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RHEUMATOLOGY

CONNECTIVE TISSUE DISEASES

•  Autoantibody testing is directed by clinical findings, as autoantibodies themselves do not define a particular connective tissue disease

• Overlap syndromes encompassing more than one connective tissue disorder may be reflected serologically by the presence of multiple autoantibodies

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

SYSTEMIC SCLEROSIS AND SCLERODERMA DISORDERS

Definition & epidemiology (Best Pract Res Clin Rheumatol 2010;24:857)

•  Scleroderma refers to the presence of tight, thickened skin

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

•  Systemic sclerosis (SSc)=scleroderma + internal organ involvement. Subgroups:

SSc w/ limited cutaneous disease

SSc w/ diffuse cutaneous disease: rapidly progressive disorder affecting skin

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

•  Peak onset of SSc between ages 30–50 > (7:1); African American > white

•  1–2/100,000 annual incidence of systemic disease in the U.S.

•  Pathogenesis: immune damage to endothelial cells and reactive O2 species production → persistent oxidative stress → perivascular inflammation → fibroblast activation and fibrosis. Cytokines, growth factors, genetics, environmental factors and autoantibodies (against PDGF receptor, endothelial cells and fibroblasts) all contribute (NEJM 2009;360:1989).

Classification criteria (1 major or 2 minor; 97% Se, 98% Sp; Arth Rheum 1980;23:581)

•  Major: skin findings extend proximal to MCP or MTP joints

•  Minor: sclerodactyly (skin findings limited to the fingers)

digital pitting scars from loss of substance on the finger pad

bibasilar pulmonary fibrosis

•  Other causes of thickened skin: diabetes (scleredema ≠ scleroderma), hypothyroidism, nephrogenic systemic fibrosis, eosinophilic fasciitis, amyloidosis, GVHD, drug or toxin

Diagnostic studies & monitoring

•  Autoantibodies

 anti-Scl-70 (antitopoisomerase 1): 40% of diffuse, 15% of limited; ↑ risk pulm fibrosis

 anticentromere: 60–80% of limited, <5% of diffuse, ↑ risk of severe digit ischemia

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

•  At baseline: ✓ BUN/Cr & UA for proteinuria, PFTs (spirometry, lung volumes, DLCO), 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

•  ↑ r/o malignancy at affected sites

Treatment (Ann Rheum Dis 2009;68:620)

•  Pulmonary Fibrosis: cyclophosphamide (NEJM 2006;354:2655), steroids

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

•  Renal: monitor BP monthly, intervene early to avoid HTN crisis; dipstick for protein

Scleroderma renal crisis: ACE inhibitors (not ARB); ACEi not indicated for prophylaxis

•  GI: PPI and/or H2-blockers for GERD; antibiotics for malabsorption

hypomotility: metoclopramide or erythromycin; nonoperative Rx of pseudo-obstruction

•  Cardiac: NSAIDs or steroids for pericarditis

•  Arthritis: acetaminophen, NSAIDs, hydroxychloroquine, PT

•  Myositis: MTX, AZA, steroids

•  Skin: PUVA for morphea. For pruritus: emollients, topical or oral steroids (↓ dose). Immunosuppressives offer only minimal to modest benefit for skin fibrosis.

INFLAMMATORY MYOPATHIES

Definition & epidemiology (JAMA 2013;305:183)

•  Polymyositis (PM): T cell–mediated muscle injury → skeletal muscle inflam & weakness

•  Dermatomyositis (DM): immune complex deposition in blood vessels with complement

activation → skeletal muscle inflam. & weakness + skin manifestations

•  Inclusion body myositis (IBM): T cell–mediated muscle injury, vacuole formation with

amyloid deposition → skeletal muscle inflam & weakness

•  10% of PM and 24% of DM a/w malignancy (typically adenocarcinomas, a/w more severe disease) (Curr Rheumatol Rep 2011;13:208)

•  PM/DM: onset typically 40s and 50s;  > ; DM also occurs in childhood

•  IBM: onset after age 50;  > ; often misdiagnosed as polymyositis

Clinical manifestations (Rheum Dis Clin N Am 2011;37:143)

•  Muscle weakness: gradual (wks → mos), progressive and painless

DM/PM: proximal and symmetric; difficulty climbing stairs, arising from chairs, brushing hair; ± tenderness of affected areas; fine motor skills (eg, buttoning, writing) lost late

