Pocket Medicine (Pocket Notebook Series)

APPROACH TO RHEUMATIC DISEASE

Major categories of inflammatory rheumatic disease

• Inflammatory arthritis: crystalline (gout, CPPD), RA, spondyloarthritis, adult-onset Still’s

• Connective tissue disease: SLE, Sjögren’s, scleroderma, myositides (DM, PM), MCTD

• Vasculitis: large (GCA, Takayasu’s); medium (PAN); small (ANCA, IgA, cryo); Behçet’s

• Other: IgG4-related disease, autoinflammatory disease (familial Mediterranean fever, TNF receptor-associated periodic syndrome, VEXAS = vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic), sarcoid (see “ILD”), HLH/MAS, relapsing polychondritis

Approach to patient with joint pain

• Articular vs. periarticular (bursitis, tendinitis) source of pain: typically active ROM more painful than passive ROM in periarticular process

• Inflammatory vs. noninflammatory pain: features of inflammatory arthropathy include joint swelling, warmth or redness, prolonged morning stiffness (>30 min), improvement of pain/stiffness w/ motion/exercise. Assess for extra-articular features.

• Physical exam: localize complaint, identify signs of inflammation, and assess number and pattern of affected joints.

^aMay initially present as arthralgia w/o overt arthritis. ^bRange of motion of joint or joint a/w bursa or tendon.

^*WBC count of aspirated fluid in septic bursitis often < WBC count in septic arthritis.

Imaging features of major arthritides

• OA: plain films: asym joint space narrowing (JSN), osteophytes, subchondral sclerosis & cysts; subchondral “gull-wing” erosions may be seen in less-common erosive OA; MRI may show early disease not seen on plain films; U/S ≈ MRI for structural damage ⊖

• RA: plain films: symmetric JSN, early = periarticular osteopenia; late = marginal erosions; subluxations; MRI & U/S can detect early and subclinical disease; MRI ≈ U/S for erosions

• Gout: plain films: early = nonspec swelling; late = tophus, joint erosions w/ overhanging edges; U/S for detection of microtophi (double-contour sign); dual-energy CT (DECT): identify articular/periarticular UrA deposits vs. calcium deposits; MRI ≈ U/S for erosions

• Spondyloarthritis: e/o sacroiliitis: plain films: early = pseudo-widening SI joint space, late = sclerosis, erosions, ankylosis; SI MRI ↑ Se for early Δ; U/S ≈ MRI to detect enthesitis

INFLAMMATORY MARKER & AUTOANTIBODY TESTING

Inflammatory markers (Mod Rheumatol 2009;19:469; NEJM 1999;340:448)

• ESR: indirect measure of inflammation [↑ RBC aggregation due to acute-phase proteins (fibrinogen, Ig)]; slow to rise; may ↑ w/ age, preg., anemia, obesity, ESRD. Ddx for >100: malig. esp. MM, lymphoma; GCA or other vasculitis; endocarditis, TB, osteomyelitis.

• CRP: direct measure of inflammation (protein produced by liver, part of innate immune system); typically rises and falls before the ESR w/ treatment/resolution of process

Autoantibody testing (Best Pract Res Clin Rheumatol 2014;28:907)

• ANA (anti-nuclear Ab): screening test for Ab directed against nuclear proteins.

• Order ANA only when clinical suspicion for CTD b/c nonspecific: 1:40 (very low ⊕, 25–30% of healthy Pts); 1:80 (low ⊕, 10–15% of healthy Pts); ≥1:160 (⊕, 5% of healthy Pts). May be ⊕ in Pts prior to clin manifest (NEJM 2003;349:1526; Arthritis Res Ther 2011;13:1).

• If ANA ⊕ and high clinical suspicion for CTD, consider testing for Ab against dsDNA, Smith, Ro/La, RNP, Scl-70 and myositis-specific Abs (highly specific for various CTD)

• ANA does not correlate well w/ disease activity, ∴ no clinical value in serial testing

• ANA also ⊕ in: AIH, PBC, thyroid disease, certain infxns and malignancies, IBD, IPF

• RF and anti-CCP (see “Rheumatoid Arthritis”)

DDX & APPROACH TO COMMON INPATIENT RHEUM PRESENTATIONS

Feature	Rheum Ddx	Rheum Lab w/up (+ ANA)
FUO	GCA/PMR, AOSD, SLE, inflamm arthr, Taka- yasu, PAN, ANCA ⊕ vasc, cryo, HSP, VEXAS	ESR, CRP, RF, ANCA, ± cryo
Pulm HTN	Scleroderma (limited >diffuse), MCTD, SLE, PM/DM (less common)	Scl-70, centromere, RNA Pol III, RNP
DAH	ANCA ⊕ vasc, Goodpasture’s, SLE, APS	ANCA, GBM, C3/C4, APLA
ILD	Scleroderma (diffuse >limited), sarcoid, RA, DM, PM, antisynthetase syndrome, Sjögren’s, MCTD, SLE (esp. pleura), ANCA ⊕ vasc (esp. MPA)	Scl-70, RF/CCP, CK, aldolase, ± myositis specific Abs, Jo-1, Ro/La, ANCA
Pleuro- pericarditis	SLE, scleroderma, RA, MCTD, DM/PM, ANCA ⊕ vasc, Sjögren’s, AOSD, PAN	dsDNA, RF/CCP, Sm, Ro/La, Scl-70, RNP, ANCA
AKI + active sed. or CTD s/s	SLE (GN or nephrotic), ANCA ⊕ vasc (GN), scleroderma renal crisis, Sjögren’s (RTA/TIN), PAN (infarct), HSP, Goodpasture’s, cryo, APS	dsDNA, Sm, Ro/La, RNP, C3/C4, Scl-70, RNA Pol III, ANCA, GBM, cryos, APLA
Neuropathy	ANCA ⊕ vasc, SLE, Sjögren’s, cryo, sarcoid, RA, PAN	Ro/La, ANCA, cryo RF/CCP, HCV, HBV

RHEUMATOID ARTHRITIS (RA)

Definition & epidemiology (Lancet 2016;388:2023)

• Chronic, symmetric, and potentially destructive inflammatory polyarthritis characterized by proliferative synovial tissue (pannus) formation in affected joints

• Pathogenesis involves overproduction of TNF, IL-1, and IL-6 (∴ used as drug targets)

• Risk stems from combination of genetics (~50% of risk), environmental influences (eg, smoking, silica dust), and Pt factors (periodontal disease, Δs in gut microbiome)

• HLA-DRB1 haplotype a/w disease suscept., severity, & response to Rx (JAMA 2015;313:1645)

• Prevalence = 1/100 adults and 1/20 ♀ >70 y; ♀ to ♂ ratio = 3:1; peak incidence 50–75 y

Clinical manifestations (JAMA 2018;320:1360)

• Usually insidious onset pain, swelling, & impaired function of joints w/ prolonged morning stiffness for ≥6 wk (typically PIPs, MCPs, wrists, knees, ankles, MTPs, cervical spine)

• Typically polyarticular (60% small joints, 30% large joints, 10% both), may be monoarticular (knee, shoulder, wrist) early in course; rheumatoid joints more susceptible to infection

• Joint deformities: ulnar deviation, swan neck (MCP flexion, PIP hyperextension, DIP flexion), boutonnière (PIP flexion, DIP hyperextension), cock-up deformities (toes)

• C1–C2 instability → myelopathy, ∴✓ C-spine flex/ext films prior to elective intubation

• Constitutional symptoms: low-grade fever, weight loss, malaise

• Extra-articular manifestations (18–41% of Pts) can occur at any time; ↑ frequency in seropositive (⊕ RF or anti-CCP) and w/ active disease (Autoimmun Rev 2021;20:102776)

Extra-Articular Manifestations
Skin	Rheumatoid nodules (20–30%, usually sero ⊕): extensor surface, bursae; can be in lung, heart, sclera Raynaud’s, pyoderma gangrenosum, cutan. vasculitis (ulcers, purpura, etc.)
Pulm	ILD (a/w MUC5B mutations), airway disease, pleuritis, effusions (low glc), nodules, pulm HTN; precedes joint sx in 20% of cases; RA med toxicity (MTX, ? anti-TNF, & anti-CD20) (Semin Arthritis Rheum 2014;43:613)
CV	Accel. athero w/ ↑ risk of MI & CV death, AF, pericarditis (effusions in ⅓ of sero ⊕), myocarditis, coronary/systemic vasculitis (Nat Rev Rheum 2020;16:361)
Nervous	Nerve entrapment (eg, carpal tunnel), stroke, mononeuritis multiplex, CNS vasculitis
Ocular	Scleritis, episcleritis, keratoconjunctivitis sicca (2° Sjögren’s)
Heme	Anemia of chronic disease, neutropenia (Felty’s syndrome: 1%, typically long- standing RA + splenomegaly; large granular lymphocyte leukemia: bone marrow infiltrated w/ lymphocytes ± myeloid hypoplasia), NHL, amyloidosis
Renal	Glomerulonephritis (usually mesangial), nephrotic syndrome (2° amyloidosis), nephrotoxicity from RA meds
Vasculitis	Small & medium vessels (usually ↑ RF titer, long-standing RA); pericarditis, ulcers, scleritis, & neuropathy most common

Laboratory & radiologic studies

• RF (IgM/IgA/IgG anti-IgGAb) ⊕ in ~70%; also seen in other rheumatic diseases (SLE, Sjögren’s), cryoglobulinemia, infection (SBE, hepatitis, TB), ~5% of healthy pop.

• Anti-CCP (Ab to cyclic citrullinated peptide): ⊕ in ~70% of Pts w/ RA, similar Se, but more Sp (>90%) than RF particularly for early RA (Arth Rheum 2009;61:1472); a/w increased joint damage and low remission rates

• ~20% are seronegative (RF and anti-CCP negative)

• ↑ ESR/CRP but nl in ~30%; ⊕ ANA in ~40%; ↑ globulin during periods of active disease

• Radiographs of hands and wrists: periarticular osteopenia, bone erosions, joint subluxation

• Increasing use of MSK U/S to diagnose synovitis, tenosynovitis, and erosive disease

ACR/EULAR classification criteria (Arth Rheum 2010;62:2569)

• Used in clinical research, but not in clinical practice

• Relevant for Pts with ≥1 joint with synovitis not better explained by another disease

• Likelihood of RA ↑ w/ higher # (espec. ≥4) of small joints involved, ⊕ RF or anti-CCP (espec. high titer), ↑ ESR or CRP, and duration ≥6 wk

Management (Lancet 2017;389:2328 & 2338; JAMA 2018;320:1360)

• Early dx and Rx (esp DMARD) w/ frequent follow-up and escalation of Rx as needed with goal to achieve clinical remission or low disease activity

• ↓ time to remission ≈ ↑ length of sustained remission (Arthritis Res Ther 2010;12:R97)

• Sero ⊕ (eg, RF or anti-CCP) a/w aggressive joint disease & extraarticular disease

• At dx, start both rapid-acting agent (to acutely ↓ inflammation) and Disease-Modifying Anti- Rheumatic Drug (DMARD) (typically take 1–3 mo to have max effect)

• Rapid-acting drugs:

NSAIDs or COX-2 inhibitors: ↑ CV risk, GI adverse events, AKI; consider starting w/ PPI

glucocorticoids: low dose (<20 mg/d oral) or joint injection

NSAIDs + glucocorticoids: ↑↑ GI events; give PPI and minimize long-term concurrent use

• DMARDs (see RA therapeutics below):

Methotrexate (1^st line unless CKD, hepatitis, EtOH, or lung disease), alternatives include sulfasalazine (SSZ) or leflunomide; consider HCQ if mild disease

If inadequate response after 3 mo (despite DMARD dose escalation) consider:

combination Rx w/ other DMARDs (eg, “triple therapy” w/ MTX, SSZ, and HCQ) or

adding biologic (anti-TNF typically 1^st line unless contraindication)

MTX/SSZ/HCQ non-inferior to etanercept/MTX (NEJM 2013;369:307)

JAKi: if fail biologics vs. initial DMARD, but ↑ serious side effect risk over abatacept or TNFi (see below) (Lancet 2018;391:2503 & 2513; NEJM 2020;383:1511; NEJM 2022;386:316)

• Given a/w CV morbidity/mortality, try to ↓ risk w/ lifestyle mgmt, lipid & DM screening

