIV), urinalysis + creatinine (glomerulonephritis), nerve studies (neuropathy); skin/renal biopsy (leukocytoclastic vasculitis / MPGN); evaluate for lymphoproliferative disorder (SPEP, imaging, marrow if indicated); CBC, LFTs

DDx: cryoglobulinemic vasculitis · other small-vessel vasculitis (ANCA, IgA) · other causes of palpable purpura · hepatitis C without vasculitis · lymphoma · other immune-complex disease · septic emboli/endocarditis

Home Meds: reconcile; plan direct-acting antiviral therapy if HCV (curative, treats the driver); immunosuppression per severity; avoid cold exposure; manage underlying cause-specific therapy

Plan

CONSULT: Rheumatology (diagnosis, immunosuppression) · Hepatology/ID (hepatitis C treatment) · Nephrology (glomerulonephritis) · Neurology (neuropathy) · Hematology (if lymphoproliferative) · ICU if organ/life-threatening

– IDENTIFY + TREAT THE UNDERLYING CAUSE (foundation):
  • Hepatitis C (most common): direct-acting antiviral therapy (curative; often resolves/controls the vasculitis) — coordinate with hepatology
  • Other: treat the infection, autoimmune disease, or lymphoproliferative disorder driving it
– TREAT THE VASCULITIS BY SEVERITY:
  • Mild (purpura/arthralgia): treat the cause; supportive; low-dose steroids if needed
  • Moderate-severe / organ-threatening (RPGN, progressive neuropathy, GI/pulmonary, severe skin ulcers): glucocorticoids + RITUXIMAB (B-cell depletion — effective for mixed cryoglobulinemia); cyclophosphamide for severe per specialist
  • Life-threatening / fulminant: plasma exchange (removes cryoglobulins) + high-dose steroids + rituximab per rheumatology/nephrology
– NOTE on sequencing: in HCV-associated disease, for severe vasculitis immunosuppression/rituximab may be needed first or concurrently to control the vasculitis, then/with antiviral therapy — coordinate hepatology + rheumatology
– SUPPORTIVE: avoid cold exposure, skin/ulcer care, manage neuropathy
– Cryoglobulinemic vasculitis is the small-vessel vasculitis that almost always points somewhere else — the cryoglobulins are the weapon, but something is making them, and most of the time that something is hepatitis C. So the defining move is to find and treat the underlying cause: testing for HCV and curing it with direct-acting antivirals frequently resolves the vasculitis itself, which makes this one of the more satisfying vasculitides to treat well. The clinical picture is palpable purpura on the legs, arthralgia, and weakness, often with a peripheral neuropathy and a membranoproliferative glomerulonephritis, and the lab clue is a strikingly low C4 with a positive rheumatoid factor. The diagnostic gotcha is the cryoglobulin sample itself — it has to be collected and transported warm or it falsely reads negative. For severe organ-threatening disease you don't just wait on the antiviral; you control the vasculitis with steroids and rituximab, adding plasma exchange to physically remove the cryoglobulins when it's fulminant. And always consider the other drivers — a lymphoproliferative disorder hiding behind a type I or mixed cryoglobulinemia.
– PT/OT: per neuropathy/functional impact
– Trend: purpura/skin, renal function + urinalysis, neuropathy, complement (rising = improving), cryoglobulin/RF, HCV viral load (if treating), response to therapy
– Escalation triggers: rapidly progressive glomerulonephritis → nephrology + aggressive immunosuppression ± plasma exchange ± dialysis; fulminant/life-threatening vasculitis → plasma exchange + ICU; severe neuropathy/GI ischemia/pulmonary → urgent immunosuppression + specialist; lymphoma identified → hematology
– Discharge checklist: underlying cause identified + treatment started (HCV antivirals if applicable) + vasculitis controlled; immunosuppression/rituximab regimen if severe; cold-avoidance; cause-specific therapy plan; rheumatology + hepatology/relevant specialist follow-up; lymphoproliferative evaluation if indicated; return precautions (worsening purpura/ulcers, decreased urine/edema, neuro symptoms, GI/chest symptoms)

117. Cryoglobulinemic Vasculitis

/CryoglobulinemicVasculitis · complete reference · purpura + arthralgia + neuropathy + GN, low C4 · usually HCV-driven — treat the cause, immunosuppress and plasma-exchange the severe · Full Card

Symptoms / Associated Sx

• A small-vessel vasculitis from cryoglobulins (immunoglobulins that precipitate in the cold) — the classic triad of palpable purpura (lower extremities), arthralgia, and weakness

• Plus peripheral neuropathy, glomerulonephritis (membranoproliferative), skin ulcers, and Raynaud; constitutional symptoms; most commonly associated with hepatitis C (type II/III mixed)

• The central principle is that cryoglobulinemic vasculitis is usually secondary — most often to hepatitis C, sometimes to other infection, autoimmune disease, or a hematologic or lymphoproliferative disorder — so identifying and treating the underlying cause, especially curing the hepatitis C, is the foundation of treatment, not just immunosuppression

Neg

• Pt denies a missed underlying cause (hepatitis C most common — must test and treat; also other infection, autoimmune disease, lymphoproliferative disorder) and missed glomerulonephritis or renal involvement (urinalysis, creatinine).

• Pt denies missed severe or organ-threatening disease (RPGN, progressive neuropathy, GI ischemia, pulmonary disease) and a missed underlying lymphoma.

• Pt denies misattributing the purpura to another cause.

Social History (SHx)

• Hepatitis C status and risk, other infections, and autoimmune disease.

• Lymphoproliferative history and purpura, neuropathy, or renal symptoms.

• Cold sensitivity and prior cryoglobulin testing.

Main Etiology

• An immune-complex small-vessel vasculitis driven by cryoglobulins (cold-precipitable immunoglobulins)

• Type I (monoclonal — lymphoproliferative disorders or myeloma), types II/III mixed (often HCV-driven, also other infection or autoimmune disease)

• Complement-consuming immune-complex deposition causes vessel inflammation

RF

• Modifiable: hepatitis C infection (dominant) and other chronic infection.

• Non-modifiable: autoimmune disease (Sjögren, SLE) and a lymphoproliferative disorder or B-cell lymphoma.

Data

• Serum cryoglobulins (collect and transport warm — false negatives if mishandled), low complement (especially a low C4), and rheumatoid factor (often positive)

• Hepatitis C testing (and HBV and HIV), urinalysis and creatinine (glomerulonephritis), and nerve studies (neuropathy)

• A skin or renal biopsy (leukocytoclastic vasculitis or MPGN); evaluate for a lymphoproliferative disorder (SPEP, imaging, marrow if indicated); CBC, LFTs.

DDx

Cryoglobulinemic vasculitis · other small-vessel vasculitis (ANCA, IgA) · other causes of palpable purpura · hepatitis C without vasculitis · lymphoma · other immune-complex disease · septic emboli or endocarditis

Home Meds

• Plan direct-acting antiviral therapy if HCV (curative, treats the driver).

