Systemic and Systemic and Localized Localized

SclerodermaSclerodermaJulie Schwartzman, MDJulie Schwartzman, MD

Assistant ProfessorAssistant Professor

Medicine and RheumatologyMedicine and Rheumatology

Director, Jacobi and NCB Arthritis Director, Jacobi and NCB Arthritis ClinicsClinics

Scleroderma: Systemic Scleroderma: Systemic SclerosisSclerosis

Chronic disease that causes skin Chronic disease that causes skin thickening and tightening, and can thickening and tightening, and can involve fibrosis and other types of involve fibrosis and other types of damage to internal body organs.damage to internal body organs.

Thought to be an autoimmune disease, Thought to be an autoimmune disease, affects both adults and children, most affects both adults and children, most commonly adult women. commonly adult women.

While effective treatments are available While effective treatments are available for some manifestations of the disease, for some manifestations of the disease, scleroderma is not yet curable. scleroderma is not yet curable.

SScSSc Uncommon problem affecting only Uncommon problem affecting only

200 to 300/million in the U.S. 200 to 300/million in the U.S. Traditional DMARDs have limited Traditional DMARDs have limited

effecteffect Increasingly, different aspects of Increasingly, different aspects of

scleroderma are becoming treatable.scleroderma are becoming treatable. Research is shedding new light on Research is shedding new light on

the relationship between the the relationship between the immune system and scleroderma. immune system and scleroderma.

CHARACTERIZED BY VASCULAR CHARACTERIZED BY VASCULAR CHANGES, INTIMAL PROLIFERATION CHANGES, INTIMAL PROLIFERATION LEADING TO DEPOSITION OF LEADING TO DEPOSITION OF COLLAGEN AND FIBROSIS.COLLAGEN AND FIBROSIS.

PRESENTATION AND PROGRESSION PRESENTATION AND PROGRESSION IS VARIABLEIS VARIABLE

NO EFFECTIVE TREATMENTNO EFFECTIVE TREATMENT

““Scleroderma” = more than one syndromeScleroderma” = more than one syndrome

Localized scleroderma or Localized scleroderma or morpheamorphea: confined to the skin and : confined to the skin and subcutaneous structuressubcutaneous structures Multiple clinical variantsMultiple clinical variants

Systemic sclerosisSystemic sclerosis: more uniform : more uniform skin involvement and the potential for skin involvement and the potential for involvment of multiple visceral organsinvolvment of multiple visceral organs Limited, Diffuse, Overlap SyndromeLimited, Diffuse, Overlap Syndrome

CRESTCREST: variant of Limited SSc: variant of Limited SSc

Localized SclerodermaLocalized Scleroderma Each of the several forms of localized Each of the several forms of localized

scleroderma is a disorder of skin and scleroderma is a disorder of skin and sometimes the deeper tissues. sometimes the deeper tissues.

The most visible effects of the disease are skin The most visible effects of the disease are skin lesions referred to as lesions referred to as morphea. morphea.

Morphea can be differentiated from SSc by Morphea can be differentiated from SSc by the distribution of lesions (no sclerodactyly or the distribution of lesions (no sclerodactyly or perioral involvement), absence of Raynaud’s perioral involvement), absence of Raynaud’s and/or periungual telangiectasia, and rarity of and/or periungual telangiectasia, and rarity of severe systemic diseasesevere systemic disease Age of diagnosis usually 20-40, linear disease Age of diagnosis usually 20-40, linear disease

<18yrs, deep morphea mean age 46<18yrs, deep morphea mean age 46

MorpheaMorphea The typical morphea lesion begins as a The typical morphea lesion begins as a

patch of erythema or edema that may patch of erythema or edema that may have an associated violaceous border have an associated violaceous border (inflammatory stage).(inflammatory stage).

Primary lesions=hyperpigmented Primary lesions=hyperpigmented

patches. Become progressively patches. Become progressively indurated, porcelain white or yellow hue. indurated, porcelain white or yellow hue.

Upon resolution, atrophy, Upon resolution, atrophy, depigmentation, or hyperpigmentation depigmentation, or hyperpigmentation may occur.may occur.

Plaque morpheaPlaque morphea

Involves dermis and, Involves dermis and, occasionally, the occasionally, the superficial panniculus. superficial panniculus.

Trunk is generally more Trunk is generally more commonly involved than commonly involved than the extremities, although the extremities, although the face, neck, or scalp the face, neck, or scalp can be involved. can be involved.

Plaque morphea comprises Plaque morphea comprises more than 50% of cases.more than 50% of cases.

Guttate morpheaGuttate morphea: This subset usually : This subset usually occurs on the upper trunk. Typically, it occurs on the upper trunk. Typically, it presents as multiple oval lesions presents as multiple oval lesions between 2-10 mm in diameter. between 2-10 mm in diameter. The lesions often manifest as faint The lesions often manifest as faint

erythema, followed by mild induration and erythema, followed by mild induration and hypopigmentation or hyperpigmentation.hypopigmentation or hyperpigmentation.

