Rheumatology

Editor: Meridith Balbach MD
Reviewed by: Tyler Reese, MD

Overview: Classification of Rheumatic Disease

Author: Meridith Balbach

Classification approach to select rheumatologic diseases. See specific sections for comprehensive review of each specific clinical entity.

Please refer to physical handbook page 540 for chart showing classification of rheumatic diseases.

Abbreviations: - SpA = seronegative spondyloarthropathy - RA = rheumatoid arthritis - SLE = systemic lupus erythematosus - SSc = systemic sclerosis - UCTD = undifferentiated connective tissue disease - MCTD = mixed connective tissue disease - IgG4-RD = IgG4-related disease - GPA = granulomatosis with polyangiitis - EGPA = eosinophilic granulomatosis with polyangiitis - MPA = microscopic polyangiitis - HSP = Henoch Schönlein purpura - Cryo = cryoglobulinemia - CTD = connective tissue disease - PMR = polymyalgia rheumatica - FMF = familial Mediterranean fever - EDS = Ehlers-Danlos syndrome

Approach to Joint Pain

Author: Tina Arkee

Background

MSK complaints account for >20% of all outpatient visits in the US
The goal is to formulate a ddx based on good history taking and thorough physical exam that leads to accurate diagnosis and timely therapy while avoiding excessive diagnostic testing and unnecessary treatment

History

Articular (within the joint) vs. extra-articular (involving muscles, tendons, bursae, bones) - Articular: pain with passive and active ROM, swelling, crepitus, joint instability, joint deformity - Extra-articular: pain with active ROM only, may have focal tenderness near the joint, typically no crepitus, instability, or deformity

Chronology - Acute: < 6 weeks - Chronic: >6 weeks

Inflammatory vs. noninflammatory - Inflammatory: swelling, warmth, erythema, worse with rest, morning stiffness > 30 min - 1 hr - Non-inflammatory: worse with activity, morning stiffness < 30 min - 1 hr

Localized (monoarticular) vs. diffuse (oligo/polyarticular) - Monoarticular: 1 joint - Oligoarticular: 2-4 joints - Polyarticular: >4 joints

Symmetric vs asymmetric

Size of joints involved (small vs. large)

Presence/absence of signs & symptoms of systemic inflammation

Physical Exam

Visually inspect the affected joint. Inflamed joints may look red, swollen, or deformed.
Palpate the joint for warmth, effusion, focal tenderness (inflammatory) or bony enlargement (non-inflammatory)
Perform passive and active ROM exam. Articular joint pain is elicited by passive and active ROM and may also have crepitus. Extra-articular joint pain is only elicited by active ROM.
Look for signs of systemic inflammation, including rashes, mucosal ulcers, hair and nail changes.
For polyarticular complaints, the goal is to determine inflammatory vs noninflammatory
Inflammatory: joint swelling, warmth, visible deformities. More common in MCP and wrist
Non-inflammatory: bony enlargement, Heberden's nodes (DIP), Bouchard's nodes (PIP), CMC squaring, prominence of the medial tibial plateau, absence of joint effusions (except the knees with severe OA). More common in DIP and weight-bearing joints.

Evaluation

CBC w/diff, ESR, CRP
Synovial fluid analysis (if joint effusion present and especially with a new acute monoarthritis; see "Arthrocentesis Quick Look" section)
Disease-specific serologies, as indicated
X-ray: may be normal in early disease; can be used to monitor disease progression
Inflammatory arthritis: early changes include soft tissue swelling and periarticular demineralization → later changes include erosions, uniform joint space narrowing, and joint subluxation
Non-inflammatory arthritis (i.e. osteoarthritis): non-uniform joint space narrowing, osteophytes, subchondral sclerosis, subchondral cysts
Ultrasound: May demonstrate findings of inflammatory arthritis including synovial hypertrophy, tissue vascularity (via doppler) and effusion; structure localization may guide arthrocentesis
MRI: more sensitive than xray and CT, but not necessarily more specific

Please refer to physical handbook page 542 for a diagram of joint pain diagnostic algorithm.

Arthrocentesis Quick Look

Author: Tina Arkee

Indications for arthrocentesis:

Monoarthritis (acute or chronic)
Suspicion for infection, crystal arthropathy, or hemarthrosis
Trauma with joint effusion
When diagnosis is unclear despite history and other workup

Relative Contraindications to arthrocentesis

Extensive cellulitis or psoriatic plaque around the site of interest (risk of introducing bacteria into a sterile space)
Coagulopathy
Bacteremia
Concern for infection of a prosthetic joint – these should only be tapped by Ortho!

What to order

Synovial fluid exam (includes cell count and crystal exam). *Note: may see similar cell counts in gout and septic arthritis. The presence of crystals does not necessarily rule out septic arthritis.
Body fluid gram stain and culture

Who should tap? Typically, start by consulting the service appropriate for the clinical entity highest on your differential (i.e. orthopedics if concern for septic arthritis; rheumatology if concern for gout)

Synovial Fluid Analysis

	Noninflammatory	Inflammatory	Septic	Hemorrhagic
Appearance	Clear straw/yellow	Clear to cloudy yellow	Opaque/turbid yellow green	Reddish brown
Cell count	<2000	>2000–50,000	>50,000	<2000
% of PMNs	<25%	>50%	>75%	<50%
Culture	Negative	Negative	Positive	Negative
Crystals	No	Yes Gout: needle shaped, negatively birefringent Pseudogout: rhomboid shaped, positively birefringent	No	No
DDx	Osteoarthritis, trauma, osteonecrosis	Inflammatory arthritis, crystal arthritis, sarcoidosis, indolent infections	Septic arthritis	Trauma, coagulopathy

Crystals

Monosodium urate: needle-shaped, negatively birefringent
Sensitivity is generally good (>90s%)
Calcium pyrophosphate dihydrate: rhomboid-shaped, positively birefringent (weakly), and appear blue when parallel to the polarizer
Weak birefringence significantly reduces sensitivity

Biologic Overview

Author: Sara Treat

Background

"-cept" refers to fusion of a receptor to the Fc part of human immunoglobulin G1 (IgG1)
"-mab" indicates a monoclonal antibody (mAb)
"-ximab" indicates a chimeric mAb
"-zumab" indicates a humanized mAb
"-umab" indicates a fully human mAb
"-tinib" indicates a tyrosine kinase inhibitor (small molecule inhibitors, not true biologics)

Safety & Monitoring

Screening prior to initiation varies based on specific agent, discuss with rheumatology. Consider latent TB (via IGRA), Hep B/C, HIV, age-appropriate cancer screening, pregnancy
Labs monitoring: CBC (for cytopenias, particularly with MTX, JAKi, IL-6i), LFTs (for hepatotoxicity, particularly with MTX, leflunomide, TNFi), Cr (especially with MTX and JAKi), lipid panel (for hypercholesterolemia, especially with JAKi and IL-6i) every 3 months minimum (depending on agent and disease)
Avoid live vaccines; use 2022 ACR guidelines for vaccinations in patients with rheumatic and MSK disease. Administer vaccines prior to initiation when possible

B-cell Depletion and Inhibition

Generic Name (Brand Name)	Mechanism of Action	Common Uses	Common Side Effects
Belimumab (Benlysta)	IgG1-lambda mAb that prevents survival of B-lymphocytes by blocking the binding of soluble human B lymphocyte stimulator protein (BLyS) to receptors on B lymphocytes	lupus nephritis, SLE	GI symptoms, hypersensitivity reaction, infections, psychiatric disturbances
Rituximab (Rituxan) and Inebilizumab (Uplinza)	mAb against CD20 antigen on surface of B-cells; B cell depletion via ab-dependent cell-mediated cytotoxicity function of NK cells	CLL, Non-Hodgkin lymphomas, GPA, microscopic polyangiitis, pemphigus vulgaris, RA; many off-label uses (GvHD, lupus nephritis, MG, neuromyelitis optica). Inebelizumab is specifically approved for IgG4-RD.	Hypogammaglobulinemia (may be persistent), infusion reaction, HTN, peripheral edema, night sweats, fever, weight gain, Angioedema, arthralgias, ⇑ ALT, hypophosphatemia, hematologic abnormalities

Complement-Inhibition

Generic Name (Brand Name)	Mechanism of Action	Common Uses	Common Side Effects
Avacopan (Tavneos)	Complement 5a receptor antagonist	ANCA vasculitis	HTN, HA, rash, GI upset/diarrhea, hepatoxicity
Eculizumab (Soliris) and Ravulizumab (Ultomiris)	mAb against C5, preventing cleavage to C5a and C5b	aHUS, PNH, myasthenia gravis, neuromyelitis optica; off-label lupus nephritis, catastrophic APS, transplant-related TMA	Infection (particularly encapsulated organisms), HA, HTN, infusion reactions

Costimulation Blockade

Generic Name (Brand Name)	Mechanism of Action	Common Uses	Common Side Effects
Abatacept (Orencia)	inhibits T-cell activation by binding CD80 and CD86 on APCs, thus blocking the required CD28 ixn between APCs and T cells.	RA, psoriasis, JIA	nausea, UTI, HA, URI, Ab development