RA Therapeutics (Arth Care Res 2021;73:924)
Class	Drug	Side Effects
Traditional DMARDs	Methotrexate (MTX) Leflunomide Sulfasalazine (SSZ)	MTX: GI distress, stomatitis, ILD, myelosuppression, hepatotoxicity Supplement MTX ± SSZ w/ folate ✓ G6PD prior to SSZ
Biologic DMARDs (all anti-TNF ≈ efficacy; if inadequate resp to anti- TNF try non-TNF)	Anti-TNF: etanercept, infliximab, adali- mumab, certolizumab, golimumab CTLA4-Ig: abatacept Anti-IL-6R Ab: tocilizumab (studied as mono-Rx w/o MTX); sarilumab Anti-CD20: rituximab Anti-IL-1R: anakinra Never use 2 biologics together	↑ risk bacterial/fungal/viral infxn ✓ TB, Hep B/C before starting Immunize against Zoster + Pneumococcus Anti-TNF: ? risk for CHF & CNS demyelinating disease Anti-IL-6R: risk of GI perf. Rituximab: infusion reaction
Other	Hydroxychloroquine (HCQ) JAKi: tofacitinib, baricitinib; upadacitinib (JAK1 selective) Rare: cyclosporine, azathioprine, gold	HCQ: retinopathy, rash JAKi: infxn, ↑ LFTs, HTN, VTE, CV events, malignancy, death CsA: ↑ Cr, HTN, gum hyperplasia

ADULT-ONSET STILL’S DISEASE (AOSD) & RELAPSING POLYCHONDRITIS

Adult-onset Still’s disease (J Autoimmun 2018;93:24)

• Rare autoinflammatory syndrome, <4/million per y incidence; ♂ = ♀ w/ bimodal typical onset 15–25 or 36–46 y; sx evolve over wks to mos

• Dx if 5 criteria are present & ≥2 major; exclude infxn, malig, other rheumatic, drug rxn

Major: fever ≥39°C for ≥1 wk (usually daily or twice daily high-spiking fever); arthralgias/ arthritis ≥2 wk; Still’s rash (qv); ↑ WBC w/ 80% PMN

Minor: sore throat; LAN; HSM; ↑ AST/ALT/LDH; negative ANA & RF

• Still’s rash (>85%): nonpruritic macular or maculopapular salmon-colored rash; usually trunk or extremities; may be precipitated by trauma (Koebner phenomenon), warm water

• Plain films: soft tissue swelling (early) → cartilage loss, erosions, carpal ankylosis (late)

• Treatment: NSAIDs; steroids; steroid-sparing (MTX, anakinra, anti-TNF, tocilizumab)

• Variable clinical course: 20% w/ long-term remission; 30% remit-relapse; ~50% chronic (esp. arthritis); ↑ risk of macrophage activation syndrome (life threatening)

Relapsing polychondritis (Rheumatology 2018;57:1525)

• Inflammatory destruction of cartilaginous structures; typical onset age 40–60, ♂=♀, <1/million per y incidence

• Subacute onset of red, painful, and swollen cartilage; ultimately atrophic & deformed

• Multiple sites of cartilaginous inflammation: bilateral auricular chondritis, nonerosive inflammatory arthritis, nasal chondritis, laryngeal or tracheal chondritis, valvulopathy. Ocular inflammation and cochlear/vestibular dysfxn also common.

• 40% of cases a/w immunologic disorder (eg, RA, SLE, vasc., Sjögren’s), cancer or MDS (including VEXAS; NEJM 2020;383:2628)

• Labs: ↑ ESR & CRP, leukocytosis, eosinophilia, anemia of chronic inflammation

• Bx (not req for dx): proteoglycan depletion, perichondrial inflammation and replacement with granulation tissue and fibrosis; immunofluorescence with Ig and C3 deposits

• Screen for pulm (PFTs, CXR/CT, ± bronch) and cardiac (ECG, TTE) involvement

• Rx guided by disease activity/severity: steroids 1st line; NSAIDs/dapsone for arthralgias, mild disease; MTX, AZA, or biologics steroid-sparing; cyclophosph if organ-threatening

CRYSTAL DEPOSITION ARTHRITIDES

Comparison of Gout and Pseudogout
	Gout (Rheumatology 2018;58:27)	Pseudogout (NEJM 2016;374:2575)
Acute clinical	Sudden onset painful mono- articular arthritis (classically podagra [MTP of great toe]) or bursitis; frequently nocturnal May be polyarticular in subseq flares Can mimic cellulitis (esp in foot)	Mono- or asymmetric oligoarthritis (esp knees, wrists, and MCP joints); rare axial involvement (eg, crowned dens syndrome)
Chronic clinical	Solid crystal deposition (tophus) in joints (esp. toes, fingers, wrists, knees) & tissue (esp. olecranon bursa, pinna, Achilles)	“Pseudo-RA” w/ polyarticular arthritis w/ morning stiffness or “Pseudo-OA”
Assoc. conditions	Metabolic syndrome; CKD; CHF	3 H’s: Hyper-PTH, Hypo-Mg, Hemochromatosis
Crystal	Monosodium urate (MSU)	Calcium pyrophosphate dihydrate
Polarized microscopy*	Needle-shaped, negatively birefringent	Rhomboid-shaped, weakly positively birefringent
Radio- graphic findings	Early = nonspecific tissue swelling Late = tophus, joint erosions w/ overhanging edges “Double contour sign” on MSK US DECT: UrA vs. Ca deposits	Chondrocalcinosis: linear densities within articular cartilage; often found in menisci, fibrocartilage of wrist, hands, symphysis pubis
Other	a/w uric acid stones; urate nephropathy	✓ Ca, Mg, Fe, ferritin, TIBC, UrA, PTH in young or severe cases

^*Crystals should be intracellular; infection can coexist with acute attacks, ∴ always ✓ Gram stain & Cx

GOUT

Definition & epidemiology (Rheumatology 2018;58:27; Lancet 2021;397:1843)

• Humans lack enzyme (uricase) to metabolize urate (end-product of purine metabolism)

• MSU crystal deposition promotes inflammation in joints and peri-articular tissue;

• Prev >1/30 American adults, ♂ >♀; peak incidence 5^th decade; most common inflamm arthritis in ♂ over 30 y; rare in premenopausal ♀ (estrogens ↑ renal urate excretion)

Etiologies

• UrA underexcretion (85–90%): meds (eg, diuretics); idiopathic; ↓ renal function; obesity

• Uric acid (UrA) overproduction (10–15%): ↑ meat, seafood, EtOH, psoriasis, idiopathic, myelo- and lymphoproliferative disease, chronic hemolytic anemia, cytotoxic drugs, rare inherited enzyme defic, genetic variants (Nature Rev Rheumatol 2018;14:341)

Diagnosis

• ↑ UrA is not diagnostic; 25% of measurements nl during flare; ± ↑ WBC & ESR

• Arthrocentesis is gold standard: intracellular negatively birefringent needle-shaped MSU crystal. U/S w/ double-contour sign or dual-energy CT can aid non-invasive dx.

• 2015 ACR/EULAR Classification Criteria (Ann Rheum Dis 2015;74:1789) used 1° in research

Acute treatment (Arthritis Care Res 2020;72:744)

• Colchinine, NSAIDs, & steroids all 1^st-line; choice guided by side effect profile/comorbidities. IL-1i (J Rheum 2019;46:1345) or ACTH if these contraindicated. Start Rx ASAP; continue until acute flare resolves; consider combo Rx if severe; rest/ice; self-limited w/in 3–21+ d w/o Rx.

• Continue urate-lowering therapy during attack if already taking

Acute Treatment for Gout
Drug	Initial Dose	Comments
NSAIDs (nonsel or COX-2 inhib)	Full anti-inflammatory dose → tapering	Gastritis & GIB risk. Avoid in CKD & CVD. ≈ efficacy among NSAIDs.
Colchicine (PO; IV no longer available in U.S.)	1.2 mg then 0.6 mg 1 h later → 0.6 mg bid	N/V/diarrhea (w/ ↑ dose), marrow suppression, myopathy, neuropathy. ↓ dose in CKD (however, not nephrotoxic).
Corticosteroids (PO, IA, IV, IM)	eg, prednisone 0.5 mg/kg/d × 5–10 d ± taper	Rule out joint infection 1st. Corticosteroid injection if <3 joints.
ACTH (IM)	eg, 100 IU IM ×1–2 doses	↑ cost, ↓ s/e, limited data (Semin Arthritis Rheum 2014;43:648)
IL-1 inhibitors (J Rheumatol 2019;46:1345)	anakinra (100 mg SC qd × 3 d); canakinumab (150 mg SC × 1)	↑↑ cost; anakinra a/w injection site pain Canakinumab approved in EU (Ann Rheum Dis 2012;71:1839; Arth Rheum 2010;62:3064)

Chronic treatment (Arthritis Care Res 2020;72:744)

• Approach: if ≥2 attacks/y, polyarticular attack, tophus, joint erosions, GFR <60, or urolithiasis → start urate-lowering therapy + pharmacologic Ppx to ↓ risk of acute attacks

• Urate-lowering therapy (ULT): goal UrA <6 mg/dL; when starting ULT, always give with pharm Ppx as below; do NOT d/c during acute attack or due to AKI

• Pharmacologic prophylaxis: continue 6 mos w/ above Rx or longer if frequent attacks:

low-dose colchicine (~50% ↓ risk of acute flare; J Rheum 2004;31:2429), NSAIDs (less evidence; Ann Rheum Dis 2006;65:1312), low-dose steroids, IL-1 inhibitors

• Lifestyle Δs: ↓ intake of meat, EtOH, & seafood, ↑ low-fat dairy, wt loss, avoid dehydration

Urate-Lowering Therapy (Chronic Treatment for Gout)
Drug (route)	Mechanism	Comments
Allopurinol (PO)	Xanthine oxidase inhibitor	1st line; adjust starting dose in CKD; titrate ↑ q2–5wk; a/w rash, hypersensitivity syndrome (see below), BM suppression (avoid w/ AZA/6-MP), diarrhea, N/V, hepatitis; monitor CBC, LFT’s; not nephrotoxic max dose = 800 mg/d
Febuxostat (PO)	Nonpurine xanthine oxidase inhib	2nd line; use if allopurinol intolerant; a/w ↑ LFT, rash, arthralgias, N/V; avoid w/ AZA/6-MP (BM suppress); start 40 mg, max dose = 120 mg/d
Pegloticase (IV)	Recombinant uricase	For refractory tophaceous gout; infusion reactions (including anaphylaxis); Ab formation may limit use (JAMA 2011;306:711); avoid w/ G6PD deficiency
Probenecid (PO)	Uricosuric	Rarely used; risk of urolithiasis

• Allopurinol hypersensitivity syndrome: 10–25% mortality; incidence ~5/1000. ↓ risk w/ starting dose 100 mg/d if eGFR >40 or 50 mg/d if eGFR ≤40. Titrate by 100 mg/d (eGFR >40) or 50 mg/d (eGFR ≤40) q2–5 wk until UrA <6 mg/dL (dose can be >300 mg/d even in CKD). A/w HLA-B5801, esp. Han Chinese, Koreans, Thai; screen in these high-risk populations prior to initiating (Arthritis Care Res 2020;72:744; JAMA Intern Med 2015;175:1550).

CALCIUM PYROPHOSPHATE DIHYDRATE (CPPD) DEPOSITION DISEASE/PSEUDOGOUT

Definition (NEJM 2016;374:2575)

• Deposition of CPPD crystals w/in tendons, ligaments, articular capsules, synovium, cartilage; frequently asymptomatic

Etiologies (Nat Rev Rheumatol 2018;14:592)

• Most cases idiopathic; consider further metabolic eval in young (<50 y) and florid forms

• Metabolic (3 H’s): hemochromatosis; hyperparathyroidism; hypomagnesemia (esp. in Gitelman’s or Bartter’s syndromes)

• Joint trauma (incl. previous surgery); intra-articular hyaluronate can precipitate attacks

• Familial chondrocalcinosis (autosomal dominant disorder); early-onset, polyarticular dis.

