Connective Tissue Diseases

% Autoantibodies in Patients with Rheumatic Diseases

Pattern

RF

dsDNA

Sm

Ro

U

Scl-70

Cent

Jo

RNP

SLE

95-99 D.S.N

20

50-70

30

35

15

0

0

0

30-50

RA

15-35 D

85

<5

0

10

5

0

0

0

10

D.S

75

<5

0

55

40

0

0

0

15

Diffuse SSc

>90 N.S.D

30

0

0

5

1

40

<5

0

30

Limited SSc

•90 S.N.D

30

0

0

5

1

<5

70

0

30

PM-DM

75-95

33

0

0

0

0

10

0

25

0

MCTD

95-99 S.D

50

0

0

<5

<5

0

0

0

100

(D = diffuse or homogeneous. S speckled. N - nucleolar. Primer on the fiheumcoc Orteoses. 12th ed.. 2001)

(D = diffuse or homogeneous. S speckled. N - nucleolar. Primer on the fiheumcoc Orteoses. 12th ed.. 2001)

* 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 and epidemiology

• Scleroderma refers to the presence of tight, thickened skin.

• Anatomic distribution of sclerodermatous skin defines subtypes and disease associations 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): multiorgan involvement SSc with diffuse cutaneous disease (Ind. proximal extremities & trunk) SSc with limited cutaneous disease (CREST syndrome) SSc sine scleroderma (visceral disease without skin involvement)

• Peak onset of SSc between ages 30-50: more common in women than men

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

• Stimulatory autoantibodies against PDGF receptor activating collagen gene expression proposed as pathogenic mechanism for development of fibrosis (NE/m 2006:354:2667) Classification criteria (1 major or 2 minor; 97% Se. 98% Sp;A/th RWn 1980.23581)

• 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

• Proposed additions to the above criteria include the presence of Raynaud's phenomenon.

findings on nailfold capillaroscopy (eg. dropout and dilatation), and serologies

• Other causes of thickened skin: diabetes (scleredema * scleroderma), hypothyroidism.

nephrogenic fibrosing dermopathy. eosinophilic fasaitis, amyloidosis. GVHD. drug or toxin Diagnostic studies

• Autoantibodies

© anti-Scl-70 (anti-topoisomerase 1): 40% of diffuse. 15% of limited © anti-centromere: 60-80% of limited. <5% of diffuse ©ANA (>90%). © RF (30%)

• If renal involvement -* 1 BUN and Cr. proteinuria

• If pulmonary involvement — interstitial pattern on CXR/chest CT. restriction and/or

A DlCO on PFTs; PHT revealed by echocardiography

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

Clinical Manifestations of Systemic Sclerosis

Organ

Involvement

Skin

Tightening and thickening of extremities, face, and trunk

"Puffy" hands, carpal tunnel syndrome, sclerodactyly

Nailfold capillary dilatation & dropout

Immobile, pinched."mouselike" fades and "purse-string" mouth

Calcinosis cutis (subcutaneous calcification)

Telangiectasias

Arteries

Raynaud's phenomenon (80%); digital or visceral ischemia

Renal

Scleroderma renal crisis sudden onset severe HTN. RPGN. MAHA Crescentic GN (rare) with - p-ANCA (/Rfcwn 2006:33 1886)

Gl

GERD and erosive esophagitis

Esophageal dysmotility — dysphagia, odynophagia, aspiration Gastric dysmotility — early satiety and gastric outlet obstruction Small intestinal dysmotility — bloating, diarrhea, malabsorption

Musculoskel

Polyarthralgias & joint stiffness: muscle weakness, tendon friction rubs

Cardiac

Myocardial fibrosis, pericarditis; conduction abnormalities

Pulmonary

Pulmonary fibrosis; pulmonary hypertension

Endocrine

Amenorrhea and infertility common; thyroid fibrosis z hypothyroidism

Systemic Sclerosis

Limited

Diffuse

Skin

Thickening on distal extremities and face only

Thickening on extremities (incl. digits), face, and trunk

Nails

Capillary dropout ♦ dilatation

Capillary dropout & dilatation

Pulmonary

PHT > fibrosis

Fibrosis > PHT

Gl

GERD. hypomotility Primary biliary cirrhosis

GERD. hypomotility

Renal

Renovascular HTN

Cardiac

Restrictive cardiomyopathy

Calcinosis. Raynaud's Esophageal dysmotility Sclerodactyly. Telangiectasias

Antibodies

Anticentromere (70%)

Anti-Scl 70 (40%)

Prognosis

Survival >70% at 10 y

Survival 40-60% at 10 y

Treatment (organ-based approach)