• Use immunosuppression per severity; avoid cold exposure.

• Manage underlying cause-specific therapy; reconcile.

Plan

CONSULT: Rheumatology (diagnosis, immunosuppression) · Hepatology/ID (hepatitis C treatment) · Nephrology (glomerulonephritis) · Neurology (neuropathy) · Hematology (if lymphoproliferative) · ICU if organ- or life-threatening

• Identify and treat the underlying cause (the foundation):

• • Hepatitis C (most common): direct-acting antiviral therapy (curative; often resolves or controls the vasculitis) — coordinate with hepatology.

• • Other: treat the infection, autoimmune disease, or lymphoproliferative disorder driving it.

• Treat the vasculitis by severity:

• • Mild (purpura, arthralgia): treat the cause; supportive care; low-dose steroids if needed.

• • Moderate-severe or organ-threatening (RPGN, progressive neuropathy, GI or pulmonary disease, severe skin ulcers): glucocorticoids and rituximab (B-cell depletion — effective for mixed cryoglobulinemia); cyclophosphamide for severe disease per specialist.

• • Life-threatening or fulminant: plasma exchange (removes cryoglobulins) with high-dose steroids and rituximab per rheumatology and nephrology.

• Note on sequencing: in HCV-associated disease, for severe vasculitis immunosuppression and rituximab may be needed first or concurrently to control the vasculitis, then or alongside antiviral therapy — coordinate hepatology and rheumatology.

• Supportive care: avoid cold exposure, skin and ulcer care, and manage the neuropathy.

• PT/OT: per neuropathy or functional impact.

• Trend: the purpura and skin, renal function and urinalysis, the neuropathy, complement (rising = improving), cryoglobulin and rheumatoid factor, the HCV viral load (if treating), and the response to therapy.

• Escalation triggers: rapidly progressive glomerulonephritis → nephrology, aggressive immunosuppression, and possible plasma exchange and dialysis; fulminant or life-threatening vasculitis → plasma exchange and ICU; severe neuropathy, GI ischemia, or pulmonary disease → urgent immunosuppression and the specialist; lymphoma identified → hematology.

• Discharge checklist: the underlying cause identified and treatment started (HCV antivirals if applicable) and the vasculitis controlled; an immunosuppression or rituximab regimen if severe; cold avoidance; a cause-specific therapy plan; rheumatology and hepatology or relevant specialist follow-up; a lymphoproliferative evaluation if indicated; return precautions for worsening purpura or ulcers, decreased urine or edema, neuro symptoms, or GI or chest symptoms.

Red Flags

• Palpable purpura with arthralgia and weakness → cryoglobulinemic vasculitis; test for the underlying cause, especially HCV.

• A rising creatinine with an active sediment → membranoproliferative glomerulonephritis; urgent immunosuppression.

• A negative cryoglobulin in a classic picture → likely a mishandled cold sample; redraw and transport warm.

• A monoclonal (type I) cryoglobulin → hunt for a lymphoproliferative disorder or myeloma.

• Fulminant multi-organ vasculitis → plasma exchange plus steroids and rituximab.

Senior IM Resident Pearls

• It almost always points elsewhere. Find the driver — most often hepatitis C — because treating it frequently resolves the vasculitis.

• Curing the HCV is therapy. Direct-acting antivirals often control the vasculitis, making this a satisfying disease to treat well.

• Low C4 and positive RF are the lab clues. A strikingly consumed C4 with a positive rheumatoid factor fits the immune-complex mechanism.

• The sample must stay warm. Cryoglobulins precipitate in the cold and read falsely negative if the specimen cools — collect and transport warm.

• Severe disease can't wait on the antiviral. Control organ-threatening vasculitis with steroids and rituximab, adding plasma exchange when fulminant.

• Consider the monoclonal driver. A type I cryoglobulin signals a lymphoproliferative disorder to find.

• Common mistake: sending a cold cryoglobulin sample, getting a false negative, and dismissing the diagnosis in a classic purpura-neuropathy-low-C4 patient.

Rheumatology — Variable-Vessel Vasculitis

118. Behçet Disease

/BehcetDisease · recurrent oral + genital ulcers · uveitis · pathergy · variable-vessel vasculitis · treat by organ severity, eye/CNS/vascular involvement is sight- and life-threatening · Super Compact

Sx: recurrent painful oral aphthous ulcers (hallmark, near-universal) + recurrent genital ulcers; ocular (uveitis — anterior/posterior, can threaten vision), skin (erythema nodosum, papulopustular, pathergy), arthritis; serious: CNS (neuro-Behçet), vascular (venous thrombosis, arterial aneurysm — incl pulmonary artery), GI ulceration; relapsing-remitting · (Behçet is a multi-system vasculitis where the severity is defined by which organs are hit: the mucocutaneous and joint disease is morbid but not dangerous, while ocular, neurologic, large-vessel, and GI involvement are organ-, sight-, and life-threatening and demand aggressive immunosuppression — so the management is entirely stratified by the organ involved)

Neg: denies missed sight-threatening uveitis (urgent ophthalmology + aggressive therapy) · denies missed neuro-Behçet (brainstem/parenchymal, dural sinus thrombosis) · denies missed vascular involvement (venous thrombosis, pulmonary artery aneurysm — can be fatal; anticoagulation alone insufficient/risky if aneurysm) · denies missed GI ulceration/perforation · denies attributing oral ulcers to benign aphthae without the pattern

SHx: ulcer frequency/pattern (oral + genital), eye symptoms, neuro symptoms, thrombosis history, GI symptoms, ethnicity/geographic origin (Silk Road), HLA-B51, family history, disease course

Etiology: variable-vessel systemic vasculitis (can affect arteries and veins of any size) of unknown cause with autoinflammatory + autoimmune features; HLA-B51 association; prominent along the "Silk Road" geographic distribution; neutrophilic hyperreactivity (pathergy)

RF: Mediterranean/Middle Eastern/East Asian (Silk Road) origin · HLA-B51 · young adult · male (more severe ocular/vascular)

Data: clinical diagnosis (International Criteria — recurrent oral ulcers plus genital ulcers, ocular, skin, pathergy, etc.); no specific diagnostic lab; CRP/ESR (activity); organ-specific workup: ophthalmology exam (uveitis), MRI brain/MRV (neuro-Behçet/dural sinus thrombosis), vascular imaging (thrombosis/aneurysm — incl CT for pulmonary artery aneurysm), GI endoscopy; HLA-B51 (supportive); pathergy test; exclude infection/IBD mimics

DDx: Behçet disease · recurrent aphthous stomatitis (isolated) · inflammatory bowel disease (oral + GI ulcers) · reactive arthritis · SLE · HSV/other infection · other vasculitis · MAGIC syndrome

Home Meds: reconcile; colchicine for mucocutaneous/joint disease; immunosuppression (azathioprine, TNF inhibitors, etc.) for major organ involvement; topical therapy for ulcers; caution with anticoagulation if pulmonary artery aneurysm (bleeding risk — immunosuppress the inflammation)