Clinical manifestations

• Chondrocalcinosis: calcification of cartilage, resulting from CPPD crystal deposition in articular cartilage, fibrocartilage, or menisci

↑ incidence w/ age; can be asymptomatic; chondrocalcinosis in 20% >60 y at autopsy

• Pseudogout: acute CPPD crystal-induced mono- or asymmetric oligoarticular arthritis, indistinguishable from gout except through synovial fluid exam for crystals

location: knees, wrists, and MCP joints; rarely, axial (eg, crowned dens syndrome due to CPPD deposition at C1–C2)

precipitants: surgery, trauma, or severe illness

• Chronic forms: “pseudo-RA” and pyrophosphate arthropathy (resembles OA, can involve axial skeleton)

Diagnostic studies

• Arthrocentesis is gold standard: rhomboid shaped, weakly positively birefringent crystals (yellow perpendicular & blue parallel to axis on polarizer; see table above)

• Radiographs: see table above

Treatment (NEJM 2016;374:2575)

• Asymptomatic chondrocalcinosis requires no treatment

• Acute therapy for pseudogout: no RCTs, extrapolated from practice in gout; ∴ same as for gout, though colchicine not as effective

• If associated metabolic disease, Rx of underlying disorder may improve arthritis sx

• Low-dose daily colchicine or NSAID may be effective for prophylaxis or chronic arthropathy

SERONEGATIVE SPONDYLOARTHRITIS

Definition and classification system (NEJM 2016;374:2563)

• Spondyloarthritis (SpA): group of inflammatory disorders that share common clinical manifestations: inflammatory spine disease, peripheral arthritis, enthesitis (see below), and extra-articular manifestations (primarily ocular and skin disease)

• Seronegative = absence of autoantibodies

• Subtypes: ankylosing spondylitis (AS), psoriatic (PsA), reactive (ReA), IBD-assoc, juvenille SpA, and undifferentiated. Distinguished by axial vs. peripheral predominant involvement.

Epidemiology & pathogenesis (Nat Rev Rheumatol 2015;11:110)

• Prevalence 1/200 to 1/50 worldwide; AS and non-radiographic axial SpA most common

• HLA-B27 accounts for ~30% of attributable genetic risk but not required for diagnosis

• Environmental factors likely critical for disease, esp reactive arthritis (ie, infection)

Spondyloarthritis (SpA) Epidemiology and Key Presentation Features
Disease	Epidemiology	Key Features
Ankylosing spondylitis (AS)	♂:♀ = 3:1; onset in teens to mid-20s (rare after 40 y)	Progressive limitation of spinal motion, a.m. stiffness, buttock pain, “bamboo spine,” ⊕ Schober test
Psoriatic arthritis (PsA)	♂ = ♀; peak incidence 45–54 y; seen in 20–30% of Pts w/ psoriasis	In 13–17% arthritis precedes skin findings by yrs; does not correlate with psoriasis activity; a/w HIV
Reactive arthritis (ReA)	♂ >> ♀; 20–40 y; 10–30 d after GI or GU infxn* in genetically susceptible host	Arthritis, urethritis, and conjunctivitis. Most resolve w/in 12 mo.
IBD- associated arthritis	♂ = ♀; seen in 20% of IBD Pts; Crohn’s >UC	Type I <5 joints: correlates w/ IBD activ. Type II >5 joints or axial disease: does not correlate w/ IBD activity

^*GU: Chlamydia, Ureaplasma urealyticum; GI: Shigella, Salmonella, Yersinia, Campylobacter, C. diff.

Major clinical manifestations (Lancet 2017;390:73)

• Inflammatory back pain: SI joints (sacroiliitis), apophyseal joints of spine

characterized by IPAIN (Insidious onset, Pain at night, Age of onset <40 y, Improves w/ exercise/hot water, No improvement w/ rest), a.m. stiffness, responsive to NSAIDs

• Peripheral arthritis: typically asymmetric, oligoarticular, large joints, lower >upper limbs; however, can be symmetric & polyarticular (thus, mimic RA), espec. in psoriatic arthritis

• Enthesitis: inflammation at site of tendon/ligament insertion into bone, esp Achilles, plantar fascia (calcaneal insertion), pre-patellar, elbow epicondyles

• Rigidity of spine: bamboo spine by X-ray, ankylosis due to progressive growth of bony spurs that bridge intervertebral disc

• Dactylitis: “sausage digit,” inflammation of entire digit (joint + tenosynovial inflamm)

• Uveitis: anterior uveitis most common extra-articular manifestation in seronegative SpA; usually unilateral and p/w pain, red eye, blurry vision, photophobia

Clinical assessment (Nat Rev Rheumatol 2021;17:109)

• Seronegative: rheumatoid factor and other autoantibodies usually ⊖; ± ↑ ESR/CRP

• HLA-B27: nonspecific, b/c common in general population (6–8%); most useful when high clinical suspicion but nl imaging; ⊕ 90% of Pts w/ AS, but only 20–80% in other SpA

• Axial disease physical exam

The following are not specific PEx findings but useful in monitoring disease during Rx:

Lumbar flexion deformity assessed by modified Schober’s test (⊕ if <5 cm ↑ in distance between a point 5 cm below the lumbosacral jxn and another point 10 cm above, when going from standing to maximum forward flexion)

T-spine mobility (extension) and kyphosis severity measured by occiput-to-wall distance (although occiput-to-wall distance also increased in osteoporotic kyphosis)

• Infectious evaluation for reactive arthritis (⊖ studies do not r/o)

GU: U/A, PCR of urine and/or genital swab for Chlamydia; urethritis usually due to Chlamydia infxn preceding arthritis, but can also see sterile urethritis post dysentery

GI: stool Cx, C. diff toxin. Consider HIV in workup for reactive or psoriatic arthritis.

• Radiology

MRI preferred for early detection of inflammation (sacroiliitis)

Plain films detect late structural changes (SI erosions/sclerosis)

Calcification of spinal ligaments w/ bridging symm syndesmophytes (“bamboo spine”)

Squaring and generalized demineralization of vertebral bodies (“shiny corners”)

Descriptions of skin manifestations

• Psoriasis: erythematous plaques with sharply defined margins often w/ thick silvery scale

• Circinate balanitis: shallow, painless ulcers of glans penis and urethral meatus

• Keratoderma blennorrhagica: hyperkeratosis of palms/soles, scrotum, trunk, scalp

• Erythema nodosum: red tender nodules in subcutan. fat (panniculitis), typically on shins Ddx includes idiopathic, infxn, sarcoid, drug rxn, vasculitis, IBD, lymphoma

• Pyoderma gangrenosum: neutrophilic dermatosis → painful ulcers w/ violaceous border Ddx incl. idiopathic, IBD, RA, heme and solid malignancies, MGUS, MDS, polycyth. vera

Psoriatic arthritis subtypes (Lancet 2018;391:2273 & 2285; Nat Rev Dis Primers 2021;7:59)

• Mono/oligoarticular (large or DIP joint, dactylitic digit): most common initial manifestation

• Polyarthritis (small joints of the hands/feet, wrists, ankles, knees, elbows): indistinguishable from RA, but often asymmetric

• Arthritis mutilans: severe destructive arthritis with bone resorption, esp. hands

• Axial disease: unilateral/asymmetric sacroiliitis

• DIP-limited: good correlation with nail pitting and onycholysis

Treatment approach (Arthritis Care Res 2019;71:2 & 2019;71:1285; NEJM 2021;385:628)

• Untreated disease may lead to irreversible structural damage and associated ↓ function

• Early physiotherapy beneficial

• Tight control of inflammation may improve outcomes (eg, in PsA; Lancet 2015;386:2489)

• NSAIDs: 1^st line; rapidly ↓ stiffness and pain; prolonged, continuous administration may modify disease course but associated w/ GI and CV toxicity (Cochrane Database Syst Rev 2015;17:CD010952); may exacerbate IBD

• Intra-articular corticosteroids in mono- or oligoarthritis; limited role for systemic steroids, esp. for axial disease

• Conventional DMARDs (eg, MTX, SSZ, leflunomide): no efficacy for axial disease or enthesitis; may have role in peripheral arthritis, uveitis, and extra-articular manifestations

• Anti-TNFs: effective for both axial and peripheral SpA, improves function and may slow progression of structural changes; adalimumab or infliximab preferred if eyes involved

• Anti-IL17A (secukinumab, ixekizumab): for both AS and axial and peripheral PsA (NEJM 2015;373:1329 & 2534; Lancet 2015;386:1137)

• Anti-IL12/23 (ustekinumab) and anti-IL23 (guselkumab) for both axial & peripheral PsA (Lancet 2020;395:1115) but not axial SpA (Arthritis Rheumatol 2019;71:258)

• PDE-4 inhibitor (apremilast): effective in PsA refractory to conventional DMARD or as first-line (Rheumatology 2018;7:1253); a/w GI side effects and wt loss

• JAK inhibitor: for conventional DMARD- or anti-TNF-resistant peripheral and/or axial SpA (NEJM 2017;377:1525 & 1537; 2021;384:1227)

• Other:

Abx indicated in ReA if active GU infxn but not typically needed for uncomplicated enteric infx. Can consider prolonged abx for refractory Chlamydia ReA (Arthritis Rheum 2010;62:1298), but controversial.

Involve ophtho if suspect eyes affected (may need steroid drops or intravitreal injection)

Treat underlying IBD when appropriate

INFECTIOUS ARTHRITIS & BURSITIS

ETIOLOGIES & DIAGNOSIS OF INFECTIOUS ARTHRITIS

Etiologies (Curr Rheumatol Rep 2013;15:332)

• Bacterial (nongonococcal): early diagnosis and treatment essential

• Gonococcal (N. gonorrhea): consider in sexually active young adults

• Viral: parvovirus, HCV, HBV, acute HIV, Chikungunya; mainly polyarticular, may mimic RA

• Mycobacterial: monoarticular or axial (Pott’s disease)

• Fungal: Candida (esp. prosthetic joints), coccidiomycosis (valley fever), histoplasmosis

• Other: Lyme, Mycoplasma, Salmonella, Brucellosis, T. whipplei

Diagnosis (JAMA 2007;297:1478)

• H&P w/ poor sensitivity and specificity for septic arthritis

• Arthrocentesis in acute onset inflammatory monoarthritis to r/o septic arthritis; if possible, obtain fluid sample prior to starting antibiotics

• Do not tap through overlying infected area to prevent introducing infxn into joint space

• ✓ Fluid cell count w/ diff, Gram stain, bacterial culture, crystal analysis; WBC >50k

w/ PMN predominance suspicious for bact. infxn; crystals do not r/o septic arthritis!

BACTERIAL (NONGONOCOCCAL) ARTHRITIS

Epidemiology & risk factors (Infect Dis Clin North Am 2017;31:203)

• 1/50,000 incidence per year

• Immunocompromised host: DM, EtOH use, HIV, age >80, SLE, cancer, steroid use, etc.

• Damaged joints: RA, OA, gout, trauma, prior surgery/prosthetic, prior arthrocentesis (rare)

• Bacterial seeding: bacteremia especially secondary to IVDU or endocarditis; direct inoculation or spread from contiguous focus (eg, cellulitis, septic bursitis, osteomyelitis)

Clinical manifestations (JAMA 2007;297:1478; Lancet 2010;375:846)

• Acute onset monoarticular arthritis (>80%) w/ pain (Se 85%), swelling (Se 78%), warmth

• Location: knee (most common), hip, wrist, shoulder, ankle. In IVDU, tends to involve other areas including axial joints (eg, SI, symphysis pubis, sternoclavicular, manubrial joints).

• Constit. sx: fevers (Se 57%), rigors (Se 19%), sweats (Se 27%), malaise, myalgias

• Infection can track from initial site to form fistulae, abscesses, or osteomyelitis

• Septic bursitis must be differentiated from septic arthritis (intra-articular infection)

Additional diagnostic studies (JAMA 2007;297:1478)

• Synovial fluid: WBC usually >50k (Se 62%, Sp 92%) but can be <10k, >90% polys; Gram stain ⊕ in ~75% of Staph, ~50% of GNR; Cx ⊕ in >90%; synovial bx most sens.

• Leukocytosis (Se 90%, Sp 36%); elevated ESR/CRP (Se >90%)

• Blood cultures ⊕ in >50% of cases, ~80% when more than 1 joint involved

• X-rays of joints should be obtained but usually normal until after ~2 wk of infection when may see bony erosions, joint space narrowing, osteomyelitis, and periostitis

• CT & MRI useful esp. for suspected hip infection or epidural abscess

Treatment for native joints (IDCNA 2017;31:203)

• Prompt empiric antibiotics guided by Gram stain after surgical drainage. If Gram stain ⊖, empiric Rx w/ vancomycin; add anti-pseudomonal agent if IVDU or immunocompromised.