Interleukin Inhibition

Type of IL inhibition	Generic Name (Brand Name)	Mechanism of Action	Common Uses	Common Side Effects
IL-1	Anakinra (Kineret)	IL-1 receptor antagonist	IL-1 receptor antagonist deficiency, gout flares, FMF, HLH, Adult-onset Still's disease (AOSD), sJIA, refractory RA	HA, vomiting, infections, nasopharyngitis, Ab development; in RA: eosinophilia, decreased WBC
IL-1	Canakinumab (Ilaris)	mAb against IL-1β	AOSD, sJIA, Cryopyrin-associated periodic syndromes (CAPS), FMF, hyperimmunoglobin D syndrome, TRAPS; off-label: gout flare	weight gain, GI sx, HA, vertigo, serious infections
IL-1	Rilonacept (Arcalyst)	IL-1 soluble decoy receptor	Cryopyrin-associated periodic syndrome, deficiency IL-1 receptor antagonist, pericarditis	Ab development, infection (including serious infection), local site reaction, URI
IL-5	Mepolizumab (Nucala)	mAb against IL-5, direct IL-5 antagonist	Eosinophilic asthma, EGPA, hypereosinophilic syndromes, rhinosinusitis with nasal polyps	local injection site reaction, HA
IL-6	Tocilizumab (Actemra)	IL-6 receptor antagonist	GCA, RA, JIA, neuromyelitis optica, systemic sclerosis, ILD, cytokine release syndrome for CAR T cells	⇑ serum cholesterol, ⇑AST/ALT, infusion rxn, HSV infection (<2%)
IL-6	Sarilumab (Kevzara)	IL-6 receptor antagonist (soluble + membrane-bound)	RA	⇑ AST/ALT, HSV infection (<2%)
IL-23	Guselkumab (Tremfya)	human IgG1 mAb against IL-23	PsA, psoriasis	URI, tinea, GI sx
IL-23	Risankizumab (Skyrizi)	mAb against IL-23 via p19	IBD, PsA, psoriasis, JIA	nausea, UTI, HA, URI, Ab development
IL-12/23	Ustekinumab (Stelara)	mAb against IL-12 + IL-23	IBD, psoriasis	nasopharyngitis, Ab development, acne vulgaris, GI sx, GU sx
IL-17	Brodalumab (Siliq)	human IgG1 mAb against IL-17A	Psoriasis	infection, tinea, GI, suicidal ideation and behavior (REMS program)
IL-17	Ixekizumab (Taltz)	human IgG4 mAb against IL-17A	AS, PsA, psoriasis	infection, tinea, neutropenia, Ab development, URI, Crohn's (<1%)
IL-17	Secukinumab (Cosentyx)	human IgG1 mAb against IL-17A	AS, psoriasis	nasopharyngitis, GI, IBD (<1%)
IL-17	Bimekizumab (Bimzelx)	Humanized IgG1 mAb against IL-17A and IL-17F	Psoriasis, PsA, axial spondyloarthritis	URI, fungal infections, HA, GI

Kinase Inhibition

BLACK BOX warning for mortality, increased malignancies, thrombosis (DVT and PE), and increased cardiovascular events. Data is from tofacitinib, but warning is applied to all JAK inhibitors.

Generic Name (Brand Name)	Mechanism of Action	Common Uses	Common Side Effects
Abrocitinib (Cibinqo)	JAK-1 inhibitor	Atopic dermatitis	nausea, infections, nasopharyngitis
Baracitinib (Olumiant)	JAK-1 and JAK-2 inhibitor	RA, alopecia areata, off-label: COVID-19	URI, nausea, ⇑AST/ALT; <1% lymphoma
Ruxolitinib (Jakafi)	JAK-1 and JAK-2 inhibitor	Topical: atopic dermatitis and vitiligo Oral: GvHD, polycythemia vera, myelofibrosis	HTN, HLD, GI upset, ⇑ LFTs, anemia, infection, dizziness, muscle spasm, fever
Tofacitinib (Xeljanz)	JAK-1 and JAK-3 inhibitor	RA, UC, JIA, psoriatic arthritis	nasopharyngitis, skin rash, GI sx, GU sx; <1% lymphoma
Upadacitinib (Rinvoq)	Non-specific JAK inhibitor	RA	URI, nausea, neutropenia, ⇑AST, ⇑CPK

TNF Inhibition

Generic Name (Brand Name)	Mechanism of Action	Common Uses	Common Side Effects
Adalilumab (Humira)	mAb against TNFα	RA, IBD, AS, psoriasis, uveitis, hidradenitis suppurativa	infection (esp mycobacterial and fungal), drug induced lupus, skin rash, HA, URI, ⇑ CPK, +ANA titer (12%), Ab development (3-26%)
Certolizumab (Cimzia)	humanized mAb Fab fragment against TNFα	RA, Crohn's, AS, psoriasis; *approved for pregnancy	skin rash, nausea, URI
Etanercept (Enbrel)	TNF receptor linked to Fc portion of IgG1 binds TNF	RA, AS, psoriasis, JIA	skin rash, diarrhea, +ANA titer (11%)
Golimumab (Simponi)	mAb against TNFα	RA, UC, AS, psoriasis, JIA	URI, Ab development (16-38%), +ANA titer (4-17%)
Infliximab (Remicade)	chimeric mAb against TNFα	RA, IBD, AS, psoriasis	abd pain, URI sx, anemia, ⇑ ALT, Ab development (10-50%)

Rheumatology Lab Testing

Author: Meridith Balbach

Test	Quick Associations	Additional Facts
ANA w/ reflex (performed if ANA ≥1:80 and includes anti-dsDNA, SSA, SSB, ScL 70, Smith, RNP)	Screening for connective tissue disease	Not disease-specific; pattern (homogeneous, speckled, nucleolar, centromere) may help narrow differential; in particular, consider addtl workup if centromere or nucleolar pattern (i.e. anti-centromere, anti-Pm/Scl)
• Anti-dsDNA	SLE	Highly specific; correlates with renal disease and disease activity; included on reflex and can also be ordered as a separate test
• Anti-Smith	SLE	Specific but low sensitivity (~20–30%)
• Anti-SSA (Ro)	Sjögren's, SLE, neonatal lupus	Associated with congenital heart block in neonates if maternal +SSA
• Anti-SSB (La)	Sjögren's (almost always with SSA)	Less sensitive; typically coexists with SSA
• Anti-RNP	MCTD, SLE	Seen in Raynaud's, swollen hands; overlaps with myositis
• Anti-Scl-70 (Topo I)	Diffuse systemic sclerosis	Associated with ILD and aggressive skin disease
Anti-centromere	Limited systemic sclerosis	Associated with PAH, CREST features, slower progression; consider if +ANA with centromere pattern (not part of reflex)
Anti-histone	Drug-induced lupus	Classically associated with hydralazine, procainamide, isoniazid
Anti-Jo-1	Antisynthetase syndrome (ILD + myositis + Raynaud's)	Associated with mechanic's hands, poor ILD prognosis
Anti-CCP	RA	High specificity (~95%); predictive of erosive disease
RF	RA (nonspecific)	Marker of chronic humoral immune stimulation; seen in HCV, cryoglobulinemia, aging
C3 / C4	SLE, cryoglobulinemia	Low C3/C4 suggests active immune complex disease; C4 often falls first
ANCA / PR3 / MPO	GPA, MPA, EGPA	PR3 (c-ANCA) → GPA; MPO (p-ANCA) → MPA/EGPA; can be drug- or infection-induced
Antiphospholipid antibody panel (includes INR, PTT, anticardiolipin, anti-beta-2-glycoprotein, lupus anticoagulant)	Antiphospholipid syndrome (may be primary or secondary to autoimmune disease—about 50% of all cases)	medium/high titers and persistent IgG or IgM positivity ≥12 weeks required for diagnosis

Serologic testing must be interpreted in the clinical context. ANA, ANCA, and even specific antibodies without typical manifestations of the disease are of unclear clinical significance

Anti-nuclear Antibodies (ANA)

Always send with reflex (if ≥ 1:80, will check for dsDNA, Sm, SSA, SSB, Scl70, RNP)
At VUMC, 1:80 is considered "positive"; a higher titer is more specific for ANA-associated rheumatologic disease
~30% of the general population has a "positive" ANA at 1:40, most clinically significant ANAs are at least 1:160
Common patterns
Smooth/homogenous: associated with anti-dsDNA and anti-histone antibodies
Speckled: associated with anti-RNP, anti-Smith, anti-SSA/Ro, anti-SSB/La
Nucleolar: associated with anti-Scl-70; notably many other scleroderma and overlap Ab produce a nucleolar pattern but are not included on reflex such as anti-RNA-polymerase 3, anti-PM/SCL, and anti-U3-RNP

Anti-neutrophil Cytoplasmic Antibodies (ANCA)

Qualitative: p-ANCA (perinuclear staining) and c-ANCA (diffuse cytoplasmic staining)
Quantitative titers: anti-proteinase 3 (PR3) and anti-myeloperoxidase (MPO) IgG antibodies

C3 and C4

Hypocomplementemia in active SLE (due to increased consumption)
Complement may also be low in diseases that decrease the liver's synthetic function
↓ C3/C4 in other diseases that form immune complexes or activate the classic complement pathway: mixed cryoglobulinemia, Sjögren's, MPGN, and antiphospholipid syndrome

C-reactive Protein (CRP) and Erythrocyte Sedimentation Rate (ESR)

Both tests are non-specific markers of inflammation
CRP measures a specific acute phase protein made by the liver
IL-6 dependent (pts on anti-IL6 therapy will have falsely decreased CRP)
Typically changes more rapidly (24h) than ESR (7-14d)
ESR is the rate at which RBCs settle to the bottom of a test tube
Presence of positively charged proteins disrupt the self-repelling negative charges of RBCs→ clumping (rouleaux formation)→ increased rate of sedimentation
ESR will increase in states with increased antibodies, acute phase proteins
Falsely high ESR: sickle cell (microcytosis and anemia leads to fewer and smaller cells that can therefore fall fast)
Falsely low ESR: low fibrinogen states (DIC, HLH), polycythemia

Creatinine Kinase (CK)

CK can be elevated by vigorous exercise, rhabdomyolysis, endocrinopathy, cardiac disease, renal disease, malignancy, medication effect, neuromuscular disease, connective tissue disease
Consider inflammatory myopathies if there is ↑CK and objective proximal muscle weakness
CK is normal in polymyalgia rheumatica

Extended Myositis Panel

Ordered as "Myositis extended Pnl-ARUP"; includes 19 separate Abs
Can be sent when suspecting various forms of myositis such as dermatomyositis, polymyositis, anti-synthetase syndrome (e.g. ILD work-up)

Cryoglobulins

Reported as qualitative (positive or negative) and quantitative (percentage = "cryocrit")
Cryoglobulin is highly prone to collection error; must be collected in pre-warmed tubes and maintained at body temperature during collection and delivery to the lab
At VUMC can only be obtained at certain times M-F; lab and nursing staff can coordinate