Plan

CONSULT: Rheumatology (diagnosis, immunosuppression) · Ophthalmology (URGENT for uveitis) · Neurology (neuro-Behçet) · Vascular/Pulmonology (thrombosis/aneurysm) · Gastroenterology (GI) · ICU if life-threatening vascular/neuro/GI

– STRATIFY BY ORGAN SEVERITY (defines everything):
– MUCOCUTANEOUS / JOINT (morbid, not dangerous): topical steroids for ulcers; colchicine for mucocutaneous + joint disease; apremilast for oral ulcers; NSAIDs for arthritis; short steroid courses for flares
– OCULAR (sight-threatening — urgent): urgent ophthalmology + systemic glucocorticoids + immunosuppression (azathioprine, cyclosporine) and/or TNF inhibitors (infliximab/adalimumab); posterior uveitis/retinal vasculitis needs aggressive therapy to save vision
– NEUROLOGIC (neuro-Behçet — organ-threatening): high-dose glucocorticoids + immunosuppression (azathioprine, TNF inhibitors); dural venous sinus thrombosis → steroids ± anticoagulation per specialists
– VASCULAR (life-threatening): immunosuppression is primary for the inflammation; venous thrombosis → immunosuppression ± anticoagulation; PULMONARY ARTERY ANEURYSM → immunosuppression (avoid anticoagulation — high hemorrhage/rupture risk), consider embolization per vascular/pulmonary
– GI (can perforate): glucocorticoids + immunosuppression (azathioprine, TNF inhibitors, etc.); surgery for perforation/bleeding
– Behçet is the disease of recurrent ulcers at both ends — painful oral aphthae that nearly everyone has, plus genital ulcers — but the recurrent ulcers are only the calling card. What actually determines how you treat it is which organ the variable-vessel vasculitis has chosen, and the spread is dramatic: the mucocutaneous and joint disease is miserable but benign and responds to colchicine and topical steroids, while the eye, the brain, the big vessels, and the gut are where Behçet maims and kills. Sight-threatening posterior uveitis, brainstem neuro-Behçet, and large-vessel disease all demand aggressive systemic immunosuppression with steroids and agents like azathioprine or TNF inhibitors. Two counterintuitive points are worth carrying: the vascular disease is inflammatory, so immunosuppression — not anticoagulation — is the primary treatment for Behçet thrombosis; and the pulmonary artery aneurysm is the one where anticoagulation is actively dangerous, because these aneurysms can rupture and bleed catastrophically, so you immunosuppress and consider embolization rather than anticoagulate.
– PT/OT: per neuro/joint involvement
– Trend: ulcer activity, eye/neuro/vascular/GI status, CRP/ESR, response to organ-directed therapy, complications
– Escalation triggers: sight-threatening uveitis → urgent ophthalmology + aggressive immunosuppression/TNF inhibitor; neuro-Behçet (parenchymal/brainstem, sinus thrombosis) → neurology + high-dose steroids; pulmonary artery aneurysm/major vascular → ICU + immunosuppression + vascular (avoid anticoagulation if aneurysm); GI perforation/bleed → surgery
– Discharge checklist: organ involvement characterized + severity-stratified therapy underway; mucocutaneous: colchicine/topical; major-organ: immunosuppression ± TNF inhibitor; vascular plan (immunosuppression-led; anticoagulation caution if aneurysm); rheumatology + relevant specialist (ophthalmology/neurology/vascular) follow-up; return precautions (eye symptoms/vision change, neuro symptoms, severe headache, chest pain/hemoptysis, severe abdominal pain, new thrombosis)

118. Behçet Disease

/BehcetDisease · complete reference · recurrent oral + genital ulcers + uveitis · variable-vessel vasculitis, management stratified by organ, vascular disease is immunosuppression-led · Full Card

Symptoms / Associated Sx

• Recurrent painful oral aphthous ulcers (the hallmark, near-universal) plus recurrent genital ulcers

• Ocular disease (uveitis — anterior or posterior, can threaten vision), skin disease (erythema nodosum, papulopustular lesions, pathergy), and arthritis; serious involvement: CNS (neuro-Behçet), vascular (venous thrombosis, arterial aneurysm including pulmonary artery), and GI ulceration; a relapsing-remitting course

• Behçet is a multi-system vasculitis where the severity is defined by which organs are hit: the mucocutaneous and joint disease is morbid but not dangerous, while ocular, neurologic, large-vessel, and GI involvement are organ-, sight-, and life-threatening and demand aggressive immunosuppression — so the management is entirely stratified by the organ involved

Neg

• Pt denies missed sight-threatening uveitis (urgent ophthalmology and aggressive therapy) and missed neuro-Behçet (brainstem or parenchymal disease, dural sinus thrombosis).

• Pt denies missed vascular involvement (venous thrombosis, pulmonary artery aneurysm — which can be fatal; anticoagulation alone is insufficient and risky if there is an aneurysm) and missed GI ulceration or perforation.

• Pt denies attributing oral ulcers to benign aphthae without the pattern.

Social History (SHx)

• Ulcer frequency and pattern (oral and genital), eye symptoms, and neuro symptoms.

• Thrombosis history, GI symptoms, and ethnicity or geographic origin (Silk Road).

• HLA-B51, family history, and the disease course.

Main Etiology

• A variable-vessel systemic vasculitis (which can affect arteries and veins of any size) of unknown cause with autoinflammatory and autoimmune features

• An HLA-B51 association; prominent along the "Silk Road" geographic distribution

• Neutrophilic hyperreactivity (pathergy)

RF

• Non-modifiable: Mediterranean, Middle Eastern, or East Asian (Silk Road) origin, HLA-B51, young adulthood, and male sex (more severe ocular and vascular disease).

Data

• A clinical diagnosis (the International Criteria — recurrent oral ulcers plus genital ulcers, ocular disease, skin disease, pathergy); there is no specific diagnostic lab

• CRP/ESR (activity)

• Organ-specific workup: an ophthalmology exam (uveitis), MRI brain and MRV (neuro-Behçet or dural sinus thrombosis), vascular imaging (thrombosis or aneurysm — including CT for a pulmonary artery aneurysm), and GI endoscopy

• HLA-B51 (supportive); a pathergy test; exclude infection and IBD mimics.

DDx

Behçet disease · recurrent aphthous stomatitis (isolated) · inflammatory bowel disease (oral and GI ulcers) · reactive arthritis · SLE · HSV or other infection · other vasculitis · MAGIC syndrome

Home Meds

• Colchicine for mucocutaneous and joint disease; topical therapy for ulcers.

• Immunosuppression (azathioprine, TNF inhibitors) for major organ involvement.

• Caution with anticoagulation if there is a pulmonary artery aneurysm (bleeding risk — immunosuppress the inflammation); reconcile.