• Pulmonary fibrosis: cyclophosphamide (N£/m 2006:354:2653). steroids PHT: pulmonary vasodilators (see "Pulmonary Hypertension")

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

ACE inhibitors (not ARB) for HTN crisis (poor prognosis w/ 50% mortality)

• Gl: PPI and/or H2-blockers or GERD; antibiotics for malabsorption hypomotility. metoclopramide or erythromycin: nonoperative Rx of pseudoobstruction

• Cardiac: NSAIDs or steroids for pericarditis

• Arthritis: acetaminophen. NSAIDs. PT

• Myositis: MTX.AZA. steroids

• Skin: PUVA for morphea: emollients or oral steroids (caution can precip HTN renal crisis)

for pruritis: immunosuppressives offer only minimal to modest benefit for fibrosis

Inflammatory Myopathies Definition and epidemiology (Lone« 2003:362:971)

• 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

• PM/DM: onset typically 40s and 50s; more common in women than men

T risk of cancer (especially ovarian) in PM ( 10% of Pts) and DM

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

Clinical manifestations

• Muscle weakness: gradual, progressive, often painless, symmetric, and proximal;

typically difficulty climbing stairs, arising from chairs, brushing hair; - tenderness of affected areas; asymmetry and distal weakness more common in IBM than PM/DM

• Dermatologic erythematous rash on sun-exposed skin: neck & shoulders (shawl sign), face, chest heliotrope rash (purplish discoloration) over upper eyelids periorbital edema Gottron's papules (pathognomonic): violaceous often scaly areas symmetrically over dorsum of PIP and MCP joints, elbows, patellae, medial malleoli subungal erythema, cuticular telangiectases."mechanic's hands" (skin cracks on digits)

• Polyarthralgias or polyarthritis

• Vasculitis of skin, muscle. Gl tract and eyes; Raynaud's (30%. usu. DM and overlap CTD)

• Visceral involvement pulmonary: acute alveolitis, chronic ILD. weakness of respiratory muscles cardiac (33%): myocarditis, pericarditis, arrhythmias Gl: dysphagia

Diagnostic studies

• ' CK. aldolase. SGOT. and LDH; ♦ t ESR & CRP

© anti-Jo-1 (25%). associated with nonerosive polyarthritis. Raynaud's. ILD © anti-Mi-2 (5-10%). more common with DM. may have better prognosis

• EMG:T spontaneous activity, i amplitude, polyphasic potentials with contraction

• Muscle biopsy: all with muscle fiber necrosis, degeneration & regeneration

PM: endomysial inflam. (CD8T cells) surrounds non-necrotic fibers,T MHC class I DM: perimysial, perivascular inflam. (B & CD4T cells), complement in vessels IBM: same as PM with eosinophilic inclusions and rimmed vacuoles (EM)

Classification criteria (nEJM 1975.292 344: revision under way to reclassify, include IBM)

• Polymyositis 4 criteria; Dermatomyositis - 3 criteria +■ derm features

1. Symmetrical weakness 4. EMG evidence

2. Muscle biopsy evidence 5. Dermatologic features

3. Elevation of muscle enzymes

Treatment (PM and DM. no effective treatment for IBM)

• High-dose steroids

• DMARDs (eg. MTX and AZA) are 2nd line cyclophosphamide if resistant. ILD or vasculitis; IVIg for resistant DM • PM or for life-threatening esophageal or respiratory muscle involvement

• / for occult malignancy; monitor respiratory muscle strength with spirometry

Disease

Myositides, Myopathies, and Myalgia;

Weakness Pain t CK

t ESR

Biopsy

DM/PM

©

e

©

±

as above

IBM

9

e

©

e

as above

Hypothyroidism

®

Ï

©

e

mild necrosis inflammation atrophy

Steroid-induced

e

e

e

e

atrophy

PMR

(limited by pain)

®

e

®

normal

Fibromyalgia

(limited by pain)

(tender points)

e

e

normal

Sjogren's Syndrome

Definition and epidemiology

• Chronic dysfunction of exocrine glands due to lymphoplasmacytic infiltration

• Can be primary or secondary (associated with RA. scleroderma. SLE. PM. HIV)

• More prevalent in women than in men; typically presents between 40-60 y of age

Clinical manifestations

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

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

• Parotid gland enlargement or intermittent swelling (bilateral)

• Other manifestations: chronic arthritis: interstitial nephritis (40%), type I RTA (20%):

vasculitis (25%): vaginal dryness/dyspareunia: pleuritis: pancreatitis

• t risk of lymphoproJiferaóve disorders (~50x t risk of lymphoma and WM in 1° Sjogren's)