Spondyloarthritis (SpA)

Author: Meridith Balbach

Background

Seronegative spondyloarthropathy: family of disorders characterized inflammatory arthritis, enthesitis, and absence of serologic markers
Includes: ankylosing spondylitis (AS), reactive arthritis, psoriatic arthritis (PsA), IBD-associated arthritis, undifferentiated spondylarthritis
Often further classified by either peripheral or axial involvement
HLA-B27 is linked to disease susceptibility (strongest link to AS); however, AS can occur in absence of the gene (~10%) and only ~3% of HLA-B27 positive subjects develop AS

Ankylosing Spondylitis

Author: Krissie Lobon

Presentation

Onset typically before age 30 (often teens to 30s)
MSK: insidious inflammatory back pain (hallmark), alternating buttock pain with sacroiliac involvement, enthesitis
Peripheral arthritis may occur and often involves larger joints such as hips, knees, and ankles.
Extra-articular: acute anterior uveitis, psoriasis, IBD
Typically encompasses 4 of 5 features: age of onset <40 years, insidious onset, improvement with exercise, no improvement with rest, pain at night (improvement upon arising)

Evaluation

Labs: No specific laboratory tests for AS
HLA-B27 is often present (90% of white patients; lower in other groups), though not necessary for diagnosis
Elevated CRP and ESR in 50-70% of pts with active AS and less frequently elevated in pts with non-radiographic subtype
Imaging
X-ray and MRI: joint space narrowing and sclerosis secondary to erosive changes in SI joint, pelvis, and/or spine; bony ankylosis/fusion can eventually be seen in progressive disease
MRI can reveal inflammatory changes (bone marrow edema); helpful in non-radiographic (X-ray negative) subtype
Classification criteria is used for diagnostic purposes
Assessment of SpondyloArthritis International Society Criteria (2011): ≥3mos back pain before 45yo and either sacroiliitis on imaging + ≥1 other axial spondyloarthritis (SpA) feature OR HLA-B27 positive + ≥2 SpA features
SpA features: arthritis, dactylitis, enthesitis, psoriasis, IBD, uveitis, FHx, HLA-B27

Management

Initial therapy: NSAIDs for symptomatic axial spondyloarthropathies. Occasionally NSAIDs alone improve symptoms and are the only medications required
Refractory symptoms: 1st line TNF inhibitors followed by IL-17 inhibitors (second option, most effective in pts with concomitant psoriasis). JAK inhibitors also approved.
Physical therapy: intensive rehabilitation and exercise improve mobility and symptoms

Psoriatic Arthritis (PsA)

Author: Tina Arkee

Background

Chronic inflammatory arthritis associated with psoriasis (occurring in up to 20-30% of psoriasis patients)
Incidence: onset usually around 30-50y; men and women equally affected. Psoriasis usually precedes the development of arthritis
Etiology: multigenic autoimmune disease that involves inflammatory infiltrate (likely driven by CD8 T cells) to entheses, synovial tissue, and skin. Joint trauma may trigger arthritis flare ("deep" Koebner phenomenon)
Classified under seronegative arthritis, though up to 15% of patients will have serologic positivity (RF most common)

Presentation

Variable joint pattern involvement (may evolve over time):
DIP arthritis
asymmetric oligoarthritis (large joint involvement in addition to small joints)
symmetric polyarthritis (may look like RA)
axial arthritis (involves the spine and SI joints)
arthritis mutilans (severe destructive joint disease leading to osteolysis and shortening of digits)
Periarticular manifestations:
Enthesitis: inflammation of tendon and ligament insertion sites, including the Achilles tendon, patellar tendon, and spinous processes of vertebral bodies
Tenosynovitis: flexor tendons of hands and posterior tibial tendons often involved
Dactylitis: diffuse swelling of a single finger or toe (sausage digit). Acute dactylitis presents with a red, hot, tender, swollen digit, whereas chronically affected digits are often just swollen.
Extra-articular manifestations: nail changes (pitting, ridging, onycholysis), psoriasis plaque, chronic bilateral uveitis, conjunctivitis
Comorbidities: Decreased bone mineral density, psychiatric disease (depression, anxiety), hyperuricemia, increased risk of CVD/metabolic syndrome/DM/fatty liver

Evaluation

Laboratory data: CBC, BMP, uric acid, ESR, CRP; consider HIV testing
Autoimmune testing to rule out other conditions: ANA (shouldn't have high titer positivity), RF (positive in 2-10%), anti-CCP
HLA-B27: present in 25-30% patients; identifies patients at risk for axial disease or acute anterior uveitis but does not diagnose them
Imaging
X-rays often show evidence of both bone erosion and new bone formation, such as the "pencil in cup" deformity (often involves the DIP), osteolysis leading to digital shortening, bone spurs at entheses, periosteal reactions (new bone formation around eroded sites), and ankylosis (fusion of adjacent joints).
MRI changes can be more sensitive in detecting articular and soft tissue inflammation and sacroiliitis; however, these do not always correlate with clinical symptoms
CASPAR classification criteria for diagnosis are >90% sensitive and specific for PsA (≥3 points = diagnostic)
Current psoriasis (2), a personal history of psoriasis (1), or family history of psoriasis (1)
Psoriatic nail findings observed on physical exam (1)
Negative test for RF (1)
Current dactylitis or a history of dactylitis documented by a rheumatologist (1)
Xray evidence of juxta-articular new bone formation in the affected hand or foot (1)

Management

Non-pharmacologic strategies: PT/OT, exercise, weight loss, nutritionist referral for metabolic syndrome, dermatology referral for comanagement
Treatment is dependent on pattern of involvement, skin disease, severity, and comorbidities
Mild: NSAIDs (e.g. naproxen 375-500mg BID)
Moderate or resistant to NSAIDs: conventional DMARDS (e.g. MTX 15-25mg q weekly or leflunomide 20mg QD) or occasionally apremilast (PDE4 inhibitor) if avoiding biologics
Severe (many joints, erosive, functional limitation) or no response to above: biologic DMARD, usually TNF inhibitor (infliximab, adalimumab, etanercept); if no response, trial to another TNF inhibitor. If TNFi are contraindicated OR psoriasis is severe, try an anti-IL17a biologic (secukinumab, ixekizumab). Patients with concomitant IBD may benefit from anti-IL12/IL-23 agents (ustekizumab). Anti-IL17 biologics are contraindicated in patients w/IBD.
Refractory to two TNFi/IL-12/IL-23: consider the JAK inhibitor tofacitinib
Note: avoid oral glucocorticoids given risk of developing erythroderma or pustular psoriasis!
Skin and joint disease often do not correlate — evaluate independently

Rheumatoid Arthritis

Author: Anika Morgado

Background

Chronic systemic inflammatory disorder of synovial joints, typically polyarticular, that results in proliferation of synovial tissue and consequent loss of articular cartilage and juxta-articular bone
Incidence: most often onset around 30-60y; female:male ratio of ~3:1.
Etiology: genetic (particularly specific HLA-DR4 and DR1 haplotypes) + environmental (e.g. smoking) triggers autoantibody formation (i.e. RF and anti-CCP) within the synovium, resulting in innate and adaptive immune cell infiltration
May be classified as seropositive (RF or anti-CCP present) or seronegative; seropositive is typically more severe joint disease, increased risk of extra-articular manifestations, stronger heritability

Presentation

Usually insidious onset of polyarticular, often symmetric joint pain and swelling; often with morning stiffness (i.e. >30min)
Classically affects MCPs, PIPs, wrists, ankles, MTPs, knees
Classically spares DIPs and axial skeleton (except for C1-C2 in severe disease)
Constitutional symptoms: fatigue, widespread pain, comorbid psychiatric disease (depression)
Extra-articular manifestations (primarily in seropositive RA only)
Osteopenia, rheumatoid nodules (usually on skin but can form anywhere including lungs), sicca symptoms, scleritis, ILD, constrictive pericarditis, rheumatoid vasculitis, anemia, neutropenia (associated splenomegaly)
RA is an independent risk factor for CAD

Evaluation

Clinical diagnosis based on symptoms as above with physical exam concerning for active synovitis/inflammatory joint changes; supported by serologic and imaging findings
MCP subluxation, ulnar deviation, Swan and Boutonnieres deformities are late findings of untreated RA
2010 ACR/EULAR classification criteria are less helpful (only 50% specific; nearly any inflammatory polyarthritis will meet criteria)
Serologic workup: anti-CCP (95% specificity), RF (75-80% sensitivity and specificity), ESR/CRP (tends to correlate with disease activity), CBC (anemia or thrombocytosis); CMP, Hep B/C, TB screen for treatment planning
RF is nonspecific; can be seen in any disease with chronic stimulation of humoral immune system (HBV, HC, Sjogren's, lymphoma, cryoglobulinemia)
Overall poor sensitivity; up to 20% of patients are seronegative
Imaging:
Baseline plain films of hands/feet; early changes include soft tissue swelling and peri-articular osteopenia; late changes include marginal erosions and joint space narrowing
Consider MRI and/or MSK ultrasound to detect early synovitis/erosions

Management

Goal of treatment: achieve early remission or low-disease activity to improve symptoms, prevent joint damage, and reduce long-term cardiovascular morbidity. Ideal response is 50% effective at 3 months and 90-100% effective at 6 months
1st line: MTX 15-25mg weekly (with folate); may use with NSAIDs and/or steroids temporarily to rapidly reduce disease activity until DMARDs take effect (~2-6 months)
2nd line: no clear guidelines, often dependent on patient-specific factors. Consider TNF inhibitors (usual preferred 2nd line agent), rituximab (particularly in seropositive disease), abatacept (particularly in the elderly), tocilizumab (especially if systemic symptoms), JAK inhibitors (if patient strongly prefers oral agent; avoid if history of DVT/PE or CAD)
If resource-limited or biologics are contraindicated, consider HCQ, sulfasalazine, and/or leflunomide (often in combination)