Plan

CONSULT: Rheumatology (diagnosis, immunosuppression) · Ophthalmology (urgent for uveitis) · Neurology (neuro-Behçet) · Vascular and Pulmonology (thrombosis, aneurysm) · Gastroenterology (GI) · ICU if life-threatening vascular, neuro, or GI disease

• Stratify by organ severity (this defines everything).

• Mucocutaneous and joint (morbid, not dangerous): topical steroids for ulcers; colchicine for mucocutaneous and joint disease; apremilast for oral ulcers; NSAIDs for arthritis; short steroid courses for flares.

• Ocular (sight-threatening — urgent): urgent ophthalmology with systemic glucocorticoids and immunosuppression (azathioprine, cyclosporine) and/or TNF inhibitors (infliximab, adalimumab); posterior uveitis or retinal vasculitis needs aggressive therapy to save vision.

• Neurologic (neuro-Behçet — organ-threatening): high-dose glucocorticoids with immunosuppression (azathioprine, TNF inhibitors); dural venous sinus thrombosis → steroids with possible anticoagulation per specialists.

• Vascular (life-threatening): immunosuppression is primary for the inflammation; venous thrombosis → immunosuppression with possible anticoagulation; a pulmonary artery aneurysm → immunosuppression (avoid anticoagulation — high hemorrhage and rupture risk), consider embolization per vascular and pulmonary.

• GI (can perforate): glucocorticoids with immunosuppression (azathioprine, TNF inhibitors); surgery for perforation or bleeding.

• PT/OT: per neuro or joint involvement.

• Trend: ulcer activity, eye, neuro, vascular, and GI status, CRP/ESR, the response to organ-directed therapy, and complications.

• Escalation triggers: sight-threatening uveitis → urgent ophthalmology and aggressive immunosuppression or TNF inhibitor; neuro-Behçet (parenchymal or brainstem disease, sinus thrombosis) → neurology and high-dose steroids; a pulmonary artery aneurysm or major vascular disease → ICU, immunosuppression, and vascular service (avoid anticoagulation if aneurysm); GI perforation or bleeding → surgery.

• Discharge checklist: organ involvement characterized and severity-stratified therapy underway; mucocutaneous: colchicine and topicals; major-organ: immunosuppression with a possible TNF inhibitor; a vascular plan (immunosuppression-led; anticoagulation caution if aneurysm); rheumatology and relevant specialist (ophthalmology, neurology, vascular) follow-up; return precautions for eye symptoms or vision change, neuro symptoms, severe headache, chest pain or hemoptysis, severe abdominal pain, or new thrombosis.

Red Flags

• Eye pain, redness, or vision change → uveitis that can be sight-threatening; urgent ophthalmology and aggressive immunosuppression.

• Brainstem signs, severe headache, or focal deficits → neuro-Behçet or dural sinus thrombosis; urgent imaging and high-dose steroids.

• Chest pain or hemoptysis → a pulmonary artery aneurysm; immunosuppress and do not anticoagulate.

• Severe abdominal pain → GI ulceration that can perforate; image and involve surgery.

• New venous thrombosis → Behçet vascular disease; immunosuppression-led, not anticoagulation alone.

Senior IM Resident Pearls

• The ulcers are the calling card, not the danger. Oral and genital aphthae define the disease, but the eye, brain, vessels, and gut decide its severity.

• Treat by organ. Colchicine and topicals for mucocutaneous and joint disease; aggressive immunosuppression for ocular, neuro, vascular, and GI involvement.

• Behçet thrombosis is inflammatory. Immunosuppression — not anticoagulation — is the primary treatment for the vascular disease.

• The pulmonary artery aneurysm is the anticoagulation trap. These can rupture and bleed catastrophically; immunosuppress and consider embolization, don't anticoagulate.

• Posterior uveitis threatens vision fast. It earns urgent ophthalmology and TNF inhibitors or potent immunosuppression.

• There's no diagnostic lab. The diagnosis is clinical by criteria; HLA-B51 and pathergy support but don't confirm.

• Common mistake: anticoagulating a Behçet patient with vascular disease and a pulmonary artery aneurysm instead of immunosuppressing — risking fatal hemorrhage.

Rheumatology — Granulomatous

119. Sarcoidosis

/Sarcoidosis · non-caseating granulomas · pulmonary disease + hypercalcemia + neurosarcoidosis · hypercalcemia from 1,25-vitamin D → steroids · treat by organ involvement · Super Compact

Sx: multisystem granulomatous disease — pulmonary (most common: cough, dyspnea, bilateral hilar lymphadenopathy, interstitial disease — staged by chest imaging), constitutional (fatigue, fevers, weight loss); hypercalcemia/hypercalciuria, skin (erythema nodosum, lupus pernio), ocular (uveitis), cardiac (conduction block, arrhythmia, cardiomyopathy — can be sudden), neuro (neurosarcoidosis — cranial neuropathy, meningitis, mass), hepatic, arthritis; Löfgren syndrome (acute, good prognosis) · (three threads matter most inpatient: the hypercalcemia is driven by granuloma macrophages making active 1,25-vitamin D — so it responds to steroids and avoidance of vitamin D/sunlight/calcium rather than the usual hypercalcemia ladder alone; cardiac sarcoid can cause sudden death and heart block; and neurosarcoidosis can be organ-threatening — so the treatment is stratified by which organs are involved)

Neg: denies missed cardiac sarcoidosis (heart block, arrhythmia, sudden death risk — needs cardiac MRI/PET + monitoring) · denies missed neurosarcoidosis (cranial nerves, meningitis, cord) · denies mismanaged hypercalcemia (1,25-vitamin D-mediated → steroids + avoid vitamin D/sun/calcium load) · denies infection/malignancy mimicking granulomas not excluded (TB, fungal, lymphoma — biopsy shows non-caseating, must exclude infection) · denies missed ocular involvement

SHx: respiratory/constitutional symptoms, organ-specific symptoms (cardiac/neuro/ocular/skin), prior sarcoid + organ involvement, occupational/environmental exposures (mimics — berylliosis), TB risk, ethnicity (more severe in some groups), steroid history

Etiology: systemic granulomatous disease of unknown cause — non-caseating granulomas in affected organs from exaggerated Th1 immune response; activated macrophages produce 1,25-dihydroxyvitamin D → hypercalcemia/hypercalciuria; ACE may be elevated (nonspecific); diagnosis of exclusion (rule out infection/malignancy)

RF: young-to-middle-aged adults · African ancestry (often more severe) · Northern European · female (slightly) · family history

Data: chest imaging (CXR staging, HRCT — hilar adenopathy/interstitial), tissue biopsy (NON-CASEATING granulomas — least invasive accessible site; EBUS for nodes); EXCLUDE infection (TB, fungal — stains/cultures) + malignancy (lymphoma) · calcium (+ ionized), 1,25-vitamin D, 24-h urine calcium, renal function; PFTs (restriction/DLCO); ACE (nonspecific); organ screening: ECG ± cardiac MRI/PET (cardiac), ophthalmology exam, MRI/LP (neuro), LFTs; CBC