IBM: may be asymmetric and distal

•  Dermatologic: may precede myositis by mos to yrs (uncommon for converse)

erythematous rash on sun-exposed skin: neck & shoulders (shawl sign), face, chest

heliotrope rash (purplish discoloration) over upper eyelids ± periorbital edema

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

subungual erythema, “mechanic’s hands” (skin cracks on digits), pruritus

dermatologic features w/o myositis=DM sine myositis (amyopathic DM) in 10–20%

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

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

•  Visceral involvement (J Rheumatol 2009;36:2711)

pulmonary: acute alveolitis; ILD; respiratory muscle weakness; aspiration

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

GI: dysphagia, aspiration

•  Antisynthetase syndrome (PM > DM): fever, ILD, Raynaud’s, mechanics hands, arthritis

•  Ddx: drug-induced 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

Diagnostic studies

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

•  Autoantibodies:  ANA (>75%),  RF (33%)

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

myositis antibody panel may assist in prognosis (anti-Mi-2 better, anti-SRP worse)

•  EMG: ↑ spontaneous activity, ↓ amplitude, polyphasic potentials with contraction

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

PM: endomysial inflam. (CD8 T cells) surrounds non-necrotic fibers, ↑ MHC class I

DM: perimysial, perivascular inflam (B & CD4 T cells), complement in vessels

IBM: same as PM with eosinophilic inclusions and rimmed vacuoles (EM)

Treatment (PM & DM, no effective treatment for IBM) (Autoimmun Rev 2011;11:6)

•  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 (DM ± PM), rituximab, MMF, cyclophosphamide (esp. if ILD or vasculitis)

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

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

SJÖGREN’S SYNDROME

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)

•  More prevalent in  than ; typically presents between 40 & 60 y of age

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%); neuropathies (10%); PNS or CNS disease; ILD; PBC

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

Diagnostic studies

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

Primary Sjögren’s:  anti-Ro (anti-SS-A, 56%) and/or  anti-La (anti-SS-B, 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): lymphoplasmacytic infiltration

Classification criteria (2 of 3 have 93% Se & 95% Sp; Arthritis Care Res 2012;64:475)

1.  anti-Ro or anti-La or RF + ANA>1:320

2. Labial salivary gland bx w/ lymphocytic sialadenitis and score >1 focus/4 mm2

3. Keratoconjunctivitis sicca w/ ocular staining score ≥3

Treatment

•  Ocular: artificial tears, cyclosporine eyedrops

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

•  Systemic: NSAIDs, steroids, DMARDs, rituximab

MIXED CONNECTIVE TISSUE DISEASE (MCTD)

Definition (Best Pract Res Clin Rheumatol 2012;26:61)

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

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

Clinical manifestations (variable clinical course)

•  Raynaud’s phenomenon 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 (if either, reconsider diagnosis of MCTD)

Diagnostic studies

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

Treatment

•  As per specific rheumatic diseases detailed above

RAYNAUD’S PHENOMENON

Clinical manifestations (NEJM 2002;347:1001 & 2013;368:1344; BMJ 2012;344:e289)

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

•  Key to diagnosis and Rx is distinguishing between primary and secondary Raynaud’s

Primary (80–90%=Raynaud’s disease; excluded all secondary causes)

•  Onset 20–40 y,  >  (5:1); thought due to functional abnl of vessel wall

•  Clinical: mild, symmetric episodic attacks; no evidence of periph vascular disease; no tissue injury; nl nail-fold capillary exam; no systemic sx;  ANA; nl ESR

Secondary (10–20%)

•  Typically >35 y of age; due to structural abnl of vessel wall

•  Tissue ischemia & injury (eg, digital ulcers), which is not seen in primary Raynaud’s

•  Etiologies: CTD (abnl nail-fold exam): SSc, SLE, PM-DM, MCTD, Sjögren’s, RA

Arterial disease: periph atherosclerosis, thromboangiitis obliterans (abnormal pulses)

Hematologic: cryoglobulinemia, Waldenström’s, antiphospholipid syndrome

Trauma (vibration or repetitive motion injury) & drugs (ergot alkaloids, estrogens, cocaine)

Treatment (Curr Opin Rheumatol 2011;23:555; BMJ 2012;344:e289)

•  All: avoid cold, maintain warmth of digits & body; avoid cigarettes, drugs and trauma

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

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

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

•  Others: fish oil (1° RP only; Am J Med 1989;86:158), abx for infected ulceration



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