Common Microbes (by Gram stain)		Population	Initial Antibiotic Regimen (tailor based on Gram stain, cx, clin course)
GPC clusters	S. aureus (most common)	Normal joints Prosthetic joints Damaged joints	Vancomycin. Can later Δ to antistaphylococcal penicillin or cefazolin based on sensitivities.
	S. epidermidis	Prosthetic joints Postprocedure
GPC chains	Streptococci	Healthy adults Splenic dysfunction	PCN-G or ampicillin
GN	Diplococci: N. gonorrhea	Sexually active young adults	Ceftriaxone or cefotaxime
	Rods: E. coli, Pseudomonas, Serratia	IVDU, GI infection immunosupp, trauma elderly	Cefepime or piperacillin/tazobactam + antipseudomonal aminoglycoside in IVDU

• IV antibiotics × ≥2 wk followed by oral antibiotics; varies by clinical course & microbiology

• Joint must be drained, often serially w/ arthroscopy (larger joints, initial Rx) or arthrocentesis. Serial synovial fluid analyses should demonstrate ↓ in WBC and sterility.

• 10–15% mortality (up to 50% w/ polyarticular); depends on virulence, time to Rx, host

Prosthetic joint infections (Infect Dis Clin North Am 2012;26:29; CID 2013;56:e1)

• ↑ risk in first 2 y s/p procedure; rate generally low (0.5–2.4%); risk factors include obesity, RA, immunocompromised state, steroids, & superficial surgical site infxn

• Staphylococci (coag negative & S. aureus) in >50%; polymicrobial in 10–20%

• Early (<3 mo s/p surgery) or delayed (3–24 mo) onset of sx from microbe typically acquired during implantation; early w/ virulent (eg, MRSA) and delayed w/ less virulent organisms (eg, P. acnes, coag negative Staph) & more indolent presentation

• Late (>24 mo) onset typically related to secondary hematogenous seeding

• Diagnosis requires arthrocentesis; ESR & CRP (CRP Se 73–91%, Sp 81– 86%; NEJM 2009;361:787) can be helpful

• Requires prolonged abx (initial empiric regimen: vanc + 3^rd/4^th gen cephalosporin) for 6 wks (NEJM 2021;384:1991) & 2-stage joint replacement (retention a/w ~40% failure; CID 2013;56:182) or life-long suppressive abx. Consult ID & orthopedics.

DISSEMINATED GONOCOCCAL INFECTION (DGI)

Epidemiology (Infect Dis Clin North Am 2005;19:853)

• N. gonorrhea; most frequent type of infectious arthritis in sexually active young adults

• Normal host as well as Pts w/ deficiencies of terminal components of complement

• ♀:♂ = 4:1 historically, but now ↑ in ♂. Occurs in <3% of N. gonorrhea infxn; ↑ incidence w/ menses, pregnancy, postpartum, SLE; ↑ incidence in MSM.

Clinical manifestations

• Preceded by mucosal infection (eg, cervix, urethra, anus, or pharynx) that is often asx

• Two distinct syndromes, although Pts can have both:

Joint-localized: purulent arthritis (40%), usually 1–2 joints (knees >wrists >ankles)

Arthritis-dermatitis syndrome: triad of polyarthralgias, tenosynovitis, skin lesions

1) polyarthralgias: migratory joint pain, can affect small or large joints

2) tenosynovitis: pain/inflammation of tendon and its sheath in wrists, fingers, ankles, toes

3) skin lesions: gunmetal gray pustules with erythematous base on extremities & trunk

• Rare complications: Fitz-Hugh-Curtis syndrome (perihepatitis), pericarditis, meningitis, myocarditis, osteomyelitis from direct extension of joint-localized infection

Additional diagnostic studies

• Synovial fluid: WBC >50k (but can be <10k), poly predominant

Gram stain ⊕ in ~25%; culture ⊕ in up to 50% if done w/ Thayer-Martin media

• Blood culture: more likely ⊕ in arthritis-dermatitis syndrome; rarely in joint-localized disease

• Gram stain and culture of skin lesions occasionally ⊕

• Cervical, urethral, pharyngeal, rectal PCR or cx on Thayer-Martin media; ✓ Chlamydia

Treatment

• Ceftriaxone × 7–14 d w/ empiric doxycycline × 7 d for Chlamydia if co-infection has not been excluded (see STI)

• Joint arthroscopy/lavage may be required for purulent arthritis; rarely >1 time

OLECRANON & PREPATELLAR BURSITIS

Epidemiology & risk factors (Joint Bone Spine 2019;86:583)

• >150 bursae in the body; 2 most commonly infected are olecranon and prepatellar

• Most commonly (esp. superficial bursae) due to direct trauma, percutaneous inoculation, or contiguous spread from adjacent infection (eg, cellulitis)

• Other risk factors: recurrent noninfectious inflammation (eg, gout, RA), diabetes

• S. aureus (80%) most common, followed by streptococci

Diagnosis

• Physical exam: discrete bursal swelling, erythema, maximal tenderness at center of bursa with preserved joint range of motion

• Aspirate bursa if concern for infxn, ✓ cell count, Gram stain, bacterial cx, crystals

WBC >20k w/ poly predominance suspicious for bacterial infection, but lower counts very common (crystals do not rule out septic bursitis!)

• Assess for adjacent joint effusion, which can also be septic

• Do not tap through infected skin to avoid introducing infxn into bursa

Initial therapy

• Prompt empiric coverage for staphylococci and streptococci: PO abx acceptable for mild presentation; vancomycin if ill appearing; broaden spectrum based on risk factors

• Modify antibiotics based on Gram stain, culture results, & clinical course. Duration of Rx is 1–3 wks. Serial aspirations every 1–3 d until sterile or no reaccumulation of fluid.

• Surgery if unable to drain bursa through aspiration, evidence of foreign body or necrosis, recurrent/refractory bursitis w/ concern for infxn of adjacent structures

CONNECTIVE TISSUE DISEASES

Centr, centromere; dcSSc, diffuse cutaneous systemic sclerosis; lcSSc, limited cSSc; IM, inflammatory myopathies; RF, rheumatoid factor; Sm, Smith (Primer on the Rheumatic Diseases, 12^th ed., 2001; Lancet 2013;382:797; J Rheumatol 2015;42:558)

• Only order auto-Ab testing if clinical suspicion for CTD, the presence of auto-Ab without characteristic clinical findings ≠ diagnosis, and auto-Ab do not define a particular CTD

• Overlap syndromes may be reflected by multiple autoantibodies

see “Systemic Lupus Erythematosus” and “Rheumatoid Arthritis” for those diseases

SYSTEMIC SCLEROSIS AND SCLERODERMA DISORDERS

Definition & epidemiology (Best Pract Res Clin Rheumatol 2018;32:223)

• Scleroderma refers to the presence of tight, thickened skin

• Localized scleroderma: morphea (plaques of fibrotic skin), linear (fibrotic bands), “en coup de sabre” (linear scleroderma on one side of scalp and forehead ≈ saber scar)

• Systemic sclerosis (SSc) = scleroderma + internal organ involvement. High-mortality.

SSc w/ limited cutaneous disease (lcSSc): formerly CREST syndrome (see below)

SSc w/ diffuse cutaneous disease (dcSSc): often rapidly progressive skin thickening

SSc sine scleroderma (visceral disease without skin involvement, rare)

• Peak onset age 30–50; ♀ >♂ (8:1). Earlier/more severe disease in African Americans

• <6/100,000 annual SSc incidence wordwide; lcSSc incidence ~2× that of dcSSc

• Pathogenesis: unclear. Endothelial injury → ROS/oxidative stress → perivascular inflammation → fibrosis. Cytokines, growth factors, genetics, environ. factors + antibodies (against PDGFR, endo. cells, fibroblasts) may contribute (NEJM 2009;360:1989).

ACR/EULAR SSc classification criteria (Ann Rheum Dis 2013;72:1747)

• Sufficient for dx: skin thickening of fingers of both hands extending proximal to MCPs

• Other items considered in criteria: Raynaud’s, SSc-related auto-Ab, pulm hypertension (PHT) and/or ILD, abnormal nailfold capillaries, telangiectasia, fingertip lesions (ulcers, scars), skin thickening distal to MCPs

• Rule out other causes of thickened skin: diabetes (scleredema), scleromyxedema, toxin, hypothyroidism, nephrogenic systemic fibrosis, eosinophilic fasciitis, amyloidosis, GVHD

Clinical Manifestations of Systemic Sclerosis (Lancet 2017;390:1685)
Skin	Tightening and thickening of extremities, face, trunk (bx not req for dx) “Puffy” hands, carpal tunnel syndrome, sclerodactyly Nailfold capillary dilatation & dropout Immobile, pinched, “mouse-like” facies and “purse-string” mouth Calcinosis cutis (subcutaneous calcification), telangiectasias
Arteries	Raynaud’s phenomenon (80%); digital or visceral ischemia
Renal	Scleroderma renal crisis (SRC) = abrupt onset of HTN (relative to Pt’s baseline), MAHA. Urine sediment typically bland. Renal bx not required but would show “onion-skin” hypertrophy of arteries & arterioles. Affects 5–10%. ACEI effective (see below) but 40% still progress to ESRD and 5y-mortality is 40% (QJM 2007;100:485). Risks: dcSSc, early disease (⅔ of cases in 1st yr), >15 mg/d prednisone, RNA Pol III Ab.
GI (>80% of Pts)	GERD and erosive esophagitis, esophageal dysmotility (dysphagia, odynophagia, aspiration), gastric dysmotility, small intestinal dysmotility (malabsorption, bact overgrowth, bloating)
Musculoskel	Arthralgias/arthritis; myositis; joint contractures; tendon friction rubs
Cardiac	Myocardial fibrosis; pericardial effusion; conduction abnormalities; CAD
Pulmonary	Pulmonary fibrosis (typically develops w/in 4 y); pulmonary arterial hypertension (typically develops after many yrs); #1 cause of mortality
Endocrine	Amenorrhea and infertility common; thyroid fibrosis ± hypothyroidism

SSc Subgroup Comparison
	Limited (lcSSc)	Diffuse (dcSSc)
General		Fatigue, weight loss
Skin	Thickening on extremities distal to elbows/knees and face only	Thickening of distal and proximal ext, face and trunk
Pulmonary	PAH (rapidly progressive) >fibrosis	Fibrosis >PAH
GI	Primary biliary cirrhosis
Renal	SRC later in disease course	SRC earlier & more common
Cardiac		Restrictive cardiomyopathy
Other	CREST syndrome = Calcinosis, Raynaud’s, Esophageal dysmotility, Sclerodactyly, Telangiectasias	Raynaud’s
Antibodies	Centromere (10–40%)	Scl 70, RNA-Pol III (40%)
Prognosis	Survival >70% at 10 y	Survival 40–60% at 10 y

Diagnostic studies & monitoring (Lancet 2017;390:1685)

• Autoantibodies: >95% Pts w/ auto-Ab; generally mutually exclusive

⊕ anti-Scl-70 (anti-topoisomerase 1): a/w diffuse SSc; ↑ risk pulm fibrosis

⊕ anticentromere: a/w limited SSc; ↑ risk of severe digit ischemia and PHT

⊕ anti-RNA-Pol III: a/w diffuse SSc; ↑ risk renal crisis; a/w cancer

⊕ ANA (>90%), ⊕ RF (30%), ⊕ anti-U1-RNP a/w overlap syndrome

Other: anti-Th/To (a/w limited SSc), U3-RNP (a/w ILD), PmScl (polymyositis-SSc overlap)

• CXCL4 levels reported to correlate w/ degree of fibrosis (NEJM 2014;370:433)

• At baseline: ✓ BUN/Cr & UA for proteinuria, PFTs (spirometry, lung volumes, D_LCO), high- res chest CT (if diffuse disease), TTE (RVSP for PHT), RHC if ↑ RVSP or suspect PHT

• Annual PFTs; TTE q1–2y

• Skin bx not routine, but helpful to assess other possible causes for skin thickening

• ↑ risk of malignancy (esp. lung cancer) compared to general population

• Frequent (eg, daily) BP ✓ to monitor for HTN suggestive of scleroderma renal crisis

Treatment (Ann Rheum Dis 2017;76:1327; Arthritis Rheumatol 2018;70:1820)

• Minimize steroid exposure to reduce risk of renal crisis

• Interstitial lung disease: tocilizumab (Lancet Respir Med 2020;8:963), MMF (↓ toxicity vs. cyclophosphamide; Lancet Respir Med 2020;8:304); nintedanib (multikinase inhibitor/antifibrotic) a/w ↓ FVC decline (NEJM 2019; 380:2518).