Keloid morpheaKeloid morphea: This presents as : This presents as nodules that resemble keloids in the nodules that resemble keloids in the presence of typical morphea.presence of typical morphea.

Lichen sclerosus et atrophicusLichen sclerosus et atrophicus: shiny, : shiny, white plaques often preceded by white plaques often preceded by violaceous discoloration of the skin; violaceous discoloration of the skin; predilection for the anogenital area. predilection for the anogenital area. There is higher incidence of autoimmune-There is higher incidence of autoimmune-

related diseases (eg, vitiligo, alopecia areata).related diseases (eg, vitiligo, alopecia areata). Atrophoderma of Pasini and PieriniAtrophoderma of Pasini and Pierini: :

asymptomatic, hyperpigmented atrophic asymptomatic, hyperpigmented atrophic patches with well demarcated "cliff drop patches with well demarcated "cliff drop borders" on the trunk. borders" on the trunk. There are no pronounced inflammatory or There are no pronounced inflammatory or

sclerotic changes. sclerotic changes. The course is chronic, with spontaneous The course is chronic, with spontaneous

resolution usually after 10 years.resolution usually after 10 years.

Localized scleroderma including Localized scleroderma including deep and extensive lesions can deep and extensive lesions can prevent normal motion of joints and prevent normal motion of joints and interfere with daily activities. interfere with daily activities.

However, localized scleroderma However, localized scleroderma does not affect internal organs of the does not affect internal organs of the body. body.

Generalized morpheaGeneralized morphea Generalized morphea Generalized morphea or or linear scleroderma: linear scleroderma:

widespread lesions; thickness and scarring widespread lesions; thickness and scarring spreads down to the underlying structures spreads down to the underlying structures including fat, muscle and, on rare occasion, bone.including fat, muscle and, on rare occasion, bone.

Disease can be more serious. Disease can be more serious. Individual plaques of morphea become confluent Individual plaques of morphea become confluent

lesions.lesions. It can affect more than 2 anatomic sites, including the It can affect more than 2 anatomic sites, including the

upper trunk, breasts, abdomen, and upper thighs. upper trunk, breasts, abdomen, and upper thighs. Arms, legs, face, neck, and scalp also may be involved. Arms, legs, face, neck, and scalp also may be involved. Bullae may develop in localized areas, particularly Bullae may develop in localized areas, particularly

around the abdomen. around the abdomen. Keratoses and calcinosis may occur. Keratoses and calcinosis may occur. Contractures may occur in limbs, and mobility may be Contractures may occur in limbs, and mobility may be

restricted.restricted.

Linear sclerodermaLinear scleroderma One or more linear streaks and induration that can One or more linear streaks and induration that can

involve dermis, subcutaneous tissue, muscle, and involve dermis, subcutaneous tissue, muscle, and bone. bone.

It occurs on the extremities, face, or scalp of children It occurs on the extremities, face, or scalp of children and adolescents. and adolescents. Linear sclerodermaLinear scleroderma: discrete linear induration that : discrete linear induration that

primarily affects the extremitiesprimarily affects the extremities. . In more than 90% involvement is unilateral. In more than 90% involvement is unilateral. Complicated by deformities, joint contractures, and Complicated by deformities, joint contractures, and

severe limb atrophy. severe limb atrophy. Can affect the growth of bony structures. Can affect the growth of bony structures.

Linear SclerodermaLinear Scleroderma Lesions en coup de sabreLesions en coup de sabre: If the face or : If the face or

scalp is affected with linear scleroderma, the scalp is affected with linear scleroderma, the involvement is often compared to a stroke involvement is often compared to a stroke from a sword (sabre). from a sword (sabre).

Lesions start with contractions and Lesions start with contractions and firmness of the skin over the affected firmness of the skin over the affected area. area.

Then, an ivory, irregular, sclerotic plaque Then, an ivory, irregular, sclerotic plaque with hyperpigmentation at the edge will with hyperpigmentation at the edge will develop. develop.

Progressive hemifacial atrophy (Parry-Progressive hemifacial atrophy (Parry-Romberg syndromeRomberg syndrome): results in ): results in hemiatrophy of the face. hemiatrophy of the face.

The primary lesions occur in the The primary lesions occur in the subcutaneous tissue, muscle, and bone. subcutaneous tissue, muscle, and bone.

The disease usually begins in the first 2 The disease usually begins in the first 2 decades of life.decades of life.

Deep morphea: deep dermis, subcutaneous tissue, Deep morphea: deep dermis, subcutaneous tissue, fascia, or superficial muscle. fascia, or superficial muscle.

Lesions more diffuse than in linear Lesions more diffuse than in linear scleroderma scleroderma Subcutaneous morpheaSubcutaneous morphea: panniculus or : panniculus or

subcutaneous tissue. The onset is rapid, subcutaneous tissue. The onset is rapid, occurring during a period of several months.occurring during a period of several months.