Diagnostic studies

Primary Sjogren's:® anti-Ro (anti-SS-A.56%) and © anti-La (anti-SS-B, 30%)

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

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

• Biopsy (minor salivary, labial, lacrimal, or parotid gland): lymphoplasmacytic infiltration Classification criteria (4 of 6 has 94% Se & 94% Sp;*thrtoi Rheum 1993:3*340)

1. Dry eyes 5. Objective i in salivary gland function

3. © Schirmer test or Rose-Bengal staining

4. Inflammatory foci on minor salivary gland bx Treatment

• Ocular: artificial tears, cyclosporine eyedrops

• Oral: sugarfree gum. lemondrops. saliva substitute, hydration, cholinergic Rx

• Systemic: NSAIDs. steroids. DMARDs; treat underlying disease (secondary Sjogren's)

Mixed Connective Tissue Disease (MCTD)

Definition

• MCTD Pts have features of SLE. systemic sclerosis, and/or polymyositis, often evolving a dominant phenotype of SLE or systemic sclerosis Clinical manifestations

• Raynaud's phenomenon typical presenting symptom

• Hand edema: "puffy hands", sclerodactyly. RA-like arthritis without erosions

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

• Low risk for renal HTN crisis or glomerulonephritis: if either, reconsider diagnosis of MCTD Diagnostic studies

• Anti-U1-RNP present by definition in MCTD. but not specific (seen in up to 50%

SLE Pts) Treatment

• As per specific rheumatic diseases detailed above

Raynaud's Phenomenon

Clinical manifestations (NifM 2002:347 iooi)

• Episodic, reversible digital ischemia, in response to cold or stress, classically: blanching

(ischemia) — cyanosis (venule dilatation) - • rubor (resolution with reactive hyperemia): color change usually well demarcated: affects fingers, toes. ears, nose

• Associated sx include cold, numbness. & paresthesias -»throbbing & pain Primary = Raynaud's disease (50%: excluded all secondary causes)

• Clinical: mild, symmetric episodic attacks; no evidence of peripheral vascular disease, no tissue injury, normal nailfold capillary examination. - ANA. normal ESR Secondary = Raynaud's phenomenon (50%)

• Collagen vascular disease: SSc. SLE. RA. PM-DM (abnormal nailfold exam)

exaggerated vascular reactivity ultimately leads to tissue ischemia & injury

• Arterial disease: peripheral atherosclerosis, thromboangiitis obliterans (abnormal pulses)

• Hematologic: cryoglobulinemia.Waldenstrom's, antiphospholipid syndrome

• Trauma (vibration or repetitive motion injury) & drugs (ergot alkaloids) Treatment

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

• Long-acting CCB.a-blockers.ARBs. PO fish oil (primary RP only; Am jMed 1989:86:158).

topical nitrates, fluoxetine. ASA; bosentan or sildenafil for mod-severe RP espec. wI PHT; IV prostaglandins (acutely) or digital sympathectomy for severe ischemia

SYSTEMIC LUPUS ERYTHEMATOSUS (SLE)

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

• Prevalence 15-50/100.000; predominandy affects women 2nd to 4th decade

• Female:male ratio 8:1; African American:Caucasian ratio 4:1

• Complex genetics; some HLA assoc.; rare c1q & c2 defic.

Classification Criteria and Other Clinical Manifestations of SLE

Organ System

Am. Coll. Rheum. Criteria

Other Features

Constitutional

(84%)

Fever, malaise, anorexia, weight loss

Cutaneous

2. Discoid rash (erythematous papules w/ keratosis & plugging)

3. Photosensitivity

4. Oral/nasopharyngeal ulcers

Alopecia Vasculitis

Subacute cutaneous lupus Panniculitis (lupus profundus) Urticaria

Musculoskeletal

episodic, oligoarticular. symmetrical, migratory

Arthralgias and myalgias Avascular necrosis of bone

Cardiopulmonary

(33%)

6. Serositis: pleuritis (37%) or pleural effusion, pericarditis (29%) or pericardial effusion

Pneumonitis. IPF. PAH Myocarditis. CAD (nqm

2003:349:2399.2407) Libman-Sacks endocarditis

Renal

(77%)

7. Proteinuria (>500 mg/dl or 3 • on dipstick) or urinary cellular casts

Nephrotic syndrome Lupus nephritis (ISN/RPS):

II mesangial prolif;

III = focal (active/chronic);

V - membranous;

VI = advanced sclerotic

Neurologic

(54%)

8. Seizures or psychosis without other cause

Organic brain syndrome. PML Cranial or periph. neuropathies

Gastrointestinal

( 30%)