PAH: pulmonary vasodilators (see “Pulm Hypertension”); early Rx a/w better outcomes

• Renal crisis: ACEI (not ARB) for Rx, not prophylaxis (Semin Arthritis Rheum 2015;44:687)

• GI: PPI/H2-blockers for GERD; promotility agents & antibx for bacterial overgrowth

• Cardiac: NSAIDs ± colchicine superior to steroids for pericarditis

• Arthritis: acetaminophen, NSAIDs, hydroxychloroquine, MTX

• Myositis: MTX, AZA, steroids

• Skin: PUVA for morphea. Pruritus: emollients, topical/oral steroids. Fibrosis: MTX; MMF? (Ann Rheum Dis 2017;76:1207; Int J Rheum Dis 2017;20:481). CYC if severe (NEJM 2006;354:2655).

• Auto-HSCT promising for severe disease (NEJM 2018;378:35)

RAYNAUD’S PHENOMENON

Clinical manifestations & diagnosis (NEJM 2016;375:556; Nat Rev Rheum 2020;16:208)

• Episodic, reversible digital ischemia, triggered by cold temp, or stress, classically: blanching (white, ischemia) → cyanosis (blue, hypoxia) → rubor (red, reperfusion); color Δ usually well demarcated; affects fingers, toes, ears, nose

Primary vs. Secondary Raynaud’s Phenomenon
	Primary (80–90%)	Secondary (10–20%)
Vessel wall	Functionally abnl	Structurally abnl
Etiologies	Idiopathic; however, can be exacerbated by comorbid conditions, including HTN, athero, CAD, DM	SSc, SLE, PM-DM, MCTD, Sjögren’s, RA Arterial disease (athero, Buerger’s), trauma Heme (cyro, Waldenström’s, APS) Drugs (ergopeptides, estrogens, cocaine)
Epidem.	20–40 y; ♀ > ♂ (5:1)	>35 y
Clinical	Mild, symm. episodic attacks. No tissue injury, PVD, or systemic sx; spares thumb.	Severe, asymm. attacks; tissue ischemia & injury (eg, digital ulcers); can be assoc w/ systemic sx; may affect thumb or prox limbs
Auto Ab	⊖ CTD antibodies	Depends on etiology, CTD Ab often ⊕
Nailfold	Normal capillaroscopy	Dropout and enlarged or distorted loops

Treatment (Curr Opin Rheumatol 2021;33:453; Clin Rheumatol 2019;38:3317)

• All: avoid cold, maintain warmth of digits & body; avoid cigarettes, sympathomimetics, caffeine, & trauma; abx for infected ulceration

• Mild–mod: long-acting CCB, topical nitrates, SSRI, ARB, α-blockers, ASA/clopidogrel

• Severe: PDE inhibitors, anti-ET-1 receptor (if ulcers esp. w/ PHT), digital sympathectomy

• Digit-threatening: IV prostaglandins, digital sympathectomy, ± anticoagulation

INFLAMMATORY MYOPATHIES

Definition & epidemiology (NEJM 2015;372:1734; Lancet Neurol 2018;17:816)

• All lead to skeletal muscle inflammation & weakness, variable extramuscular involvement

• Polymyositis (PM): incidence <1/million/y; onset typically 40s–50s; ♀ >♂

• Dermatomyositis (DM): similar to PM but w/ skin manifestations; incidence ~1/million/y; also occurs in childhood; malignancy a/w PM (10%) and DM (24%)

• Necrotizing autoimmune myositis (NM): usually adults; risk factors: statin exposure (⊕ anti-HMGCR; NEJM 2016;374:664), CTD, cancer, rarely viral infection; incidence unclear

• Inclusion body myositis (IBM): age >50; ♂ >♀; incidence ~5/million/y; often misdiagnosed as PM

• Ddx: drug-induced toxic myopathy (statins, cocaine, steroids, colchicine); infxn (HIV, EBV, CMV); metabolic (hypothyroid, hypo-K, hypo-Ca); neuromuscular dis. (eg, myasthenia gravis); glycogen storage disease; mitochondrial cytopathy; muscular dystrophy

Clinical manifestations

• Muscle weakness: typically gradual onset (wks to mos) but often accelerated in NM (days to wks) and more insidious (yrs) in IBM; progressive and painless

DM/PM/NM: proximal and symmetric; difficulty climbing stairs, arising from chairs, brushing hair; fine motor skills (eg, buttoning) lost late

IBM: weakness may be asymmetric, distal, and involve facial muscles

• Skin findings in dermatomyositis: may precede myositis by mos to yrs

Gottron’s papules: seen in >80% of Pts & pathognomonic; violaceous, often scaly, areas symmetrically over dorsum of PIP and MCP joints, elbows, patellae, medial malleoli

Heliotrope rash: purplish discoloration over upper eyelids ± periorbital edema

Poikiloderma: red or purple rash w/ areas of hyper and hypopigmentation mostly on sun- exposed areas; upper back (shawl sign), neck & chest (V sign), and hips (Holster sign)

Mechanic’s hands: cracking, fissuring radial side of digits and can include pigmentation along palmar crease; a/w antisynthetase syndrome; also seen in PM

• Pulmonary: acute alveolitis, interstitial lung disease; resp muscle weakness; aspiration

Antisynthetase syndrome: acute onset DM or PM w/ rapidly progressive ILD, fever, weight loss, Raynaud’s, mechanic’s hands, arthritis; most commonly anti-Jo-1 ⊕

MDA5-assoc. DM: ↑ amyopathic, ↑ rapidly progressive ILD, palmar papules, skin ulcers

• Cardiac: (33%): often asx; conduction abnl; myo/pericarditis; HF uncommon; ↑ CK-MB/Tn

• GI: dysphagia, aspiration

• Polyarthralgias or polyarthritis: usually early, nonerosive; small joints >large joints

• Raynaud’s (30%, DM and overlap CTD) w/ dilatation & dropout of nail bed capillaries

Diagnostic studies (Ann Rheum Dis 2017;76:1955)

• ↑ CK (rarely >100,000 U/L, can be ↑↑↑ in NM), aldolase, SGOT, LDH; ± ↑ ESR & CRP

• Autoantibodies: ⊕ ANA (>75%)

⊕ anti-Jo-1 (25%): most common specific Ab; a/w antisynthetase syndrome

⊕ anti-Mi-2 (DM >PM 15–20%) is a/w disease that responds well to steroids

⊕ anti-SRP is a/w NM, poor Rx response; ⊕ anti-HMGCR in NM a/w statin exposure

Multiple others (Best Pract Res Clin Rheumatol 2018;32:887). Often ordered as an Ab panel.

• Consider EMG (↑ spontaneous activity, ↓ amplitude, polyphasic potentials w/ contraction) or MRI (muscle edema, inflammation, atrophy) for evaluation; may guide biopsy

• Pathology and muscle biopsy: all with interstitial mononuclear infiltrates, muscle fiber necrosis, degeneration, & regeneration (required for definitive diagnosis)

PM: CD8 T cell-mediated muscle injury; perivascular and endomysial inflammation surrounds MHC class I-expressing non-necrotic fibers

DM: immune complex deposition in blood vessels with complement activation; perifascicular atrophy w/ interfascicular and perivascular inflam (B & CD4 T cells)

NM: necrotic fibers w/ macrophages

IBM: T cell-mediated injury, vacuole formation; same as PM w/ eosinophilic inclusions and rimmed vacuoles and chronic myopathic changes (variable fiber size)

Treatment (Nat Rev Rheum 2018;14:279)

• Immunosuppression not effective for IBM. For all others:

• Steroids (prednisone 1 mg/kg); MTX or AZA early if mod/severe or taper fails (2–3 mo)

• For resistant (30–40%) or severe disease: AZA/MTX combo, IVIg (NM, DM ± PM), rituximab, MMF, cyclophosphamide (esp. if ILD or vasculitis)

• IVIg w/ pulse steroids acutely for life-threatening esophageal or resp muscle involvement

• ✓ for occult malignancy (esp. if DM); monitor respiratory muscle strength with spirometry

• NM: stop statin; steroids + MTX, RTX, or IVIg

SJÖGREN’S SYNDROME (NEJM 2018;378:931)

Definition & epidemiology

• Chronic dysfxn of exocrine glands (eg, salivary/lacrimal) due to lymphoplasmacytic infiltration, extraglandular manifestations common in primary form

• Can be primary or secondary (a/w RA, scleroderma, SLE, PM, hypothyroidism, HIV)

• ~1/1000 prevelance with 9:1 ♀:♂ ratio; typically presents between age 40 & 60

Clinical manifestations

• Dry eyes (keratoconjunctivitis sicca): ↓ tear production; burning, scratchy sensation

• Dry mouth (xerostomia): difficulty speaking/swallowing, dental caries, xerotrachea, thrush

• Parotid gland enlargement: intermittent, painless, typically bilateral

• Vaginal dryness and dyspareunia

• Recurrent nonallergic rhinitis/sinusitis due to upper airway gland involvement

• Extraglandular manifestations: arthritis, interstitial nephritis (40%), type I RTA (20%), cutaneous vasculitis (25%), PNS >CNS neurological disease (20%), ILD, PBC

• ↑ risk of lymphoproliferative disorders (~50× ↑ risk of lymphoma and WM in 1° Sjögren’s)

• Neonatal lupus, including fetal skin rash or heart block (a/w SSA and/or SSB antibodies)

Diagnostic studies

• Autoantibodies: ⊕ ANA (95%), ⊕ RF (75%)

Primary Sjögren’s: ⊕ anti-Ro (anti-SSA, ~50%) ± anti-La (anti-SSB, ~30%)

• Schirmer test: filter paper in palpebral fissures to assess tear production

• Rose-Bengal staining: dye that reveals devitalized epithelium of cornea/conjunctiva

• Ocular staining score: substitute for Rose-Bengal staining to determine degree of keratoconjunctivitis sicca using fluorescein and lissamine green

• Biopsy (minor salivary, labial, lacrimal, or parotid gland): lymphocytic infiltration

Classification criteria (≥4 points 96% Se & 95% Sp; Arthritis Rheumatol 2017;69:35)

• 3 points: ⊕ anti-Ro; labial saliv. gland bx w/ lymphocytic sialadenitis & score ≥1 foci/4 mm²

• 1 point: abnormal ocular staining score ≥5; Schirmer’s test ≤5 mm/5 min; unstimulated salivary flow rate of ≤0.1 mL/min

Treatment (Ann Rheum Dis 2020;79:3)

• Ocular: artificial tears, cyclosporine eyedrops, autologous tears

• Oral: sugar-free gum, lemon drops, saliva substitute, hydration, pilocarpine, cevimeline

• Systemic: depends on extraglandular manifest.; NSAIDs, steroids, DMARDs, rituximab

MIXED CONNECTIVE TISSUE DISEASE (MCTD)

Definition (Best Pract Res Clin Rheumatol 2016;30:95)

• Features of SLE, systemic sclerosis, and/or polymyositis that appear gradually over years and often evolve to a dominant phenotype of SLE or systemic sclerosis

• Different from undifferentiated CTD (UCTD): nonspecific symptoms that fail to meet criteria for any CTD; 30% go on to develop CTD over 3–5 y (usually SLE)

Clinical & laboratory manifestations (Rheumatology 2018;57:255)

• Raynaud’s phenomenon (qv) typical presenting symptom (75–90%)

• Hand edema (“puffy hands”), sclerodactyly, RA-like arthritis w/o erosions, polyarthralgias

• Pulmonary involvement (85%) with pulmonary hypertension, fibrosis

• Pericarditis most frequent cardiovascular manifestation; GI: dysmotility (70%)

• Membranous & mesangial GN common (25%); low risk for renal HTN crisis or severe GN

• ⊕ ANA (>95%); ⊕ RF (50%); requires ⊕ anti-U1-RNP but not specific (seen in ~50% SLE)

Treatment: as per specific rheumatic diseases detailed above

SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

Definition and epidemiology (Nat Rev Rheumatol 2021;17:515)

• Multisystem inflammatory autoimmune disease with a broad spectrum of clinical manifestations in association with antinuclear antibody (ANA) production

• Prevalence 5–35/10,000 in U.S.; predominantly affects women 2^nd to 4^th decade

• ♀:♂ ratio = 8:1; African Americans affected 2–4× as often as Caucasians

• Complex genetics; some HLA association; rarely C1q & C2 deficiency

Classification Criteria (Ann Rheum Dis 2019;78:1151) for research/classification not dx
Required criteria: ANA titer ≥1:80 AND ≥10 points (at least one clinical):
Clinical domains (points*)
Renal • proteinuria >0.5 g/d (4) • class II or V nephritis (8) • class III or IV nephritis (10)	Hematologic • leukopenia (3) • thrombocytopenia (4) • autoimm. hemolytic anemia (4)	Neuropsychiatric • delirium (2) • psychosis (3) • seizure (5)
Mucutaneous • non-sclarring alopecia (2) • oral ulcers (2) • discoid lupus (4); subacute (4) or acute (6) cutaneous lupus	Serosal • pleural/pericardial effusion (5) • acute pericarditis (6)	Musculoskeletal • joint involvement (6)
		Constitutional • fever (2)
Immunology domains (points*)
Antiphospholipid antibodies • anti-CL, anti-B2GP1, or a lupus anticoagulant (2)	Complement proteins • low C3 or C4 (3) • low C3 and C4 (4)	SLE-specific Abs • anti-dsDNA or anti- Smith (6)

^*Within each domain, only the highest weighted criterion is counted toward the total score.