Crystalline Arthropathies

Author: Thomas Horton

Gout

Presentation

Red, hot, swollen joint (classically affects 1st metatarsal phalangeal joint [podagra])
May progress to involve ankles, knees, elbows, and small joints of hand if untreated
Flares may also become polyarticular over time and include systemic symptoms like fever
Tophi (firm, yellow deposits of monosodium urate in soft tissue) may develop over time in olecranon, Achilles tendon, ear helix
Gout is diagnosed with combination of clinical presentation and arthrocentesis results
Lifestyle factors:
Protective: Low fat dairy, hydration, weight loss, smoking cessation
Promoting: Meat, seafood, alcohol, high fructose corn syrup, medications that lead to hyperuricemia (e.g. thiazides)

Evaluation

Diagnosis: arthrocentesis remains gold standard but typically a clinical diagnosis. If arthrocentesis is unavailable or presentation is atypical, can use 2015 ACR/EULAR classification criteria: ≥1 episode of peripheral joint or bursa swelling, pain, or tenderness + scoring system based on uric acid level, clinical features (e.g. 1st MTP involvement, erythema over joint, tophus), imaging
Synovial fluid analysis: See "Arthrocentesis Quick Look" section for more detail
Cell count and differential: WBC 20,000-100,000, > 50% neutrophils
Examination for crystals under polarizing light microscopy: (order "Synovial Fluid Eval" so the lab knows to look for crystals)
Imaging: generally unnecessary but can be helpful (especially if no active flare or polyarticular flares)
MSK ultrasound: "Double contour sign" (hyperechoic band = urate crystals deposits)
Radiographs: Punched out erosions or lytic areas with overhanging edges
Dual energy CT scan: crystal aggregates appear green. Not routinely necessary but may be helpful to identify extraarticular locations. Do not order without rheumatology consult.

Management

Acute

Do not hold allopurinol during an acute flare if the patient is already taking chronically
1st line: NSAIDs (if not contraindicated): short course (2-5 days) at full anti-inflammatory dose (ibuprofen 800 mg TID, indomethacin 50 mg TID, naproxen 500 mg BID) with colchicine
1st line: colchicine (avoid if GFR <10 mL/min. Dose reduce by 50% if GFR <50 mL/min)
Best if used within the first 36 hours of an attack. Much less effective if started later.
Dosing: 1.2 mg then 0.6 mg one hour later, then 0.6 mg daily until clinical improvement
Note drug interactions that may require dose adjustment of colchicine: Statins, diltiazem, fluconazole, cyclosporine, tacrolimus, clarithromycin, etc.
2nd line: steroids (use if NSAIDs and colchicine are contraindicated or ineffective)
Ideally intra-articular if 1-2 joints affected and infection has been ruled out
Oral prednisone 0.5mg/kg/day until clinical improvement, then taper over 7-14 days
3rd line: IL-1 inhibitors (anakinra 100mg QD x3 days or canakinumab) if flare refractory to 1st line treatment or other treatments contraindicated. Requires rheumatology consult.

Chronic

Urate Lowering Therapy (ULT)
Indications: strong= >2 attacks/year, one or more subcutaneous tophi, radiologic changes. Conditional indication= CKD 3 or worse, urolithiasis, serum urate >9
Goal serum urate: <6.0 mg/dL, or <5.0 mg/dL in pts with tophi
Prophylaxis: ULT can precipitate an acute gout flare and should always be started with low-dose NSAIDs, colchicine (0.6 mg) or prednisone (5 mg daily or QOD). This should be continued for at least 3 months after reaching urate goal with no tophi or 6 months if tophi present
1st line: allopurinol (xanthine oxidase inhibitor)
- Start at 100 mg daily (sometimes even 50mg daily in those with advanced CKD) and titrate monthly by 100mg to target uric acid <6 (most pts will need 400-800 mg daily; consider deferring uric acid recheck until at least reaching 300mg). Slow titration decreases risk of flare and DRESS syndrome.
- Genetic testing (HLA-B*5801) recommended prior to starting for pts of Asian and African descent given ↑ incidence of allopurinol hypersensitivity if positive allele
- Allopurinol can be started during a flare if the flare is being treated.
2nd line: febuxostat (alternative xanthine oxidase inhibitor); consider for pts at risk for DRESS or SJS related to allopurinol. Black box warning for ↑ cardiovascular risk; more expensive than allopurinol
3rd line: probenecid (uricosuric); consider in patients failing XOI. Avoid in renal disease or nephrolithiasis
4th line: pegloticase (uricase); for severe, refractory gout with tophi
When to refer: consider Rheumatology consult for pts with refractory serum urate levels >6.0 despite 1st or 2nd line ULT

Additional Pearls

There is a microscope in the rheumatology clinic at VUMC (TVC 2). You can page the rheumatology fellow and they are happy to help you use it
Uric acid level is often normal during acute gout flare
Shifts in uric acid may be the trigger of the flare: diuresis, dietary changes, hospital stays

Pseudogout – Calcium Pyrophosphate Dihydrate Crystal Deposition Disease (CPPD)

Presentation

More prevalent in the elderly populations
Cannot distinguish acute episodes from gout based on clinical features alone (red, hot, swollen joint)
Can mimic OA with multiple joints affected without inflammatory arthritis ("pseudo OA"), RA with acute flare of polyarthritis ("pseudo RA"), or septic arthritis

Evaluation

No formal diagnostic criteria; clinical diagnosis +/- crystals +/- imaging
Synovial fluid analysis: See "Arthrocentesis Quick Look" section for more detail
Cell count and differential: WBC 20,000 to 100,000, >50% neutrophils
Rhomboid-shaped, positively birefringent.
X-ray: chondrocalcinosis (thin calcified line present in fibrocartilage) in the joint space; specifically often seen in the meniscus of the knee joint or triangular fibrocartilage just distal to the ulna

Management

Acute: typically mirrors gout flare treatment; ranges from NSAIDs (1st line) to colchicine (2nd line) to steroids (3rd line). Can also use anakinra in acute cases with consult to rheumatology.
Chronic: IL-1 inhibition (off-label) can be useful in chronic inflammatory CPPD. For those with frequent flares, consider daily colchicine prophylaxis

Additional Information

CPPD can be associated with other disorders: hyperparathyroidism, hemochromatosis, hypomagnesemia, hypophosphatemia, and familial hypocalciuric hypercalcemia, hypothyroidism, Wilson disease
Consider further workup for these conditions, especially in a younger pt.

Systemic Lupus Erythematosus (SLE)

Author: Lale Ertuglu

Background

Multisystemic autoimmune disease characterized by loss of immune tolerance, resulting in autoantibody formation to nuclear material and immune complex deposition
Incidence: typical onset at 16-35y but juvenile and late-onset forms exist
Prevalence: More common in women (~9:1). Affects 1:1000 in the US; more common in Black, Hispanic, Asian, and indigenous populations
Etiology: genetic predisposition (HLA-DR2/DR3 variants, as well as non-HLA genes including those involved in complement and cytokines) + environmental factors (estrogen, infection, UV light, viruses, medication, heavy metals) result in break in immune tolerance with auto-reactive antibodies and T-cells targeting antinuclear antigens, subsequently with abnormal cytokine inflammatory cascades and immune complex formation

Presentation

Constitutional: fatigue (most common complaint), fevers, myalgia, weight loss

MSK: arthralgias and arthritis (usually polyarticular, symmetric, migratory and non-erosive) often involving MCPs/PIPs/knees/MTPs, Raynaud's.

Mucocutaneous: malar rash, discoid skin lesions, photosensitivity, painless oral (usually palatal) ulcers, nasal ulcers, scarring alopecia from discoid lupus is specific (vs non-scarring diffuse alopecia which is common)

Cardiac: pericarditis (~25% of pts will develop at some point in disease course), verrucous (Libman-Sacks) endocarditis, myocarditis, increased risk CAD

Hematologic: anemia of chronic disease (most common), leukopenia, ITP, AIHA

Renal: Lupus nephritis is the most common organ-threatening manifestation, can be refractory to therapy. Diagnosed and classified with renal biopsy. - Renal biopsy indicated if idiopathic AKI or progression of CKD, or if persistent proteinuria or hematuria - Class I and II are usually clinically silent. Class III and IV typically present as nephritic syndrome, class V mostly presents as nephrotic syndrome. Most patients present as an overlap (such as III + V or IV +V)

Pulmonary: pleuritis (if chronic may be complicated by shrinking lung syndrome), pleural effusion, ILD, pHTN

Neurologic: stroke, cerebritis, psychosis, mononeuritis multiplex

Ophtho: keratoconjunctivitis sicca (2/2 Sjögren's syndrome)

GI: dysphagia due to esophageal dysmotility, intestinal pseudo-obstruction, elevation of LFTs (significant liver disease is rare)

Evaluation

Serologic workup: CBC, BMP, UA with sediment and Ur Pr:Cr ratio (screen for nephritis), ESR/CRP (nonspecific), ANA (sensitivity >98%) with reflex (including highly specific anti-dsDNA and anti-Smith), complement levels (C3 & C4 usually low in active disease)
Additional workup: if history of DVT or recurrent pregnancy loss, consider APLS antiphospholipid antibody testing (lupus anticoagulant, anti-cardiolipin, anti-β2 glycoprotein); if concern for myositis overlap, consider CK
Can use 2019 ACR/EULAR classification criteria to guide diagnosis: (requires positive ANA ≥1:80 as entry criterion; then score ≥10 points across domains meets criteria)

2019 ACR/EULAR Classification Criteria

Clinical Criteria	Weight	Laboratory Criteria	Weight
Constitutional		Antiphospholipid antibodies
Fever	2	Lupus AC, CL, β2GP1	2
Hematologic		Complement proteins
Leukopenia	3	Low C3 OR C4	3
Thrombocytopenia	4	Low C3 AND C4	4
Autoimmune hemolysis	4	SLE-specific antibodies
Neuropsychiatric		Anti-dsDNA OR Anti-Smith	6
Delirium	2
Psychosis	3
Seizure	4
Mucocutaneous
Non-scarring alopecia	2
Oral ulcers	2
Subacute cutaneous OR discoid lupus	4
Acute cutaneous lupus	6
Serosal
Pleural or pericardial effusion	5
Acute pericarditis	6
Musculoskeletal
Joint involvement (2+ joints)	6
Renal
Proteinuria (>0.5g/24h)	4
Renal Bx Class II or V lupus nephritis	8
Renal Bx Class III or IV lupus nephritis	10