Serositis (peritonitis, ascites) Vasculitis (bleeding, perf.) Abdominal pain Hepatitis, pancreatitis

Hematologic

9. Hemolytic anemia (DAT ©) or leukopenia (< 4000/mm3). or lymphopenia (< 1500/mm3). or thrombocytopenia

(< 100.000/mm1)

Anemia of chronic disease Antiphospholipid syndrome

(VTE w/ © ACL Ab or ® LAC) Splenomegaly Lymphadenopathy

Other

Sicca syndrome Conjunctivitis or episcleritis Raynaud's (20%) Nailfold capillary changes

11. © anti-ds-DNA, anti-sm, or antiphospholipid Abs

I complement (during flare). T ESR. t CRP. © anti-Ro or anti-RNP. © RF. - anti-CCP

K of 11 criteria met. Se & Sp for SLE >95%. However. Pt may have SLE but not have 4 criteria at a given point in time. (Arth Rheum 196205:1271 & 1997:40.1725. NEJM 1994:330:1871 ; Annok 1995:122540 & 123:42: J Am Soc Neph 2004:15:241; Lancet 2007:369:587)

K of 11 criteria met. Se & Sp for SLE >95%. However. Pt may have SLE but not have 4 criteria at a given point in time. (Arth Rheum 196205:1271 & 1997:40.1725. NEJM 1994:330:1871 ; Annok 1995:122540 & 123:42: J Am Soc Neph 2004:15:241; Lancet 2007:369:587)

Drug-induced lupus (DLE)

drugs: procainamide, hydralazine, pencillamine, minocycline. INH. methyldopa, quinidine.

chlorpromazine. diltiazem, anti-TNF clinical: milder disease with predominandy arthritis and serositis laboratory: © anti-histone (95%); © anti-ds-DNA & anti-Sm; normal complement levels course: usually reversible w/in 4-6 wks

AutoAb

Autoantibodies in SLE

Frequency (approx) Clinical Associations

Timeline

ANA

95-99% if active disease 90% if in remission Homogeneous or speckled

Any or all of the broad spectrum of clinical manifestations Sensitive but not specific

May appear

©anti-Ro in ANA ©SLE

Sjogren s/SLE overlap Neonatal lupus Photosensitivity Subacute cutaneous lupus

overt disease

ds-DNA

70%; very specific for SLE Titers parallel disease activity, especially renal disease

Lupus nephritis Vasculitis

Appears mos

Sm

30%; very specific for SLE

Lupus nephritis

diagnosis

U1-RNP

40%

MCTD; Raynaud's Tend not to have nephritis

histone

DLE (90%). SLE (80%)

Mild arthritis and serositis

At diagnosis

(NEJM 2003:349:1526) Workup

• Detailed history and exam to assess for signs and symptoms of disease

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

• Electrolytes, BUN. Cr. U/A. urine sediment. 24-h urine for CrCI and protein

• CBC, Coombs' test. PTT. anticardiolipin and lupus anticoagulant, complement levels

Treatment of SLE

Drug

Indication

Adverse Effects

NSAIDs

Arthralgias/arthritis. myalgias Mild serositis

Gastritis. UGIB Renal failure

Hydroxychloroquine

Mild disease complicated by serositis. arthritis, skin As

Macular damage Stevens-Johnson syndrome Myopathy

Corticosteroids

Low doses for mild disease unresponsive to hydroxychloroquine High doses for major manifestations including renal and hematologic

Adrenal suppression Immunosuppression Infection Osteopenia

Avascular necrosis of bone Myopathy

Mycophenolate Cyclophosphamide

Nephritis (induction ondlor maintenance) Severe nephritis, vasculitis or CNS disease (induction -maintenance)

Myelosuppression Infection

Myelosuppression Myeloproliferative disorders Immunosuppression Hemorrhagic cystitis, bladder cancer Infertility, teratogen

Azathioprine (AZA)

Mild nephritis (2nd line) Steroid-sparing agent

Myelosuppression Hepatotoxicity Lymphoproliferative disorders

Methotrexate (MTX)

Skin and joint disease Serositis

Myelosuppression Hepatotoxicity Pneumonitis : fibrosis Alopecia, stomatitis

Cyclosporine (CsA)

Renal disease

Hyperplastic gums. HTN Hirsutism

Renal impairment, anemia

Rituximab

Refractory to other agents

B-cell depletion; PML (?)

Prognosis

• 5-y survival rate >90%. 10-y survival rate >80%

• Leading causes of morbidity and mortality: infection, renal failure, neurologic and cardiovascular events; thrombotic complications (Medicine 2003.82:299)

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