DDx: sarcoidosis · tuberculosis · fungal infection · lymphoma/malignancy · hypersensitivity pneumonitis · berylliosis · granulomatosis with polyangiitis · other granulomatous disease · other causes of hypercalcemia

Home Meds: reconcile; for hypercalcemia: STOP vitamin D/calcium supplements, limit sunlight/dietary calcium; glucocorticoids reduce calcitriol; organ-directed immunosuppression per involvement; avoid loop-only management of calcium without addressing the mechanism

Plan

CONSULT: Pulmonology (pulmonary disease, biopsy/EBUS) · Rheumatology (multisystem/immunosuppression) · Cardiology (cardiac sarcoid) · Neurology (neurosarcoidosis) · Ophthalmology (uveitis) · Nephrology/Endocrinology (hypercalcemia) · ICU if cardiac/neuro emergency

– CONFIRM (diagnosis of exclusion): tissue biopsy showing non-caseating granulomas + EXCLUDE infection (TB/fungal) and malignancy (lymphoma) before immunosuppressing
– SCREEN ORGAN INVOLVEMENT (drives treatment + urgency): ECG ± cardiac MRI/PET, ophthalmology exam, neuro evaluation, calcium, renal, LFTs, PFTs
– HYPERCALCEMIA (1,25-vitamin D-mediated):
  • Hydration + STOP vitamin D/calcium supplements, limit sunlight + dietary calcium
  • GLUCOCORTICOIDS (prednisone) — reduce macrophage calcitriol production (the mechanism-directed treatment); ketoconazole/hydroxychloroquine as alternatives per specialist; bisphosphonate if severe
– TREAT BY ORGAN INVOLVEMENT:
  • Asymptomatic/mild (e.g. isolated hilar adenopathy, Löfgren): often observe (many remit spontaneously); NSAIDs for arthralgia/erythema nodosum
  • Symptomatic pulmonary / significant organ: glucocorticoids (prednisone) first-line, then taper; steroid-sparing (methotrexate, azathioprine); TNF inhibitors (infliximab) for refractory per specialist
  • CARDIAC sarcoid: glucocorticoids + immunosuppression; ICD/pacemaker per cardiology (sudden death/heart block risk); cardiac MRI/PET-guided
  • NEUROSARCOIDOSIS: high-dose glucocorticoids + steroid-sparing/TNF inhibitor per neurology
  • OCULAR: topical/systemic steroids + ophthalmology
– Sarcoidosis is the great multisystem mimic — non-caseating granulomas that can land in almost any organ — and the inpatient job is partly diagnostic discipline and partly knowing which organs make it an emergency. The diagnostic discipline is that it's a diagnosis of exclusion: the biopsy shows non-caseating granulomas, but tuberculosis, fungal infection, and lymphoma produce granulomas or look identical, so you exclude those before reaching for immunosuppression. Then three threads dominate management. The hypercalcemia is mechanistically distinctive — the granuloma macrophages themselves convert vitamin D into its active form, so the fix is steroids plus removing the substrate: stop the vitamin D and calcium supplements, limit sunlight, and don't just chase it with fluids and loops. Cardiac sarcoid is the silent killer — it causes heart block and ventricular arrhythmias and sudden death, so it gets actively screened with an ECG and cardiac imaging and often an ICD. And neurosarcoidosis is organ-threatening and needs aggressive steroids. Everything else is stratified: mild disease is often just observed because it remits on its own, while significant organ involvement gets prednisone with steroid-sparing agents.
– PT/OT: per functional/neuro involvement
– Trend: calcium + renal function, oxygenation/PFTs, ECG/cardiac status, neuro status, response to steroids, steroid complications, organ-specific markers
– Escalation triggers: cardiac sarcoid with arrhythmia/heart block → cardiology + monitoring/ICD ± ICU; neurosarcoidosis (cord/brainstem/severe) → neurology + high-dose steroids; severe hypercalcemia → aggressive management; respiratory failure → pulmonology + ICU; sight-threatening uveitis → ophthalmology
– Discharge checklist: diagnosis confirmed (biopsy) + infection/malignancy excluded + organ involvement screened (incl cardiac/neuro/ocular); hypercalcemia managed (steroids + vitamin D/calcium/sun avoidance); organ-directed therapy (steroids ± steroid-sparing/TNF inhibitor); bone/GI/glucose protection; pulmonology/rheumatology + organ specialists follow-up; return precautions (worsening dyspnea, palpitations/syncope — cardiac, neuro symptoms, eye symptoms, hypercalcemia symptoms)

119. Sarcoidosis

/Sarcoidosis · complete reference · non-caseating granulomas, diagnosis of exclusion · 1,25-vitamin D hypercalcemia treated with steroids, cardiac and neuro disease are the emergencies · Full Card

Symptoms / Associated Sx

• A multisystem granulomatous disease — pulmonary (most common: cough, dyspnea, bilateral hilar lymphadenopathy, interstitial disease — staged by chest imaging) and constitutional symptoms (fatigue, fevers, weight loss)

• Hypercalcemia and hypercalciuria, skin disease (erythema nodosum, lupus pernio), ocular disease (uveitis), cardiac disease (conduction block, arrhythmia, cardiomyopathy — which can be sudden), neurologic disease (neurosarcoidosis — cranial neuropathy, meningitis, mass), hepatic disease, and arthritis; Löfgren syndrome (acute, good prognosis)

• Three threads matter most inpatient: the hypercalcemia is driven by granuloma macrophages making active 1,25-vitamin D — so it responds to steroids and avoidance of vitamin D, sunlight, and calcium rather than the usual hypercalcemia ladder alone; cardiac sarcoid can cause sudden death and heart block; and neurosarcoidosis can be organ-threatening — so the treatment is stratified by which organs are involved

Neg

• Pt denies missed cardiac sarcoidosis (heart block, arrhythmia, sudden death risk — needs cardiac MRI or PET and monitoring) and missed neurosarcoidosis (cranial nerves, meningitis, cord).

• Pt denies mismanaged hypercalcemia (1,25-vitamin D-mediated → steroids and avoid vitamin D, sun, and calcium load) and infection or malignancy mimicking granulomas not being excluded (TB, fungal disease, lymphoma — the biopsy shows non-caseating granulomas, but infection must be excluded).

• Pt denies missed ocular involvement.

Social History (SHx)

• Respiratory and constitutional symptoms, and organ-specific symptoms (cardiac, neuro, ocular, skin).

• Prior sarcoid with organ involvement and occupational or environmental exposures (mimics — berylliosis).

• TB risk, ethnicity (more severe in some groups), and steroid history.

Main Etiology

• A systemic granulomatous disease of unknown cause — non-caseating granulomas in affected organs from an exaggerated Th1 immune response

• Activated macrophages produce 1,25-dihydroxyvitamin D → hypercalcemia and hypercalciuria; ACE may be elevated (nonspecific)

• It is a diagnosis of exclusion (rule out infection and malignancy)

RF

• Non-modifiable: young-to-middle-aged adults, African ancestry (often more severe), Northern European ancestry, female sex (slightly), and family history.