Autoantibodies in SLE (Nat Rev Rheumatol 2020;16:565)
Auto-Ab	Frequency (approx)	Clinical Associations	Timeline
ANA	95–99% if active disease 90% if in remission Homogeneous or speckled	Any or all of broad spectrum of clinical manifestations Sensitive but not specific	May appear yrs before overt disease
Ro La	15–35% ⊕ anti-Ro may be seen w/ ⊖ or low titer ANA	Sjögren’s/SLE overlap Neonatal lupus; photosens.; subacute cutaneous lupus
ds-DNA	70%; ~95% Sp; titers may parallel dis. activity, esp. renal	Lupus nephritis Vasculitis	Appears mos before or at dx, but may become ⊕ after dx
Sm	30%; very specific for SLE	Lupus nephritis
U1-RNP	40%	MCTD; Raynaud’s; Tend not to have nephritis
Histone	90% in DLE; 60–80% in SLE	Mild arthritis and serositis	At diagnosis

Workup

• Autoantibodies: ANA, if ⊕ → ✓ anti-ds-DNA, anti-Sm, anti-Ro, anti-La, anti-U1-RNP

• CBC, APLA (⊕ in 20–40%; ACL, B2GP1, lupus anticoagulant), total complement, C3 & C4

• Lytes, BUN, Cr, U/A, urine sed, spot microalb:Cr ratio or 24-h urine for CrCl and protein

• If ↓ GFR, active sediment, hematuria, or proteinuria (>0.5 g/dL) → renal bx to guide Rx

Treatment (Ann Rheum Dis. 2019;78:736; Lancet 2019;393:2332; Nat Rev Rheumatol 2019;15:30)
Drug	Indication	Adverse Effects
Hydroxychloroquine (HCQ)	All Pts b/c ↓ flares (NEJM 1991;324:150); monoRx for arthritis, serositis, skin disease	Retinal tox (<1%), Stevens- Johnson; myopathy. Not immunosuppressive.
NSAIDs	Arthritis, myalgias, serositis	Gastritis, UGIB, renal failure
Corticosteroids	Low dose for arthritis, serositis; high-dose (1 mg/kg) ± pulse (1 g × 3 d) for major dis. (eg, renal, CNS, heme). Minimize as able.	Adrenal suppression, diabetes, cataracts, osteopenia, avascular necrosis of bone, myopathy
Mycophenolate (MMF)	Nephritis (induction/maint); nonrenal refractory to HCQ	Cytopenias, ↑ LFTs, diarrhea, teratogen
Cyclophosphamide (CYC)	Severe organ-threatening nephritis or CNS disease (induction, minimize exposure)	Cytopenias, infertility/teratogen, myeloprolif. dis., hemorrhagic cystitis, bladder cancer
Azathioprine (AZA)	Nephritis (maintenance) Non-renal dis. refractory to HCQ	Myelosuppr. (✓TPMT), ↑ LFTs, teratogen, lymphoprolif. dis.
Methotrexate (MTX)	Arthritis (preferred over MMF/AZA) Skin disease & serositis	Myelosuppression, alopecia, hepatotoxicity, stomatitis, pneumonitis, teratogen
Cyclosporine (CsA)	Renal disease	Hyperplastic gums, HTN, hirsutism, CKD, anemia
Voclosporin (calcineurin inhibitor Lancet 2021;397:2070)	Nephritis (induction). Added to MMF+steroids; ↑ complete renal response w/ ↓ steroid.	HTN, ↓ GFR, diarrhea. (Stable PK, ∴ does not require levels like other calcineurin inhibitors)
Belimumab (NEJM 2013;368:1528 & 2020;383:1117)	Arthritis, serositis, skin disease (esp. if ⊕ ds-DNA or ↓ C3/C4). Nephritis (induction). ↑ renal response when added.	B-cell depletion by binding BLyS (less immunosuppressive than RTX)
Rituximab (RTX)	ITP, AIHA, refractory SLE	Infusion reaction / serum sickness, PML, infection
Baricitinib (Lancet 2018;392:222)	Prelim data: 4 mg w/ efficacy in arthritis, skin disease	Infections (zoster), ↑ LFTs, cytopenias, dyslipidemia
Anifrolumab (anti- IFN receptor)	Moderate to severe disease (NEJM 2020;382:211)	Infection (PNA, zoster), hypersensitivity reaction

Lupus Nephritis – 40% affected (Nat Rev Rheumatol 2020;16:255)
Class	Presentation	Treatment (all benefit from HCQ)
I: Min. mesangial	Normal U/A & eGFR	No specific treatment
II: Mesangial prolif	Micro hematuria/proteinuria	No specific treatment ± ACEI
III: Focal prolif	Hematuria/proteinuria, ± HTN, ↓ GFR, ± nephrotic	Induce: MMF or CYC + steroids Maintenance: MMF >AZA (NEJM 2004;350:971 & 2005;353:2219 & 2011;365:1886)
IV: Diffuse prolif	Hematuria/proteinuria and HTN, ↓ GFR, ± nephrotic
V: Membranous (can coexist with class III or IV)	Proteinuria, nephrotic	ACEI If nephrotic-range proteinuria, induce w/ MMF + steroids Maintenance: MMF superior to AZA
VI: Adv. Sclerotic	ESRD	Renal replacement therapy

Prognosis (Nat Rev Rheumatol 2021;17:515)

• Overall mortality 2–3× higher than general population, higher in Blacks.

• Leading causes of morbidity/mortality: infection, CV events, renal failure (nephritis remission achieved in <50%; >10% end up w/ ESRD), neurologic events, thrombosis

Drug-induced lupus (DLE) (Drug Saf 2017;16:1255; Autoimmun Rev 2018;17:912)

• Many drugs: procainamide, hydralazine, penicillamine, minocycline, INH, methyldopa, quinidine, chlorpromazine, diltiazem, anti-TNF (esp. infliximab), interferons

• Abrupt onset; generally mild disease with arthritis, serositis, skin disease; renal dx, malar and discoid rash rare; prevalence ♀:♂ = 1:1

• ⊕ Anti-histone (95%) (may be ⊖ in anti-TNF); ⊖ anti-ds-DNA (often ⊕ in anti-TNF cases, even w/o manifestations of DLE) & ⊖ anti-Sm; normal complement levels

• Usually reversible w/in 4–6 wk after stopping medication

IGG4-RELATED DISEASE

Definition & etiology (NEJM 2012;366:539; Nat Rev Rheumatol 2020;16:702)

• Characterized by tumor-like inflammatory lesions that can affect nearly any organ

• Etiology: ? autoimmune; unclear role of IgG4; may have h/o atopy

• ♂ >♀, mean age ~ 60. Incidence ~1/100,000 per y in Japan, but elsewhere unknown.

Clinical manifestations (Arthritis Rheumatol 2015;67:2466 & 2020;72:7)

• Commonly pancreatitis, aortitis, cholangitis, sialadenitis, thyroiditis, dacroadenitis, orbital myositis ± pseudotumor, retroperitoneal fibrosis, renal and lung involvement

• Insidious progression; multiple lesions may be present synchronously or metachronously

Diagnosis and management (Lancet Rheumatol 2019;1:e55)

• Biopsy w/ specific findings: lymphoplasmacytic infiltrate w/ significant IgG4+ plasma cell infiltrate, storiform fibrosis, obliterative phlebitis

• ↑ serum IgG4 (Se 90%, Sp 60%); may have low C3, C4

• Highly responsive to steroids but relapse common. Efficacy of DMARDs in maintenance remains unclear but B-cell depleting agents appear promising (Eur J Intern Med 2020;74:92).

VASCULITIS

OVERVIEW

• Inflammation w/in blood vessel walls causing end-organ damage often a/w systemic sx; may be primary or secondary (eg, infection, malignancy) in etiology

• Classified by size of predominant vessel affected (Arthritis Rheum 2013;65:1); overlap of vessel size affected is common

• Clinical manifestations based on size of vessels involved; constitutional sx (low-grade fever, fatigue, weight loss, myalgias, anorexia) common to all

TAK, Takayasu’s arteritis; GCA, giant cell arteritis; PAN, polyarteritis nodosa; ANCA-assoc. is GPA, EGPA, & MPA; IC, immune complex small-vessel vasculitis (eg, IgA, cryoglobulinemia); GN, glomerulonephritis.

LARGE-VESSEL VASCULITIS

Takayasu’s arteritis (“pulseless disease”)

• Arteritis of aorta and its branches → stenosis/aneurysm → claudication. Most often subclavian & innominate arteries (>90%); carotid, coronary, renal, or pulm a. (~50%)

• Epidemiology: most common in Asia; ♀:♂ ~9:1 in Japan but lower elsewhere; age <50 y. Prev 8/million in U.S. w/ ~4:1 ♀:♂ (J Rheumatol 2021;48:952).

• Clinical manifestations: systemic inflamm with fever, arthralgias, wt loss

Vessel inflamm w/ pain & tenderness, ↓ & unequal pulses/BPs in extremities, bruits, limb claudication, renovascular HTN (>50%), neurogenic syncope, Ao aneurysm ± AI

“Burnt out” or fibrotic period (eg, vascular stenosis)

• Dx studies: ↑ ESR (75%), CRP; arteriography (MRA, CTA) → occlusion, stenosis, irregularity, and aneurysms; carotid U/S Doppler studies; PET-CT; pathology → focal panarteritis, cellular infiltrate with granulomas and giant cells (bx not required for dx)

• Rx: steroids ± MTX, AZA, or anti-TNF; tocilizumab 2^nd line (Ann Rheum Dis. 2020;79:19); ASA if critical cerebral stenosis; if surgical/endovascular revasc, preferably done in remission

• Monitoring: MRA, CTA, or PET-CT; ESR/CRP

Giant cell arteritis (GCA) (JAMA 2016;315:2442)

• Granulomatous arteritis typically involving aorta/branches; predilection for extracranial branches of carotid a., particularly temporal a. (thus also called temporal arteritis).

• Epidemiology: 90% >60 y, peak incidence at 70–80 y, extremely rare <50 y; ♀:♂ = 3:1. Prev 2/1000 of those age ≥50 (Semin Arthritis Rheum 2017;47:253).

• Clinical manifestations (NEJM 2014;371:50): constitutional sx: fevers, fatigue, wt loss

Temporal artery (TA) → headache, tender TAs and scalp, absent TA pulse

Ophthalmic artery (20%) → optic neuropathy, diplopia, amaurosis fugax, blindness

Facial arteries → jaw claudication

Large vessel vasculitis → intermittent claudication of extremities; thoracic aorta aneurysm

Strong association w/ PMR; ~50% of Pts w/ GCA ultimately received PMR diagnosis

• Dx: ↑ ESR (Se 84%, Sp 30%), ↑ CRP (Se 86%, Sp 30%), anemia.

Temporal artery bx (shows vasculitis & granulomas) whenever GCA suspected (Se ≤85%); consider bilat to ↑ yield (3–7% discordant). If bx ⊖ or suspect aortitis/large vessel involvement: U/S (halo sign) or MRA of temporal/cranial arteries, or CTA, MRA, or PET of aorta/large arteries (Arthritis Rheumatol 2021;73:1349). Some advocate imaging upfront to r/o, but requires imaging expertise (Ann Rheum Dis 2018;77:636 & 2020;79:19).