Management

Treatment goal: control flares and prevent end-organ damage
Acute flare: often will require steroids; aim for lowest dose for shortest possible period
Mild disease: prednisone ≤ 10mg/daily
Severe/organ-threatening: steroid pulses (e.g., methylprednisolone 500–1000 mg IV x 3 days) + biologic (e.g. MMF or cyclophosphamide in lupus nephritis) with subsequent steroid taper
Maintenance therapy should be changed if regular flares occur
Maintenance:
1st line: HCQ 200-400mg/day (5mg/kg)
- Requires retinal screening at baseline and annually after 5 years of therapy
- Not immunosuppressive
- Safe in pregnancy with improved pregnancy outcomes and reduced neonatal lupus
2nd line: highly dependent on organ involvement; consider MTX, azathioprine, MMF, belimumab, anifrolumab, rituximab
Lupus nephritis: increasing emphasis on upfront combination therapies with mycophenolate mofetil combined with either belimumab or voclosporin
Monitoring: usual biologic toxicity monitoring. Additionally, at least semiannual UA, UPCR, and creatinine to evaluate for lupus nephritis, even if asymptomatic. Trending rising dsDNA and low complements can predict flare.

Systemic Sclerosis (SSc)

Author: Eva Niklinska and Raeann Whitney

Background

Multisystem autoimmune disease characterized by immune dysregulation causing vascular dysfunction and fibrosis of skin and internal organs
Distinguish from localized scleroderma (morphea or linear scleroderma) which is dermal fibrosis without internal organ involvement
Categorized into 2 major subtypes:
Limited cutaneous (lcSSc): skin thickening limited to the neck, face, or distal to elbows and knees; spares the trunk and proximal extremities. Raynaud's may develop years before other manifestations, which then slowly accumulate over 5-10 years.
- + anticentromere antibody
- Renal crisis is rare
- High risk for developing PAH
Diffuse cutaneous: skin thickening extends proximal to the elbows/knees or trunk; rapid development of cutaneous and multiorgan involvement
- More associated with anti-Scl-70 ab
- Typically more abrupt onset and rapid progression compared to limited
- High risk for progressive ILD
- + RNA polymerase III Ab = high risk of renal crisis, higher risk for malignancy
Incidence: onset typically 30-60y, more common in females (~4:1)
Etiology: unknown trigger causes microvascular injury and activation of collagen → excess collagen deposition

Presentation

CREST: Calcinosis cutis, Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly, Telangiectasia (CREST syndrome is no longer a discrete diagnosis but incorporated into lcSSc)
Systemic: fatigue, weight loss
Vascular: Raynaud's +/- digital tip ulcers, telangiectasias, nailfold capillaroscopy with dilated capillary loops
Skin: Sclerodactyly, loss of facial wrinkles, decreased oral aperture, calcinosis cutis
MSK: arthralgias, myalgias, flexion contractures
GI: Esophageal or intestinal dysmotility, GERD, GAVE (watermelon stomach)
Pulm: ILD (NSIP, UIP), pulmonary arterial hypertension
Cardiac: pericardial effusions, myocarditis, cardiomyopathy, conduction system disease
Renal: renal crisis

Evaluation

2013 ACR/EULAR Classification Criteria → weight-based symptom scoring
Laboratory workup: ANA w/ reflex, Scl70, anticentromere, RNA pol III (separate order in Epic, increased risk of scleroderma renal disease)
Imaging/Procedures: Baseline PFTs, lung HRCT, TTE, EKG, 6-minute walk test, EGD
Skin biopsy: Not often used for dx, may be required to differentiate other rare disorders (eosinophilic fasciitis, linear scleroderma, scleromyxedema)

2013 ACR/EULAR Classification Criteria

Items	Sub-items	Weight
Skin thickening of fingers of both hands extending proximal to metacarpophalangeal (MCP) joints		9
Skin thickening of fingers (only count the highest score)	Puffy fingers	2
	Whole finger, distal to MCP	4
Fingertip lesions (only count the highest score)	Digital tip ulcers	2
	Pitting scars	3
Telangiectasia		2
Abnormal nailfold capillaries		2
Pulmonary arterial hypertension and/or interstitial lung disease		2
Raynaud's phenomenon		3
Scleroderma-related antibodies (any of anti-centromere, anti-topoisomerase I [anti-ScL 70], anti-RNA polymerase III)		3

Pts with a total score of ≥9 are classified as having definite systemic sclerosis (sensitivity 91%, specificity 92%)

Management

Organ-Based Symptomatic Therapy
Raynaud's: CCB (amlodipine, nifedipine), PDE5i, topical nitroglycerin
GERD: PPI
Renal: Monitor BP and Cr
- Scleroderma renal crisis: abrupt onset of HTN and renal dysfunction that typically presents early in disease course (can precede skin thickening), usually triggered by steroids
- Workup: AKI, proteinuria, MAHA, elevated renin
- Treatment: short-acting ACEi (captopril, enalapril); may require HD
ILD: Periodic PFTs (isolated DLCO may suggest PAH); monitor for respiratory symptoms, pulmonology referral
Cardiac/PAH: annual TTE, cardiology referral
Systemic Immunosuppression (if progressive skin thickening or organ involvement)
MTX, MMF, tocilizumab, cyclophosphamide, if refractory rituximab, IVIG
Nintedanib may be used in combination with immunosuppression in ILD

Idiopathic Inflammatory Myopathies (IIM)

Author: Tina Arkee

Background

Heterogenous group of disorders that classically present with painless proximal muscle weakness; some subtypes may present with additional systemic features such as antisynthetase syndromes (e.g. ILD, rash, inflammatory arthritis, mechanics' hands, Raynaud phenomenon)
Subtypes (non-exhaustive): dermatomyositis (DM), polymyositis (PM), antisynthetase syndrome, immune-mediated necrotizing myopathy (IMNM), inclusion body myositis (IBM)
Differential diagnosis: statin-induced myopathy, metabolic (hypothyroid, electrolyte), viral/infectious myositis, diabetic myonecrosis
Important point: PMR= painful, preserved strength vs inflammatory myopathy = painless weakness
Consider screening patients for underlying malignancy, particularly in DM and PM – up to 15-30% of cases are associated with malignancy (specific antibody present can further risk stratify)

Presentation

Acute vs. Chronic
Acute or subacute: DM, PM, IMNM
Gradual and progressive: IBM
Distribution of weakness
Proximal and symmetric: DM, PM, IMNM
Distal and asymmetric: IBM (often involves weakness of finger flexor muscles)
Systemic signs or symptoms: fever, rash, dyspnea, dysphagia, arthritis
DM: Gottron's papules, heliotrope rash, shawl sign, mechanics hands
Anti-synthetase syndrome: cough/dyspnea, arthritis, Raynaud's or mechanics hands, and sometimes fever
IBM: can present with dysphagia; advanced cases may present with muscle atrophy
Consider patient's medications including exposure to statins and steroids

Evaluation

Diagnosis: clinical but can use 2017 EULAR/ACR Classification Criteria for Adult and Juvenile Myositis; weighted point system including age of onset, distribution, skin involvement, elevated muscle enzymes, EMG, muscle biopsy, myositis-specific antibodies
Labs: CMP, TSH, CK level, LDH and aldolase + extended myositis panel (screens commonly associated antibodies including anti-Jo1, anti-Mi2, etc.)
MDA5 Ab is associated with rapidly progressing ILD, which may present with AHRF
TIF1 and NXP2 Abs are associated with underlying malignancy
EMG: useful for ruling out neuromuscular etiologies
MRI extremity/affected muscle group: can help guide biopsies and evaluate edema on T2 and STIR (high signal intensity on these sequences may reflect active inflammation) and fatty replacement (reflects muscle damage) on T1.
Skin biopsy in dermatomyositis: "interface dermatitis," notably the same findings as skin biopsy of lupus rashes
Muscle biopsy: gold standard for diagnosis but not always necessary (especially in dermatomyositis)
Do not do biopsy in same muscle as EMG done
Dermatomyositis: perifascicular and perivascular inflammatory infiltrate (CD4+ T cells and dendritic cells)
Polymyositis: endomysial inflammatory infiltrate (CD8 T cells)
IMNM: variable stage necrotic fibers, scant inflammatory infiltrate
IBM: endomysial infiltrate, intracellular vacuoles, protein aggregates

Management

If suspected, consult Rheumatology!
1st line:
DM/PM: high-dose steroids (1mg/kg/day prednisone) for 4-6 weeks PLUS steroid-sparing agent (MTX, azathioprine, or mycophenolate mofetil)
IMNM: high dose steroids for 4-6 weeks PLUS IVIG and rituximab
IBM: poor response to immunotherapy; focus on supportive care and aggressive PT/OT/SLP
2nd line: IVIG, rituximab, abatacept, or tofacitinib

Sjögren's Syndrome

Author: Meridith Balbach

Background

Systemic autoimmune disorder primarily targeting exocrine glands causing sicca symptoms; may also involve musculoskeletal, pulmonary, renal, neurologic, and hematologic features
May be primary or secondary (occurring alongside another autoimmune disease such as RA or SLE)
Incidence: presents most often around age 40-60y; female-to-male ratio ~9:1
Etiology: genetic predisposition (e.g. increased risk with specific HLA-DQA_DQB_ haplotypes) + environmental factors triggers aberrant autoantibody production and lymphocytic infiltration of glands (predominantly CD4+ T cells; also B cells), resulting in glandular dysfunction