More inflammatory condition than other types. More inflammatory condition than other types.

Morphea profundaMorphea profunda: entire skin feels : entire skin feels thickened, bound down, and taut. Patients thickened, bound down, and taut. Patients develop deep sclerosis of the skin. develop deep sclerosis of the skin.

Patients younger than 14 years. Patients younger than 14 years. The extensor aspect of the extremities and trunk The extensor aspect of the extremities and trunk

develops sclerotic plaques that extend deep into develops sclerotic plaques that extend deep into the subcutaneous tissue, fascia, muscle, and the subcutaneous tissue, fascia, muscle, and bone.. bone..

Deep morphea: deep dermis, subcutaneous Deep morphea: deep dermis, subcutaneous tissue, fascia, or superficial muscletissue, fascia, or superficial muscle

Disabling pansclerotic morphea of Disabling pansclerotic morphea of childhoodchildhood: aggressive and mutilating : aggressive and mutilating generalized, full-thickness involvement of generalized, full-thickness involvement of the trunk, extremities, face, and scalp. the trunk, extremities, face, and scalp. Fingertips and toes usually are spared. Fingertips and toes usually are spared.

Eosinophilic fasciitisEosinophilic fasciitis: painful : painful peau peau d'oranged'orange appearance involving the appearance involving the extremities, proximal to the hands and feet. extremities, proximal to the hands and feet. The fascia is the predominant level of The fascia is the predominant level of

involvement. involvement. Patients seem to spontaneously regress or Patients seem to spontaneously regress or

remain unchanged for years.remain unchanged for years.

The diagnosis of morphea is based on The diagnosis of morphea is based on clinical findings, although clinical findings, although histopathologic confirmation is often histopathologic confirmation is often needed to exclude other disordersneeded to exclude other disorders

Eosinophilia can be seen in generalized Eosinophilia can be seen in generalized and linear scleroderma and often and linear scleroderma and often correlates with extent of disease.correlates with extent of disease.

Polyclonal hypergammaglobulinemia Polyclonal hypergammaglobulinemia can occur in 50% of patients with linear can occur in 50% of patients with linear sclerodermascleroderma

Autoantibodies?Autoantibodies? Most titers correlate with the burden of skin Most titers correlate with the burden of skin

diseasedisease antinuclear antibodies (46%-80%)antinuclear antibodies (46%-80%) anti–single-stranded DNA antibodies (50%)anti–single-stranded DNA antibodies (50%) antihistone antibodies (47%).antihistone antibodies (47%).

The presence of The presence of rheumatoid factor (60% rheumatoid factor (60% of cases) may predict articular of cases) may predict articular involvmentinvolvment

Although anticentromere antibodies have Although anticentromere antibodies have been detected in up to 12% of patients with been detected in up to 12% of patients with morphea, anti-topoisomerase I antibodies morphea, anti-topoisomerase I antibodies have only been reported in a handful of have only been reported in a handful of cases.cases.

Progression to SSc is rare (0.9%-5.7% of Progression to SSc is rare (0.9%-5.7% of cohorts)cohorts)

Despite this, certain extra-cutaneous Despite this, certain extra-cutaneous manifestations can occur. manifestations can occur.

Arthralgias commonly occur, then resolve Arthralgias commonly occur, then resolve with progression of skin disease.with progression of skin disease.

Other findings: synovitis, uveitis, congenital Other findings: synovitis, uveitis, congenital vertebral abnormalities (especially spina vertebral abnormalities (especially spina bifida), cardiomyopathies, fever, and bifida), cardiomyopathies, fever, and lymphadenopathy.lymphadenopathy.

Raynaud’s and carpal tunnel syndrome can Raynaud’s and carpal tunnel syndrome can develop as a secondary result of extensive develop as a secondary result of extensive extremity fibrosis.extremity fibrosis.

Morphea rarely coexists with other systemic Morphea rarely coexists with other systemic autoimmune disorders, including autoimmune disorders, including dermatomyositis, polymyositis, systemic lupus dermatomyositis, polymyositis, systemic lupus erythematosus, primary biliary cirrhosis, erythematosus, primary biliary cirrhosis, rheumatoid arthritis, and MCTDrheumatoid arthritis, and MCTD

Lesions typically regress spontaneously over 3 Lesions typically regress spontaneously over 3 to 5 years, usually with residual pigmentary to 5 years, usually with residual pigmentary and atrophic changes.and atrophic changes.