• Rx: steroids: do not await bx/path! Have >2 wks to bx w/o Δ. Pred 40–60 mg/d w/ slow taper; ASA if critical cerebral narrowing; consider IV steroids if vision threatened (Arthritis Rheumatol 2021;73:1349). Adding tocilizumab ↑ sustained remission (NEJM 2017;377:317).

• Polymyalgia rheumatica (JAMA 2016;315:2442; Lancet 2017;390:1700)

Prev 7/1000 of age ≥50. In 50% of GCA Pts; 15% of PMR Pts develop GCA. ♀:♂ ≈ 2.

ESR >40 mm/h (and/or ↑ CRP); bilateral pain & morning stiffness (>30 min), involving 2 of 3 areas: neck or torso, shoulders or prox. arms, hips or prox. thighs; nighttime pain; ± subdeltoid bursitis on U/S; exclude other causes of sx (eg, RA); nl CK

Rx: pred 12.5–25 mg/d; if clinical response, initiate slow taper. If not, consider alternate dx or ↑ dose. Consider MTX if at ↑ risk of steroid side effects (Ann Rheum Dis 2015;74:1799).

• Follow clinical status & ESR/CRP; ~⅓relapse over 2 y (J Rheum 2015;42:1213)

MEDIUM-VESSEL VASCULITIS

Polyarteritis nodosa (“classic” PAN) (Nat Rev Rheumatol 2017;13:381)

• Necrotizing nongranulomatous vasculitis of medium & small arteries (w/in muscular media) w/o glomerulonephritis or capillary involvement (ie, no DAH), not a/w ANCA

• Incidence ~2/million/y; ↑ in HBV-endemic areas; ♂ >♀; av. age ~50; 10% HBV-assoc

• Clinical manifestations (Arth Rheum 2010;62:616): const. sx (80%): wt loss, fever, fatigue

Neuro (79%): mononeuritis multiplex, peripheral neuropathies, stroke

Musculoskeletal (64%): extremity pain, myalgias, arthralgias, arthritis

Renal (51%): HTN, hematuria, proteinuria, renal failure; glomerulonephritis unusual

GI (38%): abd pain, GIB/infarction, cholecystitis; GU (25%): ovarian or testicular pain

Skin (50%): livedo reticularis, purpura, nodules, ulcers, Raynaud’s

Ophthalmic (9%): retinal vasculitis, retinal exudates, conjunctivitis, uveitis

Cardiac (22%): coronary arteritis, cardiomyopathy, pericarditis

Pulmonary: rare; if lung involvement, suspect other vasculitis

• Dx (Arthritis Care Res 2021;73:1061): ↑ ESR/CRP; r/o ANCA, HBV; ↓ C3/C4 if HBV-assoc.

Angiogram (mesenteric or renal vessels) → microaneurysms & focal vessel narrowing

CTA or MRA may be adequate for dx, but conventional angiogram is most sensitive

Biopsy (nerve, deep-skin, or affected organ) → vasculitis of small and medium a. w/ fibrinoid necrosis w/o granulomas

• Rx: based on severity; steroids ± DMARD (MTX, AZA; CYC if severe); antivirals if HBV. Most dis. monophasic so consider stopping DMARD if in steroid-free remission at 18 m.

ANCA-ASSOCIATED SMALL-VESSEL VASCULITIS

Microvascular vasculitis (eg, capillaries, postcapillary venules, & arterioles)

^aPredominant type, can see either type (NEJM 2012;367:214). ^bGPA is formerly Wegener’s granulomatosis, EGPA is formerly Churg-Strauss. Microscopic polyangiitis (MPA).

Differential diagnosis of ANCA (Nat Rev Dis Primers 2020;6:71)

• anti-PR3: GPA, EGPA, microscopic polyangiitis (rarely), levamisole (contam. in cocaine)

• anti-MPO: microscopic polyangiitis, EGPA, GPA, drug-induced vasculitis, nonvasculitic rheumatic dis., levamisole (contaminant in cocaine)

• Atypical ANCA patterns: drug-induced vasculitis, nonvasculitic rheumatic diseases, ulcerative colitis, primary sclerosing cholangitis, endocarditis, cystic fibrosis

Granulomatosis with polyangiitis (GPA, formerly Wegener’s granulomatosis)

• Necrotizing granulomatous systemic vasculitis frequently affecting upper respiratory tract (nose, sinuses) in addition to kidneys, lower resp tract (lungs), and other organs

• Epi: incidence 12/million/y; any age but ↑ in young/middle-aged adults; ♂=♀

• Clinical manifestations

Constitutional: fever, fatigue, malaise, anorexia, weight loss

Respiratory (90%): Upper: recurrent sinusitis, rhinitis, oral/nasal ulcers, nasal crusting, saddle-nose deformity, otitis, hearing loss, subglottic stenosis Lower: infiltrates, nodules, & hemorrhage → cough, dyspnea, hemoptysis, pleurisy

Renal (80%): RPGN, microscopic hematuria (dysmorphic RBCs and casts)

Skin (50%): palpable purpura, livedo reticularis

Ocular (50%): episcleritis, scleritis, uveitis, orbital granulomas → proptosis, corneal ulcer

Neuro: cranial + peripheral neuropathies, mononeuritis multiplex.

Heme: ↑ incidence DVT/PE (20×) when disease active (Ann Intern Med 2005;142:620)

• Dx studies: 90% ⊕ ANCA (80% PR3, 20% MPO), less Se in limited upper-airway disease

CXR or CT → nodules, infiltrates, cavities; sinus CT → sinusitis ± bone erosions

↑ BUN & Cr, proteinuria, hematuria; sediment w/ RBC casts, dysmorphic RBCs

Biopsy → necrotizing granulomatous inflammation of arterioles, capillaries, veins. Renal bx w/ pauci-immune (minimal immune deposition) necrotizing and crescentic GN.

• Treatment: assess severity w/ BVAS/GPA score (Arth Rheum Dis 2009;68:1827)

Mild disease (no end-organ dysfxn; BVAS 0–3): MTX + steroids (Arth Rheum 2012;64:3472)

Severe disease (end-organ damage incl. pulm hemorrhage, RPGN etc.; BVAS >3):

Induction: [RTX 375 mg/m²/wk × 4 wk or 1000 mg on d1 + d15 or CYC 2 mg/kg/d × 3–6 mo or pulse 15 mg/kg q2–3 wk] + steroids 1 g IV × 3 d → ~1 mg/kg/d (Ann Rheum Dis 2015;74:1178). RTX preferred as ↓ toxicity (Arth Rheum 2021;73:1366).

Plasma exchange (PLEX) may ↓ risk of ESRD in those most at risk (NEJM 2020;382:622; Arth Rheum 2021;73:1366).

Adding avacopan (oral C5a receptor inhibitor) increases remission rate and allows ↓ steroids (NEJM 2021;384:599)

Maintenance: RTX q6mo superior to AZA or observ. (Ann Intern Med 2020;173:179)

Relapse: mild → steroids ± MTX or AZA; severe → reinduce w/ steroids + RTX or CYC

↑ ANCA w/o clinical evidence of flare should not prompt Δ Rx (Annals 2007;147:611)

Microscopic polyangiitis (MPA) (Rheum Dis Clin North Am 2010;36:545)

• Similar to GPA, but w/o ENT/upper airway involvement & nongranulomatous

• Epidemiology: incidence 4/million/y. ♂ = ♀; avg onset 50–60 y

• Clinical manifestations

Constitutional, neuro sx similar to GPA

Renal (80–100%): glomerulonephritis

Skin lesions (eg, palpable purpura) in 30–60%

Pulmonary (25–50%): pulmonary capillary alveolitis, pulmonary fibrosis

• Dx studies: 70% ⊕ ANCA (almost all anti-MPO)

Biopsy → necrotizing, nongranulomatous inflammation of small vessels, pauci-immune

Urine sediment and CXR findings similar to those seen in GPA

• Treatment: as for GPA (Arth Rheum 2021;73:1366); ↓ relapse rate compared to GPA

Eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss)

• Similar to GPA w/ more frequent cardiac involvement, a/w asthma and eosinophilia

• Epi: rare (incidence 2/million/y); any age (typically 30–40 y); ♂ = ♀; a/w HLA-DRB4

• Clinical manifestations (Rheumatol 2020;59:iii84)

Initial sx: asthma, sinusitis, allergic rhinitis (new asthma in adult raises suspicion)

Eosinophilic infiltrative disease: transient pulm infiltrates, gastroenteritis, or esophagitis

Systemic small-vessel vasculitis: neuropathy (mononeuritis multiplex), renal (glomerulonephritis), skin (palpable purpura, petechial, nodules)

Cardiac: coronary arteritis, myocarditis, CHF, valvular insufficiency (Medicine 2009;88:236)

• Dx studies: 50% ⊕ ANCA (MPO >PR3), eosinophilia (>1500/uL or 10%, often >60%),

biopsy → microgranulomas, fibrinoid necrosis, small artery/vein thromboses w/ eosinophilic infiltrate

• Treatment: high-dose steroids + mepolizumab (anti-IL-5) (if nonsevere) or RTX or CYC (if severe) (Arth Rheum 2021;73:1366); mepolizumab for relapse/refractory (NEJM 2017;376:1921)

Renal-limited vasculitis

• Small vessel pauci-immune vasculitis causing RPGN w/o other organ involvement

• Dx studies: 80% ⊕ ANCA (MPO >PR3); biopsy with pauci-immune GN ± granulomas

• Treatment identical to that for GPA/MPA

IMMUNE COMPLEX (IC)–ASSOCIATED SMALL-VESSEL VASCULITIS

IgA vasculitis (formerly Henoch-Schönlein purpura [HSP]) (Rheumatol 2019;58:1607)

• IgA-mediated small-vessel vasculitis w/ predilection for skin, GI tract, and kidneys

• Epidemiology: incidence 140/million/y; ♂ >♀, children >adults, winter >summer

• May develop ~10 d after onset of upper resp infx or after drug exposure

• Clinical manifestations

Palpable purpura on extensor surfaces (lower extremity first) & buttocks

Polyarthralgias (nondeforming) esp. involving hips, knees, & ankles

Colicky abdominal pain ± GIB or intussusception

Nephritis ranging from microscopic hematuria & proteinuria to ESRD

• Dx studies: skin bx w/ immunofluorescence → leukocytoclastic vasculitis w/ IgA

and C3 deposition in vessel wall; renal bx → mesangial IgA deposition

• Treatment: often self-limiting over 4 wk; steroids ± DMARDs for renal or severe disease

Cryoglobulinemic vasculitis (Lancet 2012;379:348; Nat Rev Dis Primers 2018;4:11)

• Cryoglobulins: proteins that precipitate from serum or plasma on exposure to cold and redissolve on rewarming, characterized by their composition; a/w chronic immune stimulation and/or lymphoproliferation

• Distinguish from cryofibrinogenemia = proteins (eg, fibrin, fibrinogen) that precipitate only from plasma; found in autoimmune dis, malignancies, infxns; unclear clinical significance

Types of Cryoglobulinemia (J Autoimmun 2019;105:102313)
Feature	Type I (monoclonal)	Type II (mixed)	Type III (mixed)
Frequency	10–15%	50–60%	25–30%
Cryoglobulin composition	Monoclonal Ig (usually IgM or IgG)	Monoclonal IgM w/ RF activity + polyclonal IgG	Polyclonal IgG and IgM
Common etiologies	Plasma cell dyscrasias	Infection, malignancy, autoimmune syndromes	Autoimmune synd., infxn
Primary manifestations	Hyperviscosity ± thrombosis → ischemia	IC-mediated vasculitis, w/ multiorgan involvement. Can be asx.

• Epidemiology: ~1/100,000, but prevalence varies with HCV rates; ♀ >♂

• Etiologies (idiopathic in ~10%)

Hematologic diseases: multiple myeloma, MGUS, Waldenström’s, chronic lymphocytic leukemia in type I; B-cell lymphomas or solid-organ malignancies in type II

Infxns (types II & III): viral (HCV [>80% RNA ⊕], HBV, HIV, HAV, EBV, CMV), bacterial (endocarditis, strep, etc.), fungal (coccidiomycosis, etc.), parasitic (malaria, amoebiasis)

Autoimmune syndromes (type III >II): Sjögren’s syndrome, SLE, RA, PAN

Renal transplant recipients (Clin Nephrol 2008;69:239)

• Pathophysiology

Type I: cryo precipitation in microcirculation → hyperviscosity & vascular occlusion

Types II/III: defective/insufficient immune complex (IC) clearance → IC-mediated inflammation of blood vessels w/ complement activation → vasculitis

• Clinical manifestations (most Pts w/o sx)

Type I: hyperviscosity (cold worsens sx) → HA, visual Δ, livedo, digital ischemia

Type II/III: vasculitis (not affected by cold) → fever, derm (54–80%; purpura, livedo reticularis, ulcers), arthralgia (44–70%; symmetric migratory, small/med joints), glomerulonephritis (50%; MPGN), neurologic (17–60%; peripheral neuropathy (polyneuropathy >mononeuritis multiplex), ↓ Hgb, ↓ plt, ↑ B-cell lymphoma risk, GI (5%; pain, HSM, ↑ LFTs). “Meltzer’s triad”: purpura, arthralgias, weakness in 25–30%.