Presentation

Classic sicca: dry eyes (gritty, burning, or foreign body sensation) and dry mouth (difficulty chewing/swallowing dry foods, frequent water intake, dental caries)
Extra-glandular features:
MSK: arthralgias, arthritis, myalgias
Dermatologic: eyelid dermatitis, Raynaud's, cutaneous vasculitis
Hematologic: cytopenias, hyper- and hypogammaglobulinemia, monoclonal gammopathy, cryoglobulinemia; non-Hodgkin lymphoma, particularly MALT lymphoma (most feared complication; higher risk if persistent parotid enlargement or hypocomplementemia)
Pulmonary: ILD, xerotrachea, bronchiectasis
Gastrointestinal: dysphagia, chronic diarrhea, abdominal pain
May also include neurologic, renal, cardiovascular (but typically <5%)

Evaluation

Serologic workup: ANA with reflex (typically + Anti-Ro/SSA or anti-La/SSB), RF (often positive, even in the absence of RA), immunoglobulins, ESR (often elevated) and CRP (usually normal or mildly elevated)
Anti-Ro/SSA is most sensitive and specific but is not diagnostic
Additional workup: Schirmer test, slit-lamp exam, salivary flow rate
Gold standard: labial salivary gland biopsy
Clinical diagnosis but 2016 ACR/EULAR classification criteria can help guide in unclear cases (score ≥4 confirms classification):
+ anti-Ro/SSA (3)
Focal lymphocytic sialadenitis (3)
Ocular staining score ≥5 (1)
Schirmer's test ≤5 mm/5 min (1)
Unstimulated salivary flow ≤0.1 mL/min (1)

Management

Treatment is currently targeted to organ involvement (though several biologics are being studied). Immunosuppression is not used for dryness symptoms.
Xerophthalmia: preservative-free artificial tears, cyclosporine eye drops; punctal plugs if refractory
Xerostomia: frequent sips, sugar-free lozenges or gum, saliva substitutes + good dental hygiene; muscarinic agonists (e.g. pilocarpine) if persistent
MSK: hydroxychloroquine
Organ-threatening disease: steroids +/- steroid-sparing agent (MMF, azathioprine, rituximab)

Author: Meridith Balbach

Background

Multi-organ, immune-mediated fibrotic disease characterized by diffuse or focal organ enlargement with tumor-like mass formation secondary to massive infiltration of IgG4-positive plasma cells with storiform fibrosis
Incidence: usually >60y; more often affects men
Prevalence: unclear but quite rare; pancreatic involvement most common
Etiology: poorly understood; genetic predisposition + environmental factors lead to CD4+ T cell and B cell activation that stimulate fibroblasts and promote tissue remodeling through unclear mechanisms

Presentation

Usually subacute related to gradual progressive enlargement of affected organ(s) or found incidentally. Fevers and acute illness are not expected features.
Presentation highly variable, dependent on affected organ:
Pancreas ("type 1 autoimmune pancreatitis"): painless obstructive jaundice, mild abdominal discomfort, weight loss; rarely acute pancreatitis
Biliary duct: obstructive jaundice
Glands (lacrimal, salivary; "Mikulicz disease")
Retroperitoneum: periaortic inflammation, ureter compression
Also: central nervous system, thyroid gland, lungs, liver, gastrointestinal tracts, kidneys, prostate, mesentery, lymph nodes, etc.
2+ organ involvement most often (60-90%)

Evaluation

Serologic: IgG4 (fairly sensitive: >130mg/dL in 70-80%; at higher levels, very specific: if >280mg/dL, 99%), elevated ESR and CRP, +ANA (nonspecific but seen in 50%), elevated RF (nonspecific but seen in 20%), low C3/4 (particularly in renal and pancreas involvement)
Gold standard: biopsy of affected organ with abundant infiltration of IgG4-positive plasma cells and lymphocytes, storiform fibrosis, and obliterative phlebitis
ACR/EULAR classification criteria can help guide diagnosis (meets criteria if entry criteria met, no exclusion criteria present, total points ≥20):
Entry: clinical or radiologic involvement of a classically affected organ OR pathologic evidence of inflammatory process with lymphoplasmacytic infiltrate
Exclusion: clinical (fever, absence of objective response to steroids), serologic (numerous including presence of several other autoantibodies, peripheral eosinophilia, etc.), radiologic (findings suspicious for malignancy, rapid interval progression, splenomegaly), pathologic (findings suggestive of alternative pathology), known alternative diagnosis (multicentric Castleman's disease, etc.)
Inclusion criteria: consistent features on histopathology (0-13), IgG4 immunostaining (0-16), serum IgG4 (0-11), glandular involvement (0-14), chest (0-10), pancreas and biliary tree involvement (0-19), renal involvement (0-10), retroperitoneal involvement (0-8)

Management

Indications for treatment: (1) demonstrated or anticipated organ damage, (2) high disease activity, (3) symptomatic relief.
Consider watchful waiting in those with mild, asymptomatic disease or stable remission
Induction: oral prednisolone starting at 0.6 mg/kg/day, x2–4 weeks, followed by gradual taper over 2-3 months to maintenance dose
Organ-specific management (e.g. biliary stenting)
Monitoring: highly individualized based on number and severity organ involvement, initial IgG4 level, initial response to steroids (can use IgG4-RD Responder Index scores to help guide) but combination of symptoms, IgG4 levels, imaging (CT/MRI/PET)
Maintenance: oral prednisolone 2.5–5 mg/day; depending on medical comorbidities, may continue indefinitely versus attempt taper within 3 years
Relapse: Re-induction with steroids and/or steroid-sparing agents (azathioprine, mycophenolate mofetil, methotrexate, rituximab)

ANCA-Associated Vasculitis

Granulomatosis with Polyangiitis (GPA)

Author: Hannah Angle

Background

Necrotizing vasculitis of small vessels characterized by granulomatous inflammation

Presentation

Constitutional symptoms: fevers, fatigue, weight loss
Vasculitis: pulmonary hemorrhage, mononeuritis multiplex, glomerulonephritis (hematuria, proteinuria)
Granulomatous inflammation: sinus and/or middle ear involvement, rhinorrhea, epistaxis, pulmonary nodule, cavitary pulmonary lesions (dyspnea, cough, hemoptysis)

Evaluation

ANCA + (typically PR3-cANCA)
ESR/CRP, ANA, anti-GBM, C3/C4, cryoglobulins, HBV/HCV, HIV
UA with microscopy (hematuria, proteinuria, RBC casts, dysmorphic RBCs)
CT chest if pulmonary symptoms
Biopsy: necrotizing granulomatous vasculitis, pauci-immune glomerulonephritis
Clinical Pearl: If you suspect renal disease (elevated Cr, hematuria), ask the renal or rheum fellow to help spin the urine to evaluate for RBC casting or dysmorphic cells. Quick way to confirm active GN, since renal biopsy takes time to arrange.

Management

Mild-moderate disease: MTX + prednisone 0.5 mg/kg/day followed by steroid taper
Severe disease: rituximab (first line) + prednisone 1mg/kg/day (60-80mg max)
If failed response to rituximab, cyclophosphamide can be used.
For pts with RPGN, pulmonary hemorrhage, mononeuritis multiplex or optic neuritis: IV methylprednisone 7-15mg/kg/d (1000mg max) x3d for induction therapy
DVT ppx (high risk for DVT/PE)

Microscopic Polyangiitis (MPA)

Author: Hannah Angle

Presentation

Similar to GPA, but without granulomatous involvement (no upper respiratory tract involvement or pulmonary nodules); classically only involves lungs and kidneys

Evaluation

ANCA + (typically MPO-pANCA)
ESR/CRP, ANA, anti-GBM, C3/C4, cryoglobulins, HBV/HCV, HIV
UA with microscopy (hematuria, proteinuria, RBC casts, dysmorphic RBCs)
CT chest if pulmonary symptoms
Biopsy: necrotizing vasculitis (no granulomas), pauci-immune glomerulonephritis

Management

Same as GPA, see above

Eosinophilic Granulomatosis with Polyangiitis (EGPA)

Author: Hannah Angle

Presentation

Similar to GPA/MPA. Predominant symptoms include atopic symptoms (asthma, rhinosinusitis) and peripheral eosinophilia.
Vasculitis manifestations are more rare, and when they occur, mononeuritis multiplex is the most common, unlike pulmonary hemorrhage or renal involvement in GPA/MPA.
Cardiac involvement (accounts for 50% deaths from EGPA): coronary arteritis, myocarditis, heart failure, arrhythmias
Skin involvement (>50%): tender subcutaneous nodules

Evaluation

ANCA + (typically MPO-pANCA, positive in about 50-60% of pts)
Peripheral eosinophilia
IgE, ANA, RF, C3/C4
Biopsy: necrotizing granulomatous vasculitis, eosinophilic infiltrates with fibrinoid necrosis, pauci-immune glomerulonephritis

Management

Mild-moderate disease: prednisone 0.5-1 mg/kg/day for 6-12 weeks followed by steroid taper
Severe: cyclophosphamide + prednisone 0.5-1 mg/kg/day for 6-12 weeks followed by steroid taper
For pts with life-threatening multiorgan involvement (cardiac, pulmonary, renal, neurologic): IV methylprednisone 1000mg daily x 3 days for induction therapy
ACR guidelines now also recommend mepolizumab for non-severe disease (instead of rituximab or cyclophosphamide) plus steroids as initial induction therapy. Severe disease still requires rituximab or cyclophosphamide)
DVT ppx (high risk for DVT/PE)

Cryoglobulinemic Vasculitis

Author: Meridith Balbach

Background

Cryoglobulins = Circulating immunoglobulins precipitate in the cold
Classification of cryoglobulins:
Type I: monoclonal immunoglobulin (IgM or IgG); associated with lymphoproliferative disorders (Waldenström's, MM, CLL, B cell lymphomas)
Type II: mixed (monoclonal IgM with +RF* polyclonal IgG); associated with chronic infection (particularly chronic Hepatitis C)
Type III: polyclonal IgM + IgG with +RF; associated with autoimmune disease

*RF activity by definition is the reactivity of an IgM component with the Fc portion of an IgG