Although the few controlled trials did not Although the few controlled trials did not

show efficacy compared with placebo several show efficacy compared with placebo several therapeutic options are available particularly therapeutic options are available particularly for patients with evidence of inflammatory for patients with evidence of inflammatory changes and/or progressive lesionschanges and/or progressive lesions

Systemic SclerosisSystemic Sclerosis Diffuse systemic sclerosisDiffuse systemic sclerosis: can : can

affect the skin over almost any body affect the skin over almost any body area. Fibrosis proximal to elbows, area. Fibrosis proximal to elbows, knees.knees. Rapid onset of disease following Rapid onset of disease following

appearance of appearance of RaynaudsRaynauds More likely to have pulm fibrosis, GI, More likely to have pulm fibrosis, GI,

renal, cardiacrenal, cardiac ANA, Scl-70ANA, Scl-70 Variable but overall poor prognosis, Variable but overall poor prognosis,

survival 40-60% at 10 yearssurvival 40-60% at 10 years

Systemic SclerosisSystemic Sclerosis Limited systemic sclerosisLimited systemic sclerosis: skin : skin

involvement is limited to forearms, hands, involvement is limited to forearms, hands, legs, feet, and face.legs, feet, and face. Pts usually have Raynauds for years. Pts usually have Raynauds for years. Late visceral disease w/ prominent HTN and digital Late visceral disease w/ prominent HTN and digital

amputationamputation CREST subgroupCREST subgroup Anti-centromere AbAnti-centromere Ab Relatively good prognosis, >70% survival at 10 Relatively good prognosis, >70% survival at 10

yearsyears Overlap SyndromesOverlap Syndromes

Diffuse or limited SSc with one or more features of Diffuse or limited SSc with one or more features of another CTDanother CTD

MCTD: features of SLE, SSc, PM, RA and presence MCTD: features of SLE, SSc, PM, RA and presence of anti- Uof anti- U11 RNP RNP

SScSSc Pathologic remodeling of connective tissues

Cardinal features: excessive collagen production and deposition, vascular damage, and inflammation/autoimmunity.

Widespread small-vessel vasculopathy Widespread small-vessel vasculopathy and fibrosis in the setting of immune and fibrosis in the setting of immune system activationsystem activation

Vascular injury affects small arteries, Vascular injury affects small arteries, arterioles, capillariesarterioles, capillaries

The pathogenesis is initiated by microvascular injury (i). This induces The pathogenesis is initiated by microvascular injury (i). This induces inflammation and autoimmunity (ii), which have direct and indirect roles inflammation and autoimmunity (ii), which have direct and indirect roles in inducing fibroblast activation (iii), a key event in the development of in inducing fibroblast activation (iii), a key event in the development of fibrosis. fibrosis.

The number of fibroblasts and their precursors in affected tissues is The number of fibroblasts and their precursors in affected tissues is increased by trafficking as well as by the differentiation of mesenchymal increased by trafficking as well as by the differentiation of mesenchymal cells (iv). cells (iv).

Activated myofibroblasts in the lesional tissue perform a series of Activated myofibroblasts in the lesional tissue perform a series of functions culminating in fibrosis (v). MSC, mesenchymal stem cell.functions culminating in fibrosis (v). MSC, mesenchymal stem cell.

Transforming growth factor–b

Stimulates cell growth, apoptosis, and differentiation

Promotes collagen and matrix protein production

Decreases the synthesis of collagen-degrading metalloproteinases

Stimulates fibroblasts to maintain an activated state.

Stimulates CTGF synthesis in fibroblasts, vascular smooth muscles,and endothelial cells. CTGF can trigger angiogenesis, apoptosis, chemotaxis,

extracellular matrix formation, and the structural organization of connective tissues.

Non–TGFb–related pathways that involve the

activities of p38 kinase,C-delta kinase, and phosphatidylcholine phospholipase C kinase may also play a role

Genetics likely predisposes patients to the Genetics likely predisposes patients to the disease, but whether scleroderma is the result disease, but whether scleroderma is the result of some combination of genetic factors and of some combination of genetic factors and other exposures is unknown. other exposures is unknown.

Some data suggests that exposure to industrial Some data suggests that exposure to industrial solvents or an environmental agent may play a solvents or an environmental agent may play a role in predisposing to scleroderma. role in predisposing to scleroderma.

Scleroderma-like syndromes also have been Scleroderma-like syndromes also have been clearly linked to agents as varied as clearly linked to agents as varied as contaminated rapeseed oil, polyvinylchloride, contaminated rapeseed oil, polyvinylchloride, and a contaminant in one preparation of L-and a contaminant in one preparation of L-tryptophan. tryptophan.

Majority of patients with scleroderma do not Majority of patients with scleroderma do not have a history of exposure to any suspicious have a history of exposure to any suspicious toxins. toxins.

Who gets sclerodermaWho gets sclerodermaRelatively rare, affecting only 75,000 – Relatively rare, affecting only 75,000 –

100,000 people in the United States. 100,000 people in the United States.

75% percent are women usually diagnosed 75% percent are women usually diagnosed between the ages of 30 and 50 years.between the ages of 30 and 50 years.

Twins and family members of patients with Twins and family members of patients with scleroderma or other autoimmune CTD scleroderma or other autoimmune CTD appear to be at a slightly increased risk. appear to be at a slightly increased risk.

Children can get scleroderma, although Children can get scleroderma, although the pattern and extent of disease may be the pattern and extent of disease may be different in children. different in children.