Data

• Chest imaging (CXR staging, HRCT — hilar adenopathy or interstitial disease), a tissue biopsy (non-caseating granulomas — the least invasive accessible site; EBUS for nodes); exclude infection (TB, fungal — stains and cultures) and malignancy (lymphoma)

• Calcium (and ionized calcium), 1,25-vitamin D, 24-hour urine calcium, renal function; PFTs (restriction, DLCO); ACE (nonspecific)

• Organ screening: ECG with possible cardiac MRI or PET (cardiac), an ophthalmology exam, MRI and LP (neuro), LFTs; CBC.

DDx

Sarcoidosis · tuberculosis · fungal infection · lymphoma or malignancy · hypersensitivity pneumonitis · berylliosis · granulomatosis with polyangiitis · other granulomatous disease · other causes of hypercalcemia

Home Meds

• For hypercalcemia: stop vitamin D and calcium supplements, limit sunlight and dietary calcium; glucocorticoids reduce calcitriol.

• Organ-directed immunosuppression per involvement.

• Avoid loop-only management of calcium without addressing the mechanism; reconcile.

Plan

CONSULT: Pulmonology (pulmonary disease, biopsy or EBUS) · Rheumatology (multisystem disease, immunosuppression) · Cardiology (cardiac sarcoid) · Neurology (neurosarcoidosis) · Ophthalmology (uveitis) · Nephrology or Endocrinology (hypercalcemia) · ICU if cardiac or neuro emergency

• Confirm (a diagnosis of exclusion): a tissue biopsy showing non-caseating granulomas and exclude infection (TB, fungal) and malignancy (lymphoma) before immunosuppressing.

• Screen organ involvement (drives treatment and urgency): ECG with possible cardiac MRI or PET, an ophthalmology exam, a neuro evaluation, calcium, renal function, LFTs, and PFTs.

• Hypercalcemia (1,25-vitamin D-mediated):

• • Hydration and stop vitamin D and calcium supplements, limit sunlight and dietary calcium.

• • Glucocorticoids (prednisone) — reduce macrophage calcitriol production (the mechanism-directed treatment); ketoconazole or hydroxychloroquine as alternatives per specialist; a bisphosphonate if severe.

• Treat by organ involvement:

• • Asymptomatic or mild (e.g. isolated hilar adenopathy, Löfgren): often observe (many remit spontaneously); NSAIDs for arthralgia or erythema nodosum.

• • Symptomatic pulmonary or significant organ disease: glucocorticoids (prednisone) first-line, then taper; steroid-sparing agents (methotrexate, azathioprine); TNF inhibitors (infliximab) for refractory disease per specialist.

• • Cardiac sarcoid: glucocorticoids with immunosuppression; an ICD or pacemaker per cardiology (sudden death and heart block risk); cardiac MRI or PET-guided.

• • Neurosarcoidosis: high-dose glucocorticoids with a steroid-sparing agent or TNF inhibitor per neurology.

• • Ocular: topical or systemic steroids with ophthalmology.

• PT/OT: per functional or neuro involvement.

• Trend: calcium and renal function, oxygenation and PFTs, ECG and cardiac status, neuro status, the response to steroids, steroid complications, and organ-specific markers.

• Escalation triggers: cardiac sarcoid with arrhythmia or heart block → cardiology and monitoring or ICD with possible ICU; neurosarcoidosis (cord, brainstem, or severe disease) → neurology and high-dose steroids; severe hypercalcemia → aggressive management; respiratory failure → pulmonology and ICU; sight-threatening uveitis → ophthalmology.

• Discharge checklist: the diagnosis confirmed (biopsy) with infection and malignancy excluded and organ involvement screened (including cardiac, neuro, ocular); hypercalcemia managed (steroids with vitamin D, calcium, and sun avoidance); organ-directed therapy (steroids with a possible steroid-sparing agent or TNF inhibitor); bone, GI, and glucose protection; pulmonology and rheumatology and organ specialist follow-up; return precautions for worsening dyspnea, palpitations or syncope (cardiac), neuro symptoms, eye symptoms, or hypercalcemia symptoms.

Red Flags

• Palpitations, syncope, or heart block → cardiac sarcoidosis with sudden death risk; cardiac MRI or PET and monitoring.

• Cranial neuropathy, meningitis, or a cord lesion → neurosarcoidosis; high-dose steroids.

• Hypercalcemia → 1,25-vitamin D-mediated; steroids and removal of vitamin D, calcium, and sun, not just fluids and loops.

• Granulomas on biopsy → still exclude TB, fungal disease, and lymphoma before immunosuppressing.

• Eye pain or vision change → uveitis; ophthalmology and steroids.

Senior IM Resident Pearls

• It's a diagnosis of exclusion. Non-caseating granulomas still demand ruling out TB, fungal infection, and lymphoma before immunosuppression.

• The hypercalcemia is mechanistically special. Granuloma macrophages make active vitamin D — treat with steroids and remove vitamin D, calcium, and sunlight.

• Cardiac sarcoid is the silent killer. Heart block and ventricular arrhythmia cause sudden death — screen with ECG and cardiac imaging, and consider an ICD.

• Neurosarcoidosis is organ-threatening. It earns high-dose steroids and often a steroid-sparing agent or TNF inhibitor.

• Mild disease is often observed. Many cases, including Löfgren syndrome, remit spontaneously without immunosuppression.

• ACE is unreliable. It's neither sensitive nor specific — don't lean on it for diagnosis or monitoring.

• Common mistake: chasing the sarcoid hypercalcemia with fluids and loops while continuing vitamin D supplements and missing that steroids are the mechanism-directed fix.

Rheumatology / Heme-Onc — EMERGENCY

120. Macrophage Activation Syndrome / HLH

/MASHLH · hyperinflammatory cytokine storm · fever + splenomegaly + cytopenias + VERY high ferritin + high triglycerides + low fibrinogen · rare but rapidly fatal — recognize early, treat urgently · Super Compact

Sx: a hyperinflammatory syndrome (uncontrolled cytokine storm with macrophage activation/hemophagocytosis) — persistent high fever, hepatosplenomegaly, cytopenias (≥2 lines), and rapid clinical deterioration; hepatic dysfunction, coagulopathy/bleeding, CNS involvement (seizure, altered mentation), multi-organ failure; macrophage activation syndrome (MAS) is HLH secondary to rheumatic disease (esp adult-onset Still, systemic JIA, SLE) · (this is a true emergency that is missed because it hides inside another illness — a deteriorating patient with sepsis, a rheumatic flare, or a malignancy who isn't behaving as expected, with a skyrocketing ferritin and falling counts, should trigger an HLH workup, because untreated it is rapidly and frequently fatal and the treatment must start before full criteria are confirmed)