Deposition of cryoprecipitate may result in small vessel vasculitis

Presentation

Systemic features (fatigue, arthralgia, myalgia) + organ-specific
Skin (most common): palpable purpura (usually in lower extremities/colder areas), livedo reticularis
Renal: proteinuria, hematuria, HTN (MPGN)
Neurologic: peripheral neuropathy (mononeuritis multiplex)

Evaluation

General: Serum cryoglobulins (fastidious collection, see above), C3/C4 (hypocomplementemia), RF (positive in types II/III), ANA w/ reflex (evaluate for underlying autoimmune etiology), hepatitis B and C serologies, SPEP with immunofixation
End-organ specific: urinalysis +/- renal biopsy (if findings c/f MPGN), skin biopsy (leukocytoclastic vasculitis)

Management

Treat underlying etiology, if possible
For moderate-severe disease or end-organ disease, consider corticosteroids, rituximab, cyclophosphamide

Polyarteritis Nodosa (PAN)

Author: Hannah Angle

Background

Necrotizing vasculitis of medium-sized muscular arteries, leading to segmental transmural inflammation with fibrinoid necrosis, aneurysm formation, thrombosis, and downstream ischemia
Incidence: onset usually in middle age/older adults (peaks in the 5th decade)
Often idiopathic but frequently associated with Hepatitis B (historically up to 30% of cases), Hepatitis C, hairy cell leukemia, monogenic forms

Presentation

Systemic + vessel-specific symptoms
Constitutional symptoms: fatigue, weakness, fevers, arthralgias, myalgias, rash, weight loss
Vasa nervorum: Asymmetric polyneuropathy with motor and sensory deficits (foot drop, radial/ulnar neuropathy)
Cutaneous: livedo reticularis, palpable purpura, ulcers, tender erythematous nodules, bullae, vesicles
Renal: HTN
Mesenteric: abdominal pain and melena
Coronary: ischemic cardiomyopathy
Testicular: orchitis

Evaluation

Elevated ESR/CRP, CBC (normocytic anemia and leukocytosis), Hepatitis B panel, Hep C with reflex, negative ANCA
Arteriography: MRI, CT, or angiogram with classic "string of pearls" appearance
Biopsy: segmental transmural inflammation of muscular arteries, fibrinoid necrosis of arterial wall (no granulomas, presence suggests another process)

Management

Mild disease (e.g. isolated cutaneous disease): prednisone 1mg/kg daily (max 60-80mg) for 4 weeks followed by steroid taper
Moderate disease: cyclophosphamide + prednisone 1mg/kg daily (max 60-80mg) for 4 weeks followed by steroid taper
Severe/life-threatening disease (renal failure, significant proteinuria, GI/cardiac/neurologic involvement): cyclophosphamide + 500-1000mg IV methylprednisolone daily for 3 days, followed by prednisone 1mg/kg daily (max 60mg) for 4 weeks followed by steroid taper

Giant Cell Arteritis (GCA)

Author: Lauren Waskowicz

Background

Most common large-vessel vasculitis characterized by granulomatous inflammation of medium and large arteries, particularly the cranial branches of the carotid artery
Incidence: most commonly >50 years old, slight F > M predominance
Closely linked to PMR (up to 50% of patients with GCA have PMR, and ~15–30% of PMR patients develop GCA)
T-cell dysregulation, IL-6-mediated inflammation, and macrophage-driven vascular remodeling cause intimal hyperplasia and vessel occlusion

Presentation

Systemic + vessel-specific symptoms
Systemic: Fatigue, low-grade fever, malaise, weight loss
Extracranial arteries: temporal unilateral headache, scalp tenderness, jaw claudication, visual disturbance (blurred vision, amaurosis fugax, or sudden irreversible loss), diplopia
Large-vessel arteries: arm claudication, bruits, aortic aneurysm or dissection. 15-20% of patients will have large vessel involvement without extracranial arterial involvement.

Evaluation

ESR/CRP (almost always elevated), CK, TSH
Evaluate for any temporal artery abnormalities (tenderness to palpation, presence of nodules)
Ophthalmology evaluation if any concern for ocular involvement
Temporal artery biopsy by vascular surgery (typical in the US) OR temporal artery ultrasound (evaluate for presence of Halo sign)
If high suspicion for GCA with negative biopsy or ultrasound, perform further imaging to evaluate for large vessel involvement (CT/CTA or MRI/MRA of aorta and/or branches)

Management

1st line treatment → glucocorticoids are cornerstone of treatment
Start glucocorticoids as soon as GCA is suspected, do not delay while awaiting biopsy; early treatment can prevent irreversible vision loss!
No vision symptoms: prednisone 1mg/kg daily (max 60 mg) for 2-4 weeks followed by taper over months
Vision symptoms: IV methylprednisolone 500–1000 mg/day × 3 days → then prednisone 1 mg/kg/day (max 60 mg) with taper
Consider tocilizumab as adjunctive in those with steroid-refractory disease or those at higher risk for glucocorticoid-related side effects (since most pts with GCA are elderly, this applies to most pts)
Bisphosphonates will be commonly indicated for prevention of glucocorticoid-induced osteoporosis. A bone density test should be obtained at baseline to assess if other anabolic therapies should be used in higher risk pts.

Takayasu's Arteritis

Author: Hannah Angle

Background

Chronic large-vessel vasculitis that primarily affects the aorta and its major branches, often leading to vascular stenosis, occlusion, or aneurysm formation
Incidence: onset usually <30 years old; 80-90% cases in females; strong predilection for individuals of Asian, Middle Eastern, and Latin American descent
Etiology: T-cell and pro-inflammatory cytokines drive granulomatous inflammation of vessel wall

Presentation

Biphasic course: initial systemic inflammatory phase followed by vascular occlusive phase
Subacute constitutional symptoms: fevers, arthralgias, myalgias, rash, weight loss
Cardiovascular: angina from coronary arteritis, HTN (renal a. involvement), discrepant BP between arms (arterial stenosis), diminished or absent pulses ("pulseless disease"), carotidynia (tenderness of the carotid a.), arterial bruits, limb claudication, carotid/vertebral arteritis (vertigo, headache, syncope, strokes), mesenteric ischemia

Evaluation

ESR/CRP: often elevated, though can be normal during active disease
Arteriography: MRA or CTA of head/neck, chest, and abdomen/pelvis

Management

New arterial stenosis or aorta/carotid artery involvement: 1mg/kg prednisone daily (max 60-80mg) for 2-4 weeks followed by steroid taper
Organ threatening disease (coronary artery involvement, critical stenosis of carotid/vertebral arteries): 500-1000mg IV methylprednisolone daily for 1-3 days, then 1mg/kg prednisone daily for 2-4 weeks followed by steroid taper

Behçet's Disease

Author: Meridith Balbach

Background

Chronic relapsing variable vessel (i.e. affects small, medium, large) vasculitis preferentially affecting veins with consequent wide-ranging mucocutaneous, ocular, neurologic, vascular, GI, and joint manifestations.
Incidence: usually onset age 20-40y (rare >40y); equally affects men and women (but men more likely to have severe disease); coined the "Silk Road disease" due to increased frequency in the Middle East and Central Asia
Etiology: genetic predisposition (strongest risk conferred by HLA-B*51 allele) + environmental factors results in (via unclear mechanisms) prominent neutrophil activation and MHC class I regulation defect → dysregulated innate (autoinflammatory) and adaptive (autoimmune) immunity
Differential diagnosis (consider very broad DDx given many nonspecific features): Sweet syndrome, IBD, HSV, reactive arthritis, erythema multiforme, bullous disease

Presentation

Initial relapsing-remitting course with symptoms dependent on vessels involved
Mucosa: painful, shallow oral ulcers (seen in >90%); scarring painful genital ulcers
Skin: erythema nodosum-like nodules, papulopustular lesions, acne, pyoderma gangrenosum, pathergy reaction
Ocular: uveitis (anterior, posterior, or pan-uveitis) and retinal vasculitis
Arthritis: non-erosive, oligoarticular; often migratory
Vascular: pulmonary artery aneurysm, DVT/PE, dural venous thrombosis, Budd-Chiari syndrome, retinal vasculitis
CNS: brainstem or hemispheric lesions, aseptic meningitis, meningoencephalitis
Gastrointestinal: ileocecal ulceration, abdominal pain, bleeding
Subsequent undulating course: most patients manifest symptoms within 5 years of diagnosis, then improve slowly over time

Evaluation

Diagnosis is clinical; no diagnostic criteria
2014 IBCD International Criteria for Behçet's Disease (classification criteria) can help guide (score ≥4 supports diagnosis): recurrent oral ulcers (2), genital ulcers (2), ocular lesions (2), skin lesions (1), vascular lesions (1), positive pathergy test (1)

Management

Highly individualized based on specific organ involvement and severity
Mucocutaneous and/or arthritis: colchicine +/- topical steroids (1st line), apremilast, azathioprine, biologics (adalimumab, etanercept, etc.)
Thrombotic: anticoagulation is controversial. Very important to exclude pulmonary artery aneurysms prior to initiating anticoagulation due to risk of bleeding.
Moderate/severe disease (uveitis, major organ involvement, vascular, CNS): systemic steroids, azathioprine, cyclosporine; if refractory, consider biologics (TNFi and IL-1/IL-6 inhibitors) or cyclophosphamide

Polymyalgia Rheumatica (PMR)

Author: Tina Arkee

Background

PMR is a disorder of inflammatory pain and stiffness predominantly affecting shoulders and pelvic girdle (hips, sacrum, and coccyx)
Incidence: typically >50 years, peak ages 70-80; more common in women (2:1)
PMR is often seen in patients with GCA; occurs in up to 50% of GCA, while 15-30% of PMR patients develop GCA. Either condition may present initially, or may occur concomitantly
Etiology: poorly understood but likely genetic predisposition (HLA DR4 allele, Caucasian background) and environmental factors (including infections) contribute to IL-6-mediated inflammatory response