Who gets sclerodermaWho gets scleroderma Ethnicity influences severity and survivalEthnicity influences severity and survival

Progressive IPF less frequent and w/ Progressive IPF less frequent and w/ better survival rates in Caucasiansbetter survival rates in Caucasians

Caucasians: inc rate of anti-centromere AbCaucasians: inc rate of anti-centromere Ab

African Americans: inc rate Scl 70African Americans: inc rate Scl 70

Inc presence of parvovirus B19 in BMInc presence of parvovirus B19 in BM

Occupational exposure to silica: RR 25, Occupational exposure to silica: RR 25, silicosis RR 110silicosis RR 110

Clinical Features: CutaneousClinical Features: Cutaneous

Thickened skinThickened skin: abnl production of : abnl production of type 1 collagen by fibroblasts, type 1 collagen by fibroblasts, accumulation of GAG and fibronectin accumulation of GAG and fibronectin in ECM. Begins in fingers and handsin ECM. Begins in fingers and hands

CalcinosisCalcinosis: deposits of basic CaPhos : deposits of basic CaPhos

TelangiectasiasTelangiectasias: dilated sm v. : dilated sm v. More common in LSScMore common in LSSc Can bleed when in GI mucosaCan bleed when in GI mucosa

SYSTEMIC SCLEROSISSYSTEMIC SCLEROSISCREST VARIANTCREST VARIANT

CCALCINOSISALCINOSIS

RRAYNAUD’SAYNAUD’S

EESOPHOGEAL DYSFUNCTIONSOPHOGEAL DYSFUNCTION

SSCLERODACTALYCLERODACTALY

TTELANGECTASIAELANGECTASIA

Clinical Features – Clinical Features – Raynaud’sRaynaud’s

Almost all (more than 90%) of people Almost all (more than 90%) of people with scleroderma also have with scleroderma also have Raynaud's phenomenon. Raynaud's phenomenon.

RaynaudsRaynauds Triphase event affecting the hands and feet, the

nose, the ears, and the tongue

Characterized by abrupt pallor (white), followed by cyanosis (blue), and sometimes, painful erythema secondary to restoration of blood flow.

The succession of phases is linked to 3 pathogenic mechanisms—vasoconstriction, ischemia, and reperfusion.

Small areas of fingertip ischemic necrosis are frequent, often leaving pitted scars or ulcerations.

On microscopic examination in Raynaud’s of some duration, the capillary circulation is altered by the appearance of tortuous and dilated or giant loops and, in dcSSc, by a paucity of nailfold vessels or dropout

Primary RaynaudsPrimary Raynauds FEMALE PREDOMINENCEFEMALE PREDOMINENCE ONSET AT MENARCHEONSET AT MENARCHE ALL DIGITS INVOLVEDALL DIGITS INVOLVED MULTIPLE ATTACKS DAILYMULTIPLE ATTACKS DAILY EMOTIONAL AND COLDEMOTIONAL AND COLD NO ISCHEMIC ULCERSNO ISCHEMIC ULCERS NORMAL NAIL BED CAPILLARIESNORMAL NAIL BED CAPILLARIES NO SYSTEMIC SYMPTOMSNO SYSTEMIC SYMPTOMS NORMAL SEROLOGYNORMAL SEROLOGY

Secondary RaynaudsSecondary Raynauds LATER ONSETLATER ONSET MAY INVOLVE ONLY A FEW DIGITSMAY INVOLVE ONLY A FEW DIGITS EMOTION IS LESS OF A TRIGGEREMOTION IS LESS OF A TRIGGER ISCHEMIC ULCERS MAY BE PRESENTISCHEMIC ULCERS MAY BE PRESENT EDEMA MAY BE PRESENTEDEMA MAY BE PRESENT PERIUNGUAL CAPILLARIES MAY BE PERIUNGUAL CAPILLARIES MAY BE

ABNORMALABNORMAL SYSTEMIC FEATURESSYSTEMIC FEATURES ANAANA

Pt with Raynauds may Pt with Raynauds may progress to SSc if:progress to SSc if:

+ANA, anti-centromere, anti-Scl-70+ANA, anti-centromere, anti-Scl-70 Nailfold capillary abnl, dropout or Nailfold capillary abnl, dropout or

dilatationdilatation Tendon friction rubsTendon friction rubs Puffy swollen fingersPuffy swollen fingers Associated GERDAssociated GERD If Raynauds preceeds skin changes by If Raynauds preceeds skin changes by

>1 yr, likely Limited SSc>1 yr, likely Limited SSc If Raynauds and skin changes occur at If Raynauds and skin changes occur at

same time, likely dSScsame time, likely dSSc

TREATMENT OF TREATMENT OF RAYNAUD’SRAYNAUD’S

NON-PHARMACOLOGIC – LIFESTYLE ASJUSTMENTS TO PRECIPITANTS: STOP SMOKING, AVOIDANCE OF b-BLOCKERS, EXERCISE, KEEP WARM

ORAL VASODILATOR DRUGS: CALCIUM CHANNEL BLOCKERS, ACE INHIBITORS/ANGIOTENSION RECEPTOR ANTAGONISTS, TOPICAL NITROGLYCERINE, PROSTACYCIN (IV) IF AVAILABLE