Neg: denies HLH/MAS not recognized in a deteriorating patient (rapidly fatal — very high ferritin + cytopenias + fever should prompt workup) · denies trigger not identified/treated (infection esp EBV, malignancy esp lymphoma, rheumatic flare, drug) · denies missed CNS-HLH · denies treating as sepsis alone while the hyperinflammation progresses · denies delaying treatment to await all criteria

SHx: underlying rheumatic disease (Still/sJIA/SLE — MAS), recent infection (EBV/CMV/other), malignancy history (esp lymphoma), immunosuppression, recent drugs, prior episodes, family history (primary/genetic HLH in younger)

Etiology: dysregulated, uncontrolled immune activation — impaired cytotoxic (NK/T-cell) function → unchecked macrophage and T-cell activation → cytokine storm (IL-1, IL-6, IL-18, IFN-γ, high soluble CD25) + hemophagocytosis; primary (genetic) or secondary (infection, malignancy, rheumatic disease = MAS); a trigger usually present

RF: systemic rheumatic disease (Still/sJIA/SLE) · EBV/viral infection · hematologic malignancy (lymphoma) · immunosuppression · genetic predisposition (younger/recurrent)

Data (HLH-2004 / MAS criteria): VERY high ferritin (often very markedly elevated), cytopenias (≥2 lines), high triglycerides, LOW fibrinogen, high soluble CD25 (sIL-2R), low/absent NK-cell activity, hemophagocytosis on marrow/tissue, fever, splenomegaly; in MAS, watch the trend: rising ferritin with a paradoxically FALLING ESR and fibrinogen; LFTs (hepatitis), coagulation/DIC, triglycerides; identify the trigger: infection workup (EBV/CMV PCR, cultures), malignancy evaluation (imaging, marrow/node biopsy — exclude lymphoma); LP if CNS

DDx: HLH/MAS · severe sepsis/septic shock · malignancy (lymphoma — can cause AND mimic) · adult-onset Still/severe rheumatic flare · severe liver failure · DIC from other cause · multi-organ dysfunction syndrome

Home Meds: reconcile; treat/withdraw triggers (treat infection, stop offending drug); urgent immunosuppression — do NOT delay for complete criteria; supportive (transfusion for coagulopathy, organ support); coordinate hematology + the relevant underlying-disease specialist

Plan

CONSULT: Hematology (URGENT — HLH diagnosis/therapy) · Rheumatology (if MAS/underlying rheumatic disease) · Infectious Disease (trigger — EBV/infection) · Oncology (lymphoma) · ICU (organ support — usually needed)

– RECOGNIZE EARLY + WORK UP URGENTLY: in a deteriorating patient with very high ferritin + cytopenias + fever, send the HLH panel (ferritin, triglycerides, fibrinogen, soluble CD25, NK activity), marrow biopsy (hemophagocytosis), and trigger workup — do NOT wait for all criteria to start treatment in a deteriorating patient
– IDENTIFY + TREAT THE TRIGGER (essential): infection (esp EBV — antiviral/rituximab for EBV-driven; treat other infections), malignancy (lymphoma — treat the lymphoma), rheumatic flare (MAS), drug (stop it)
– IMMUNOSUPPRESSION / HLH-DIRECTED THERAPY (urgent, per hematology):
  • High-dose glucocorticoids (e.g. dexamethasone or IV methylprednisolone pulse) — first-line, start promptly
  • MAS (rheumatic-associated): high-dose glucocorticoids ± anakinra (IL-1 inhibitor) ± cyclosporine — often responsive; per rheumatology
  • Severe/primary/refractory HLH: HLH-94 protocol (dexamethasone + etoposide) ± cyclosporine; emapalumab (anti-IFN-γ) for refractory primary HLH; consider hematopoietic stem cell transplant for primary/relapsing per hematology
  • CNS-HLH: intrathecal therapy per protocol
– SUPPORTIVE / ORGAN SUPPORT: transfuse for coagulopathy/bleeding (cryoprecipitate/FFP for low fibrinogen, platelets), manage DIC, organ support, ICU monitoring; treat hepatic failure, respiratory/renal support as needed
– HLH and its rheumatic cousin MAS are the cytokine storm that kills by hiding — they almost always sit inside another illness, so the patient looks like refractory sepsis, a vicious lupus or Still flare, or a complication of lymphoma, and the diagnosis is missed precisely because everyone is anchored on the underlying problem. The pattern to burn in is a patient who is deteriorating faster than their apparent diagnosis explains, with a ferritin that is climbing into the thousands or tens of thousands, falling blood counts across at least two lines, high triglycerides, and — the counterintuitive tell in MAS — a fibrinogen and ESR that are dropping even as inflammation rages, because consumptive coagulopathy has set in. When you see it, you do two things at once: hunt for and treat the trigger (EBV and lymphoma above all), and start immunosuppression urgently with high-dose steroids, because waiting to confirm every HLH-2004 criterion in a crashing patient costs lives. MAS from rheumatic disease often responds beautifully to steroids plus anakinra; severe or primary HLH needs the HLH-94 etoposide-based protocol, and the sickest go to ICU for organ support and to hematology for everything beyond the first steroid dose.
– PT/OT: rehabilitation in recovery phase
– Trend: ferritin (response/relapse), CBC/cytopenias, fibrinogen/triglycerides/coagulation, LFTs, soluble CD25, organ function, trigger workup, response to therapy, neuro status
– Escalation triggers: multi-organ failure / hemodynamic instability / severe coagulopathy → ICU + urgent HLH-directed therapy + hematology; CNS involvement → neuro + intrathecal therapy; refractory to first-line → etoposide/emapalumab/transplant evaluation; underlying lymphoma → urgent oncology; relapse → re-intensify per hematology
– Discharge checklist: (after acute crisis resolved) trigger identified + treated; HLH/MAS therapy + taper plan; underlying disease (rheumatic/malignancy/infection) management; transfusion/organ-support needs resolving; hematology + underlying-disease specialist follow-up; monitoring for relapse (ferritin/counts); education on recurrence warning signs; return precautions (recurrent high fever, bruising/bleeding, confusion, rapid deterioration, abdominal swelling)

120. Macrophage Activation Syndrome / HLH

/MASHLH · complete reference · hyperinflammatory cytokine storm · recognize early in the deteriorating patient, identify the trigger, start immunosuppression before full criteria confirm · Full Card

Symptoms / Associated Sx

• A hyperinflammatory syndrome (an uncontrolled cytokine storm with macrophage activation and hemophagocytosis) — persistent high fever, hepatosplenomegaly, cytopenias (at least 2 lines), and rapid clinical deterioration

• Hepatic dysfunction, coagulopathy or bleeding, CNS involvement (seizure, altered mentation), and multi-organ failure; macrophage activation syndrome (MAS) is HLH secondary to rheumatic disease (especially adult-onset Still disease, systemic JIA, SLE)

• This is a true emergency that is missed because it hides inside another illness — a deteriorating patient with sepsis, a rheumatic flare, or a malignancy who isn't behaving as expected, with a skyrocketing ferritin and falling counts, should trigger an HLH workup, because untreated it is rapidly and frequently fatal and the treatment must start before full criteria are confirmed

Neg

• Pt denies HLH or MAS not being recognized in a deteriorating patient (rapidly fatal — a very high ferritin with cytopenias and fever should prompt the workup) and a trigger not identified or treated (infection especially EBV, malignancy especially lymphoma, a rheumatic flare, a drug).