Presentation

Acute or subacute onset of:
bilateral, symmetric pain and stiffness of shoulders (in almost all cases), neck, and/or pelvic girdle that is worse in the morning and with inactivity
+/- Difficulty with ADLs such as brushing their hair or teeth, lifting their arms to put clothing on, and rising from a seated position
+/- Non-specific constitutional symptoms (fatigue, low-grade fever, weight loss)
Physical exam: normal muscle strength. Objective muscle weakness should raise suspicion for another disease process.
Screen for GCA red flag symptoms (headache, jaw claudication, visual changes, scalp tenderness)

Evaluation

Diagnosis: clinical diagnosis; can use ACR/EULAR 2012 classification criteria for patients ≥50 with new shoulder pain and elevated ESR/CRP (≥4 if not using ultrasound; ≥5 if using ultrasound): morning stiffness lasting >45 min (2 points), hip pain or limited range of motion (1 point), negative RF and CCP titers (2 points), presence of pain in other joints (1 point), shoulder/hip ultrasound findings of inflammation (1 point)
Labs: elevated ESR and CRP (almost always); consider TSH, CK, RF, anti-CCP to rule out mimics
Imaging: MSK ultrasound may demonstrate bursitis, tenosynovitis, or non-PMR etiologies; similarly, MRI may confirm inflammation or demonstrate structural pathology

Management

1st line: steroids, initially 12.5-25mg prednisone daily → assess response with expected improvement within 2-4 weeks. Lack of improvement strongly suggests an alternative diagnosis unless the patient has GCA.
Taper: decrease slowly to the minimum effective dose (often 5mg/day for up to 1-2 years). CRP/ESR can help provide additional insight into disease remission/guide taper
Refractory disease or high risk of steroid side effect: consider steroid-sparing agent (MTX, tocilizumab, sarilumab)

Adult-Onset Still's Disease (AOSD)

Author: Meridith Balbach

Background

Rare autoinflammatory syndrome characterized by systemic inflammation, spiking fevers, arthralgia/arthritis, and a salmon-colored rash
Autoinflammatory diseases involve dysregulation of innate immune system (rather than dysregulation of the adaptive immune system, as in autoimmune disease)
Includes both inherited (e.g. monogenic syndromes like Familial Mediterranean Fever (FMF), cryopyrin-associated periodic syndromes (CAPS), and TNF receptor–associated periodic syndrome (TRAPS)) and acquired syndromes (e.g. AOSD and VEXAS)
Incidence: generally sporadic (no clear genetic predisposition) at 16-35y but can occur at any age. Slight female predominance (51-60%). Rare (~0.16–0.4 cases per 100,000 persons annually)
AOSD is the adult counterpart to systemic juvenile idiopathic arthritis

Presentation

Classic triad: quotidian fevers (often late afternoon/evening), arthralgias/arthritis (often polyarticular and migratory), evanescent salmon-colored rash (maculopapular, often non-pruritic)
Additional features: sore throat, lymphadenopathy, hepatosplenomegaly, serositis, elevated LFTs, hyperferritinemia

Evaluation

Diagnosis of exclusion: must rule out infection, malignancy, other inflammatory etiologies
Serologic workup: elevated ESR/CRP, very high ferritin, CBC (mild leukocytosis, thrombocytosis, anemia), elevated LFTs, ANA and RF (should be negative)
Imaging workup: consider to identify serositis or lymphadenopathy (nonspecific)
2023 ACR/EULAR classification criteria may help with diagnosis (requires ≥5 points total, including ≥2 clinical criteria; sensitivity: ~85% and specificity: ~99%)
Clinical criteria: fever ≥39°C for ≥3 days (2), arthralgia or arthritis (2), evanescent rash (2), pharyngitis (1), lymphadenopathy and/or hepatosplenomegaly (1), serositis (pleuritis or pericarditis) (1)
Laboratory criteria: neutrophils ≥80% (1), ferritin >1000 ng/mL (1), negative ANA and RF (1)

Management

Treatment is based on severity:
Mild/moderate: NSAIDs and/or steroids
Moderate/severe or steroid-refractory: steroids (prednisone 0.5–1 mg/kg/day) + MTX
Severe systemic or refractory: steroids + IL-1 or IL-6 inhibitor
Monitor for progression to secondary macrophage activation syndrome (progressive cytopenias, hyperferritinemia, coagulopathy, liver dysfunction, multiorgan failure)

Sarcoidosis

Author: Lale Ertuglu

Background

Multisystem disorder defined by forming noncaseating granulomas in different tissues

Presentation

Constitutional symptoms: fatigue, night sweats, weight loss, fevers, arthralgias, myalgias
Pulmonary symptoms (most common): dyspnea, cough, and chest pain
Extrapulmonary manifestations
Cutaneous: Highly variable, but present in 25% of patients
- Papules, macules, or plaques commonly involving neck, upper back, extremities
- Lupus pernio: indurated, violaceous bumps on nose, lips, cheeks, ears
- Erythema nodosum
Neuro
- Affects 5-10% of patients; involving any part of CNS or PNS
- CN palsies, hypothalamic/pituitary dysfunction, seizures, myelopathy or radiculopathy, hydrocephalus, aseptic meningitis
CV: may affect pericardium, myocardium, and/or endocardium
- Valvular disorders
- Arrhythmias (most common CV manifestation)
- Cardiomyopathy
Liver/Spleen: transaminitis, cirrhosis, anemia, leukopenia, and thrombocytopenia
Ocular: Uveitis, secondary glaucoma, retinal vasculitis, keratoconjunctivitis
Löfgren Syndrome: acute presentation with fever, bilateral hilar adenopathy, erythema nodosum or ankle arthralgia
Incidental finding in chest imaging: >90% of patients have pulmonary or thoracic lymphadenopathy on presentation and ~50% of patients present with only incidental radiological findings

Evaluation

Combination of clinical features, radiographic manifestations, exclusion of other similarly presenting diseases, and noncaseating granulomas on pathology
CXR: hilar and mediastinal lymphadenopathy ± pulmonary infiltrates. CXR stages are defined as below (stages do not represent disease activity)
Stage 1: bilateral hilar adenopathy only
Stage 2: bilateral hilar adenopathy + pulmonary infiltrates
Stage 3: pulmonary infiltrates without hilar adenopathy
Stage 4: pulmonary fibrosis that mainly involves upper lung zones
High-resolution chest CT: lymphadenopathy (bilateral and symmetric), perilymphatic micro or macronodules, fibrotic changes (reticular opacities, traction bronchiectasis, volume loss, cysts)
PFTs: may show restrictive disease (decreased TLC & VC) and diffusion impairment (reduced DLCO). Occasionally obstructive with endobronchial disease.
Labs: CBC w/ diff, CMP, UA, quant-gold for TB or tuberculin skin test, HIV. Depending on endemic fungi, serologic testing for histoplasmosis or coccidiomycosis can also be included.
ECG: should be obtained since AV block is the most common finding of cardiac sarcoidosis.
Biopsy
Important to rule out mimics. The differential for "noncaseating granulomas" is extensive, including lymphoma and fungal infections
Not required for patients with asymptomatic bilateral hilar adenopathy or pathognomonic presentations including Löfgren syndrome and some cases of lupus pernio

Management

Most do not require therapy: monitor symptoms, CXR, PFTs at 3-6 month intervals
Indications for treatment: highly symptomatic, progressive disease or severe disease at presentation
Mainstay of treatment is oral steroids
Dosing usually 0.3-0.6 mg/kg daily for 4-6 weeks
If only symptom is cough, could consider inhaled glucocorticoids
If unresponsive or unable to tolerate steroids may require alternative agents (MTX, AZA, TNFi)

Fibromyalgia

Author: Tina Arkee

Background

Heterogenous chronic pain syndrome characterized by widespread, constant pain and fatigue
Incidence: 2-3% of adults in the United States, and up to 5% of adults worldwide. Similar prevalence in men and women but discordant diagnosis (account for more than 80% of diagnosed cases). Most often onset at 30-50y, but can occur at any age
Etiology: poorly understood but likely multifactorial in the setting of hypersensitization to pain, physiologic and emotional/psychological stressors, sleep disturbances, and genetic and environmental factors

Presentation

Commonly presents with widespread musculoskeletal pain, fatigue, and sleep disturbances lasting at least 3 months and NOT explained by another medical condition
Patients may report concomitant brain fog, depression/anxiety, or GI symptoms
Physical exam is most notable for tenderness to palpation of multiple sites, hyperalgesia (greater pain than expected), and allodynia (pain to nonpainful stimuli)

Evaluation

Rule out other medical conditions with a thorough history, exam, and labs and imaging as indicated (with the caveat that patients can have fibromyalgia and comorbid conditions)
Workup: consider TSH, CK, CRP/ESR, vitamin D, CBC, CMP; additional workup based on presentation
In unclear cases, can use the 2016 ACR fibromyalgia diagnostic criteria to assist: (1) generalized pain in at least 4 of 5 body regions (2) that is present for at least 3 months and (3) not attributed to another medical condition, AND (4): WPI of 7+ and SSS of 5+ OR WPI of 4-6 and SSS of 9+ (see below)
Monitor symptom evolution with pain using patient-reported outcome scales:
Widespread Pain Index (WPI, 0-19): areas on the body where a patient experienced pain in the past week
Symptom Severity Score (SSS, 0-12): severity of symptoms including fatigue, unrefreshing sleep, cognition, headache, abdominal pain or cramps, and depression

Management

1st line: Multidisciplinary approach with initial focus on non-pharmacologic measures such as low-impact exercise (can be very beneficial), optimizing sleep hygiene, ruling out sleep disorders, mindfulness and meditation, cognitive-behavioral therapy, and treating any mood disorders
2nd line: for refractory cases, start medications based on the predominant symptom (pain, mood, or sleep)
FDA-approved: Pregabalin (pain and sleep), duloxetine (pain and depression/anxiety), and milnacipran (pain and mood)
Off-label: TCAs (low-dose amitriptyline or nortriptyline for sleep and/or pain), gabapentin, SSRIs, muscle relaxers, low-dose naltrexone
AVOID steroids or opioids