DIGITAL SYMPATHECTOMY

PROMPT TREATMENT OF FINGERTIP ULCERATIONS- ANTIBIOTICS AND DEBRIDEMENT

GI- 2GI- 2ndnd most commonly affected organ most commonly affected organ systemsystem

75-90% patients75-90% patients

Lower Esoph Dysmotility: smooth muscle Lower Esoph Dysmotility: smooth muscle fibrosis, esophageal dysfunction in 80% pts- fibrosis, esophageal dysfunction in 80% pts- GERD, fibrosis and stricture formation, GERD, fibrosis and stricture formation, aspiration PNAaspiration PNA

Gastroparesis, telangiectases, watermelon Gastroparesis, telangiectases, watermelon stomachstomach

SI: malabsorption and diarrhea secondary to SI: malabsorption and diarrhea secondary to bacterial overgrowth, functional ileus from bacterial overgrowth, functional ileus from musclar fibrosis w/ hypomotility and dilatationmusclar fibrosis w/ hypomotility and dilatation

Colorectal: severe constipation, megacolon, Colorectal: severe constipation, megacolon, wide mouth diverticulawide mouth diverticula

GI MANAFESTATIONSGI MANAFESTATIONS

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© 2005 Elsevier

Treatment - GITreatment - GI Elevation of the head of the bed at night and

appropriate diet plus the use of H2 blockers and/or proton pump inhibitors.

Metoclopramide and erythromycin are prokinetic drugs that can be used to promote GI motility, particularly of the upper GI. Esophageal stricture requires periodic endoscopic dilatation.

The bleeding telangiectasias and ecstatic superficial vessels of watermelon stomach can be treated with sclerotherapy and laser coagulation, respectively.

In the lower GI tract, symptoms related to bacterial overgrowth may improve with 2- to 4-week courses of broad-spectrum antibiotics

Octreotide, given subcutaneously, is moderately effective as a prokinetic agent for lower GI symptoms.

Rarely, TPN will be needed in patients whose small intestine is essentially nonfunctional.

SYSTEMIC SCLEROSIS SYSTEMIC SCLEROSIS PULMONARY DISEASEPULMONARY DISEASE

INTERSTIAL FIBROSISINTERSTIAL FIBROSIS PULMONARY HYPERTENSIONPULMONARY HYPERTENSION ASPIRATION PNEUMONIAASPIRATION PNEUMONIA PLEURAL DISEASEPLEURAL DISEASE NEOPLASMNEOPLASM Most common initial respiratory sx is Most common initial respiratory sx is

DOE, w/o cough or chest painDOE, w/o cough or chest pain

Pulmonary Pulmonary manifestations of SSc

occur in more than 70% of patients. Most common SSc-related cause of

death.

Pulmonary fibrosis is a common cause of severe restrictive lung disease

CXR shows interstitial thickening in a reticular pattern of linear, nodular densities most easily seen in the lower lung fields.

Pulmonary High-resolution CT more sensitive

for detecting interstitial lung disease Abnormal findings: ground-glass

appearance possibly associated with inflammation/alveolitis, bronchiectasis and/or honeycombing (associated with fibrosis).

Alveolitis can be documented by

either broncho-alveolar lavage or open lung biopsy

Pulmonary Restrictive lung disease on PFTs used as a

marker for pulmonary fibrosis.

In a somewhat later disease, the presence of bibasilar rales on physical examination is found.

Some patients with interstitial lung disease develop slowly progressive respiratory failure over the course of 2 to 10 years, especially those with anti-topoisomerase I antibody.

In Diffuse SSc, ILD more common In Limited SSc P HTN more common

PAHPAH Pulmonary hypertension is more common

than previously thought (up to 30% of patients) and can occur early.

Signs of pulmonary arterial hypertension (PAH) occur in approximately 10% to 15% patients with SSc but may be found on echocardiogram or right heart catheterization in 20% to 40% of patients.

There are 3 patterns of PAH: severe isolated PAH without significant

interstitial fibrosis, which occurs predominantly in patients with lcSSc after 10 to 30 years;

PAH complicating interstitial pulmonary fibrosis, which occurs predominantly in dcSSc patients

Third type of pulmonary vascular disease reflects the combined vascular and fibrotic pathologic processes of the disease and results in a more indolent pulmonary process. Found in those patients who have very slow

progressive PAH and who have a secondary pulmonary vascular component in the context of relatively mild fibrosis, distinct from the severe interstitial process seen in true secondary PAH.

Symptomatically, patients will present with progressive dyspnea but, in late PAH, may present with syncopy.

The pulmonic component of the second heart sound is accentuated, and ultimately, right-sided cardiac failure develops.

The diffusing capacity for carbon monoxide is very low relative to the forced vital capacity, consistent with impaired gas exchange across thickened small pulmonary blood vessels.