• Dx studies

✓ Cryoglobulins (keep blood warmed to 37°C en route to lab to avoid false ⊖, loss of RF and ↓↓ C3, C4). Cryocrit quantifies cryoprotein but not always indicative of disease activity. May see false ↑ in WBC or plt on automated CBC due to precipitation.

Type I: ✓ serum viscosity, symptomatic if ≥4.0 centipoise; complement normal.

Type II: ↓ C4, variable C3, ↑ ESR, ⊕ RF. ✓ HCV, HBV, HIV in mixed cryoglobulinemia. Bx: hyaline thrombi; small vessel leukocytoclastic vasculitis w/ mononuclear infiltrate.

• Treatment (Blood 2017;129:289; J Inflamm Res 2017;10:49): Rx underlying disorder. Heme malig → chemoradiation; HCV → antivirals; CTD → DMARD/steroids ± RTX. Type I: plasma exchange if hyperviscosity; steroids, alkylating agents, RTX, chemo. For mixed cryo, steroids and RTX; CYC or plasma exchange for major organ involvement.

Connective tissue disease–associated vasculitis

• Small-vessel vasculitis a/w RA, SLE, or Sjögren’s syndrome

• Clinical sx: distal arteritis (digital ischemia, livedo reticularis, palpable purpura, cutaneous ulceration); visceral arteritis (pericarditis, mesenteric ischemia); peripheral neuropathy

• Dx studies: skin/sural nerve bx, EMG, angiography; ↓ C3, C4 in SLE; ⊕ RF, anti-CCP in RA

• Treatment: steroids, cyclophosphamide, MTX (other DMARDs)

Cutaneous leukocytoclastic angiitis (Arthritis Rheumatol 2018;70:171)

• Most common type of vasculitis; heterogeneous group of clinical syndromes due to IC deposition in capillaries, venules, and arterioles; includes hypersensitivity vasculitis

• Etiol: drugs (PCN, ASA, amphetamines, levamisole, thiazides, chemicals, immunizations, etc.); infection (Strep, Staph, endocarditis, TB, hepatitis); malignancy (paraneoplastic)

• Clinical manifestations: abrupt onset of palpable purpura and transient arthralgias after exposure to the offending agent; visceral involvement rare but can be severe

• Dx studies: ↑ ESR, ↓ complement levels, eosinophilia; ✓ U/A; skin biopsy → leukocytoclastic vasculitis w/o IgA deposition in skin (to distinguish from IgA vasculitis); if etiology not clear, consider ANCA, cryoglobulins, hepatitis serologies, ANA, RF

• Treatment: withdrawal of offending agent ± rapid prednisone taper

VARIABLE-VESSEL VASCULITIS

Behçet’s syndrome (Nat Rev Dis Primers 2021;7:67)

• Systemic vasculitis affecting all vessel sizes, venous and arterial, a/w painful oral and/or genital ulcers

• Epi: usually young adults (25–35 y); ♂ = ♀, ↑ severity in ♂; a/w HLA-B51; ↑ prev on old Silk Road (Turkey, Middle East, Asia) w/ 5 vs. 370/100,000 in U.S. vs. Turkey

• Classification criteria (#1 + ≥2 others is 91% Se & 96% Sp; Lancet 1990;335:1078)

1. Recurrent oral aphthous ulceration (≥3× in 1 y, usually 1^st manifestation)

2. Recurrent genital ulceration (labia in females, scrotum in males)

3. Eye lesions: uveitis, scleritis, retinal vasculitis, optic neuritis; may threaten vision

4. Skin lesions: pustules, papules, folliculitis, erythema nodosum (scarring)

5. ⊕ pathergy test (prick forearm w/ sterile needle → pustule) (not sensitive in Caucasians)

• Other clinical manifestations: most recur but are not chronic

Arthritis: mild, ± symmetric, nondestructive, involving knees and ankles

Neurologic: usually involvement of midbrain parenchyma; peripheral neuropathy rare

Vascular: superficial or deep vein thrombosis (25%); arterial stenosis, occlusion, and aneurysm can also occur; low incidence of thromboembolism

• Dx studies: ↑ ESR/CRP; ulcer swab to r/o HSV; ulcer bx nonspecific; ophtho eval if sx

• Treatment (Ann Rheum Dis 2018;77:808)

Mucocutaneous: Mild: topical steroids, colchicine (esp. for erythema nodosum), dapsone, apremilast (PDE-4 inhib) for oral ulcers and ? genital ulcers (NEJM 2019;381:1918). Severe: oral steroids, steroid-sparing agents.

Arthritis: NSAIDs, colchicine, steroids, steroid-sparing agents

Ocular: topical and/or systemic steroids ± steroid-sparing agents

Steroid-sparing: AZA, anti-TNF, CYC (large vessel and CNS ds), CsA, MTX, IFNα-2A

Venous thrombosis: steroids and anticoagulation (careful if aneurysm present)

AUTOINFLAMMATORY SYNDROMES

Immune-mediated diseases thought to result from overactivation of innate immunity

Familial Mediterranean fever (FMF) (Ann Rhem Dis 2016;75:644)

• Recessive MEFV mutations (activating pyrin, upstream of inflammasome)

• Febrile episodes for 1–3 d w/ abd pain (serositis, can mimic acute abdomen), pleurisy, lg joint monoarthritis/arthralgia, erysipelas-like skin lesions. Variable time between attacks.

• Epidemiology: ↑ prev in Armenians (1/500), Sephardic Jews, North Africans, Turks, Arabs; onset usually as child

• Risk of ESRD due to amyloidosis (AA), peritoneal adhesions, or infertility if untreated

• Colchicine effective prophylactic and ↓ amyloid; anti-IL1 is alternative (NEJM 2018;378:1908)

TNF receptor-associated periodic syndrome (TRAPS)

• TNF receptor mutations → febrile episodes q 5–6 wks each lasting >7 d w/ myalgia, abd pain/nausea, migratory rash, periorbital edema; risk of amyloidosis (AA)

• Epidemiology: autosomal dom. w/ variable penetr.; prev 1/million; onset usually as child

• Rx: steroid taper; NSAID alone if mild flare. If freq or severe flares, anti-IL1 (canakinumab) induction and maintenance (NEJM 2018;378:1908) appears more effective than anti-TNF

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome

• Acquired/mosaic UBA1 (ubiquitylation enzyme on X chr) mutation in HSCs → myeloid + erythroid cytoplasmic vacuoles → heterogeneous but fever, cytopenias, chondritis, vasculitis, thrombosis, aveolitis, neutrophilic dermatoses common (NEJM 2020;383:2628)

• Epidemiology: ♂, mean onset age >60

• Steroids reduce symptoms but Rx otherwise unclear

Hemophagocytic lymphohistiocytosis (HLH)

• ↑↑ immune activity; failure to ↓ activated macrophages by NK cells/CTLs → ↑ cytokines (IFNλ, IL18) → macrophages phagocytize other blood cells, cytokine storm, organ failure

• Triggered by disruption of immune homeostasis: immune activation (infxn, autoimmune flare) or immunodeficiency; ~25% familial (mutations in perforin-mediated cytotoxicity)

• HLH 2/2 rheumatologic disease termed macrophage activation syndrome (MAS)

• Fever, ↑ spleen, cytopenias, ↑ TG, ↓ fibrinogen, ↑ LFTs, hemophagocytosis, ↓ NK cell activity, ↑ ferritin, ↑ soluble IL2R; H-score for HLH likelihood (Arthritis Rheum 2014;66:2613)

• Rx trigger (eg, rheum flare w steroids/biologics); if insufficient, HLH-04 protocol (etoposide + steroids ± CsA ± intrathecal MTX; BMT if genetic or relapsed/refractory; Blood 2017;130:2728), anti-IL1/IVIg/steroids (Lancet Rheumatol 2020:2:e358), or emapalumab (anti-IFNγ) (NEJM 2020;382:1811); high mortality if no Rx (Blood 2019;133:2465)

AMYLOIDOSIS

Deposition of misfolded proteins as insoluble fibrils (β-pleated sheets) in normal tissues

(NEJM 2007;356:2361; 2020;282:1567; Circulation 2020;142:e7; Nat Rev Dis Primers 2018;4:38)

Clinical Manifestations of Amyloidosis (Lancet 2016;387:2641; JAMA 2020;324:79)
System	Manifestations	Amyloid
Renal	Proteinuria or nephrotic syndrome	AL, AA
Cardiac	Restrictive CMP (↓ EF late), thick walls but ↓ QRS amplitude, conduction abnl, AF, syncope	AL, mATTR, wt ATTR
GI	Diarrhea, malabsorption, protein loss; ulcers, hemorrhage, obstruction; macroglossia (dysphonia/dysphagia)	All systemic
Neuro	Periph neuropathy w/ painful paresthesia; carpal tunnel; Autonomic neuro → impotence, dysmotility, ↓ BP	mATTR, Aβ2M, AL, localized
Skin	Waxy, nonpruritic papules; periorbital ecchymoses; “pinch purpura” = skin bleeds with minimal trauma	AL
HSM	Hepatosplenomegaly w/o hepatic dysfnx or cytopenias	All systemic
Endo	Deposition with rare hormonal insufficiency	localized
MSK	Arthralgias and arthritis (especially shoulder)	AL, Aβ2M
Pulm	Airway obstruction; pleural effusions	AL, AA
Heme	Factor X deficiency	AL

Diagnostic studies

• Biopsy (abd fat pad, rectal, etc.): apple-green birefring w/ Congo red (Se <85% Sp >90%)

• If suspect AL: SPEP & UPEP + immunofixation, free light chains, ± BM biopsy

• If suspect renal involvement: U/A for proteinuria

• If suspect CMP: ECG (↓ volt, conduction abnl), TTE (↓ longitudinal strain, LVH, valve & septal thickening, myocard. speckling), MRI (late gad. enhancement). R/o plasma cell dyscrasia; if ⊖ → (99m)Tc-pyrophosphate (PYP) SPECT for TTR. ± Cardiac bx.

• Mass spec of biopsy to ID fibril type. Genetic testing to distinguish wt vs. hereditary ATTR.

Treatment of Amyloidosis
AL	Limited involvement: high-dose melphalan → auto HSCT (NEJM 2007;357:1083) Not HSCT candidate: dara-CyBorD [daratumumab + CYC + bortezomib + dexameth.] (NEJM 2021;385:46). [Low-dose melphalan + D] if Bor not tolerated. Relapse: dara, ixazomib, Bor, or lenalidomide (Blood 2020;136:2620)
AA	Rx underlying disease. Colchicine for FMF, esp. to ↓ renal dis. ? Anti-cytokine Rx (anakinra or tocilizumab) (Clin Exp Rheumatol 2015;33:46; Amyloid 2017;24:189).
ATTR	Stabilize TTR tetramers: diflunisal slows neuropathy; tafamidis ↑ QoL, ↓ CV hosp/mortality (JAMA 2013;310:2658; NEJM 2018;379:1007) ↓ hepatic mut TTR production: siRNA (patisiran) or anti-sense oligo (inotersen) -improve neuropathy (NEJM 2018;379:11 & 22); CRISPR in trials (NEJM 2021;385;493) Liver transplant can benefit some mATTR forms (Muscle Nerve 2013;47:157)

• Clearance of amyloid by Ab under study (NEJM 2015;373:1106; Br J Haematol 2020;189:228)

• Cardiac: diuretics; avoid CCB; ↑ dig toxicity risk (? amyloid binding); anticoag all AF

• Heart, kidney, and liver transplant may be considered in those w/ advanced disease

• Median survival: 5y AL (~6 m if CM); 11y AA; 4y wt ATTR & 2.5y ATTR V122I CM w/o Rx