• Pt denies missed CNS-HLH and treating as sepsis alone while the hyperinflammation progresses.

• Pt denies delaying treatment to await all criteria.

Social History (SHx)

• An underlying rheumatic disease (Still disease, sJIA, SLE — MAS) and recent infection (EBV, CMV, other).

• Malignancy history (especially lymphoma), immunosuppression, and recent drugs.

• Prior episodes and family history (primary or genetic HLH in younger patients).

Main Etiology

• Dysregulated, uncontrolled immune activation — impaired cytotoxic (NK and T-cell) function leading to unchecked macrophage and T-cell activation → a cytokine storm (IL-1, IL-6, IL-18, IFN-γ, high soluble CD25) and hemophagocytosis

• Primary (genetic) or secondary (infection, malignancy, rheumatic disease = MAS)

• A trigger is usually present

RF

• Modifiable: EBV or viral infection, immunosuppression, and offending drugs.

• Non-modifiable: a systemic rheumatic disease (Still disease, sJIA, SLE), a hematologic malignancy (lymphoma), and genetic predisposition (younger or recurrent disease).

Data (HLH-2004 / MAS criteria)

• A very high ferritin (often very markedly elevated), cytopenias (at least 2 lines), high triglycerides, a low fibrinogen, a high soluble CD25 (sIL-2R), low or absent NK-cell activity, and hemophagocytosis on marrow or tissue, fever, and splenomegaly

• In MAS, watch the trend: a rising ferritin with a paradoxically falling ESR and fibrinogen; LFTs (hepatitis), coagulation studies (DIC), triglycerides

• Identify the trigger: an infection workup (EBV and CMV PCR, cultures), a malignancy evaluation (imaging, marrow or node biopsy — exclude lymphoma); an LP if CNS involvement.

DDx

HLH or MAS · severe sepsis or septic shock · malignancy (lymphoma — can cause and mimic it) · adult-onset Still disease or a severe rheumatic flare · severe liver failure · DIC from another cause · multi-organ dysfunction syndrome

Home Meds

• Treat or withdraw triggers (treat infection, stop the offending drug).

• Start urgent immunosuppression — do not delay for complete criteria.

• Provide supportive care (transfusion for coagulopathy, organ support); coordinate hematology and the relevant underlying-disease specialist; reconcile.

Plan

CONSULT: Hematology (urgent — HLH diagnosis and therapy) · Rheumatology (if MAS or underlying rheumatic disease) · Infectious Disease (trigger — EBV or infection) · Oncology (lymphoma) · ICU (organ support — usually needed)

• Recognize early and work up urgently: in a deteriorating patient with a very high ferritin, cytopenias, and fever, send the HLH panel (ferritin, triglycerides, fibrinogen, soluble CD25, NK activity), a marrow biopsy (hemophagocytosis), and a trigger workup — do not wait for all criteria to start treatment in a deteriorating patient.

• Identify and treat the trigger (essential): infection (especially EBV — antiviral or rituximab for EBV-driven disease; treat other infections), malignancy (lymphoma — treat the lymphoma), a rheumatic flare (MAS), or a drug (stop it).

• Immunosuppression / HLH-directed therapy (urgent, per hematology):

• • High-dose glucocorticoids (e.g. dexamethasone or IV methylprednisolone pulse) — first-line, start promptly.

• • MAS (rheumatic-associated): high-dose glucocorticoids with possible anakinra (an IL-1 inhibitor) and cyclosporine — often responsive; per rheumatology.

• • Severe, primary, or refractory HLH: the HLH-94 protocol (dexamethasone with etoposide) with possible cyclosporine; emapalumab (anti-IFN-γ) for refractory primary HLH; consider hematopoietic stem cell transplant for primary or relapsing disease per hematology.

• • CNS-HLH: intrathecal therapy per protocol.

• Supportive and organ support: transfuse for coagulopathy or bleeding (cryoprecipitate and FFP for low fibrinogen, platelets), manage DIC, provide organ support, and ICU monitoring; treat hepatic failure and provide respiratory or renal support as needed.

• PT/OT: rehabilitation in the recovery phase.

• Trend: ferritin (response or relapse), CBC and cytopenias, fibrinogen, triglycerides, and coagulation, LFTs, soluble CD25, organ function, the trigger workup, the response to therapy, and neuro status.

• Escalation triggers: multi-organ failure, hemodynamic instability, or severe coagulopathy → ICU, urgent HLH-directed therapy, and hematology; CNS involvement → neurology and intrathecal therapy; refractory to first-line → etoposide, emapalumab, or transplant evaluation; an underlying lymphoma → urgent oncology; relapse → re-intensify per hematology.

• Discharge checklist: (after the acute crisis resolves) the trigger identified and treated; HLH/MAS therapy with a taper plan; management of the underlying disease (rheumatic, malignancy, or infection); transfusion and organ-support needs resolving; hematology and underlying-disease specialist follow-up; monitoring for relapse (ferritin, counts); education on recurrence warning signs; return precautions for recurrent high fever, bruising or bleeding, confusion, rapid deterioration, or abdominal swelling.

Red Flags

• A patient deteriorating faster than their diagnosis explains, with a skyrocketing ferritin → work up HLH/MAS immediately.

• A rising ferritin with a falling fibrinogen and ESR → the counterintuitive MAS signature; consumptive coagulopathy is setting in.

• Cytopenias across two or more lines with fever and splenomegaly → HLH until excluded; don't anchor on sepsis alone.

• Altered mentation or seizure → CNS-HLH; needs intrathecal therapy.

• Awaiting all HLH-2004 criteria in a crashing patient → don't; start steroids and treat the trigger.

Senior IM Resident Pearls

• It kills by hiding. HLH and MAS sit inside sepsis, a rheumatic flare, or lymphoma — suspect them when the patient deteriorates faster than the apparent diagnosis explains.

• The MAS tell is counterintuitive. A climbing ferritin with a falling fibrinogen and ESR signals consumptive coagulopathy, not improving inflammation.

• Don't wait for all the criteria. In a crashing patient, start high-dose steroids and pursue the trigger — confirmation can come alongside treatment.

• Find and treat the trigger. EBV and lymphoma above all — treating the driver is as important as immunosuppression.

• MAS often responds to steroids plus anakinra. Rheumatic-associated disease is frequently steroid- and IL-1-inhibitor responsive.

• Severe HLH needs etoposide. The HLH-94 protocol is the backbone for severe or primary disease; emapalumab and transplant for refractory primary disease.

• Common mistake: treating a deteriorating febrile patient as refractory sepsis while the ferritin climbs and the fibrinogen falls — the missed cytokine storm.