Diagnosis is confirmed by echocardiogram or by right heart catheterization.

TreatmentTreatment Prophylactic influenza and Streptococcus

pneumoniae vaccinations

In persons with alveolitis, immunosuppressive drugs, cyclophosphamide and azathioprine, may be effective.

In intrinsic PAH intermittent and continuous intravenous prostacyclin analogs; the endothelin-1 antagonist, bosentan; and the phosphodiesterase type 5 inhibitor, sildenafil have been approved.

Anticoagulation is often prescribed.

Heart-lung or single lung transplantation is an option for end-stage lung disease

RenalRenal Kidney involvement in SSc may be

manifested by scleroderma renal crisis (SRC).

Scleroderma renal crisis used to be the most severe complication in scleroderma and the most frequent cause of the death in these patients.

RenalRenal Over the last 20 to 25 years, ACE-I have

dramatically improved SRC outcome.

Although death and dialysis within 6 weeks were common before the advent of aggressive ACE inhibitor use, 60% of patients with SRC no longer require dialysis or require only temporary dialysis.

Clinically evident renal involvement is almost exclusive to persons with dcSSc, especially those with rapidly progressive skin thickening than 5 years in duration.

Renal CrisisRenal Crisis

Scleroderma renal crisis develops in Scleroderma renal crisis develops in about 18% of pts with dcSSC about 18% of pts with dcSSC Abrupt onset of accelerated Abrupt onset of accelerated

hypertension, followed by oliguric renal hypertension, followed by oliguric renal failure. failure.

Sx: headache and visual blurring from Sx: headache and visual blurring from hypertensive retinopathy, seizures, and hypertensive retinopathy, seizures, and acute dyspnea due to sudden left acute dyspnea due to sudden left ventricular failure.ventricular failure.

Renal CrisisRenal Crisis

Microscopic hematuria and low-grade Microscopic hematuria and low-grade proteinuria within several days or proteinuria within several days or weeks along with rapidly increasing weeks along with rapidly increasing serum Cr, oliguria or anuria.serum Cr, oliguria or anuria.

Risks: diffuse skin disease, new Risks: diffuse skin disease, new unexplained anemia, use of steroids, unexplained anemia, use of steroids, pregnancy, and anti-RNA polymerase III pregnancy, and anti-RNA polymerase III AbAb

Poorer outcome in males, older, Cr >3 Poorer outcome in males, older, Cr >3 mg/dlmg/dl

Microangiopathic hemolytic anemia with thrombocytopenia frequently occurs

Non renal crisis abnormalities: Mild proteinuria, mild elevation in the plasma

creatinine concentration, and/or hypertension are observed in as many as 50% of patients.

Impaired renal reserve may be present in patients in the absence of clinical renal disease.

Clinically evident disease is less common, but autopsy studies suggest that 60% to 80% of patients with dcSSc have pathologic evidence of renal involvement

TreatmentTreatment Prompt detection is the most important aspect of Prompt detection is the most important aspect of

therapy for renal crisis. therapy for renal crisis.

Patients with early dcSSc are advised to take Patients with early dcSSc are advised to take their blood pressure every several days to weekly their blood pressure every several days to weekly and to report a rise of systolic pressure of 30 mm and to report a rise of systolic pressure of 30 mm Hg or greater.Hg or greater.

ACE inhibitors are the drugs of choice, but early ACE inhibitors are the drugs of choice, but early aggressive therapy with other potent aggressive therapy with other potent antihypertensive agents can also be successful. antihypertensive agents can also be successful.

Some patients may require dialysis, but most can Some patients may require dialysis, but most can be maintained on ACE inhibitors, and dialysis be maintained on ACE inhibitors, and dialysis can be discontinued after 3 to 24 months.can be discontinued after 3 to 24 months.

Successful renal transplants have been reported.Successful renal transplants have been reported.

CardiacCardiac Primary cardiac involvement: myocardial

fibrosis, LV or biventricular CHF, myocarditis, pericarditis with or without effusion, valvular abnormalities, or supraventricular or ventricular arrhythmias.

Acute symptomatic pericarditis is unusual.

Left sided congestive heart failure secondary to myocardial fibrosis occurs in fewer than 5% of dcSSc patients.

CardiacCardiac Cardiac arrhythmias include complete

heart block and other EKG abnormalities.

Valvular disease usually minor, not hemodynamically significant.

Secondary cardiac disease occurs in association with SSc pulmonary or renal disease or in overlap with other illnesses such as systemic lupus erythematosus or polymyositis.

TreatmentTreatment Nonsteroidal anti-inflammatory drugs or low-dose

corticosteroids can be used for symptomatic pericarditis.

If myocarditis is identified clinically or by endomyocardial biopsy, high-dose glucocorticoid therapy should be tried.

Digitalis and diuretics are the mainstay of therapy.

The typical progressive left ventricular failure caused bymyocardial fibrosis is unaffected by any therapy and may lead to cardiac transplantation.

Serious arrhythmias are treated in the standard way

MSKMSK Manifestations may include muscle weakness

and rheumaticcomplaints ranging from simple arthralgias to frank arhtritis.

In dcSSc, symptoms often start with symmetric polyarthralgia and joint stiffness (with or without gross synovitis), myalgia, and puffiness of the skin.

Joint pain, immobility, and contractures are the result of fibrosis around tendons and other periarticular structures.

Contractures of the hands from this process are most common, but large joint contractures involving the wrists, elbows, hips and ankles may also occur.

MSKMSK Some patients may have palpable and/or audible

deep periarticular tendon friction rubs during motion; this may be due to fibrinous tenosynovitis.

Severe arthritis or destructive joint disease should make one suspect an overlap syndrome with rheumatoid arthritis.

2 principal patterns of muscle involvement Scleroderma myopathy, frequently mild and relatively

nonprogressive, p/w minor proximal weakness and slight to moderate elevations of CPK

Sclerodermatomyositis, a true overlap between scleroderma and polymyositis

Far less common. Weakness is often more profound, with significantly

elevated CPK and EMG/muscle biopsy abnormalities typical for inflammatory myopathy.

NeuroNeuro Neurologic involvement occurs in up to

40% of patients with SSc.

Manifestations include cranial nerve abnormalities, peripheral nerve involvement, and autonomic neuropathy.

Central nervous system involvement is usually secondary to SSc renal or cardiopulmonary involvement.

Neuropathy can be asymptomatic or can be life-threatening if autonomic nervous system is involved.

Disease Modifying TreatmentsDisease Modifying Treatments While some treatments have proven effective in While some treatments have proven effective in

treating the disorder, scleroderma is not yet treating the disorder, scleroderma is not yet curable. curable.

Much research has gone into addressing the Much research has gone into addressing the various manifestations of the disease, but no various manifestations of the disease, but no drug has been found that can arrest or reverse drug has been found that can arrest or reverse the skin thickening that is the hallmark of the skin thickening that is the hallmark of disease.disease.

Treatments are disease modifying vs. Treatments are disease modifying vs. symptomatic (by organ system affected) as symptomatic (by organ system affected) as presentedpresented

DMARDs can be selected on basis of other DMARDs can be selected on basis of other coexisting conditions if there is disease overlapcoexisting conditions if there is disease overlap

Suppression of autoimmunity and Suppression of autoimmunity and inflammationinflammation

CyclophosphamideCyclophosphamide: : data NIH randomized, double-blind, placebo-controlled trial (The Scleroderma Lung Study) showed beneficial effects of cyclophosphamide over placebo in SSc patients with active alveolitis. Treatment had a modest effect on pulmonary

function, a larger effect on pulmonary symptoms and a clear, and a statistically significant effect on skin in patients with diffuse skin involvement.

MTXMTX ChlorambucilChlorambucil 5-FU5-FU Stem cell transplantStem cell transplant

Since 1996, autologous peripheral blood stem cell (PBSC) transplantation used worldwide with a low early mortality of 5%

Based on these data, intensive myelo- and immuno suppression followed by autologous hematopoietic stem cell transplantation (HSCT) has been used to treat severe SSC

Since 1996, approx 1000 PBSC transplants for autoimmune diseases have been reported 140 SSc patients in the EBMT (European Group

for Blood and Marrow Transplantation) and EULAR (European League Against Rheumatism) database as to March 2007.

The early results from the phase I/II clinical trials showed that HSCT is feasible in carefully selected patients with diffuse SSc

2004 follow up report from the EBMT-EULAR database, consisting of different centers and treatment schemes, showed positive responses at 3 years in two thirds of 57 patients with an early treatment related mortality of 8.7%

The specific aims of this study: evaluate the survival and the durability of responses up to 7 years of follow-up in SSc patients treated by autologous HSCT. Long-term follow up results of all the

Dutch and French patients included in two similar phase I/II trials, using uniform eligibility criteria and a single transplantation protocol

Patients and MethodsPatients and Methods All patients-ACR preliminary criteria

for SSc and had the diffuse cutaneous form.

Patients eligible if : (a) age < 66 years

(b) rapidly progressive disease (2 years duration with a modified Rodnan skin score (mRSS) above 20,

ESR > 25 mm/first h and/or Hb < 11 g/dL, not explained by other causes than active SSc

Patients and MethodsPatients and Methods OR (c) a disease duration >2 years plus a

progression of the mRSS (20%) plus major organ involvement related to SSc as defined by either: (1) lung involvement: with a vital capacity (VC) or

DLCO below 70% predicted, or a mean pulmonary artery pressure (PAP) above 40 mmHg (measured by echocardiography);

(2) digestive tract involvement: with serum albumin <25 g/L or weight loss exceeding 10% body weight in the preceding year;

(3) kidney involvement: with 24-h urinary protein above 0.5 g or serum creatinine above 120 mmol/L.

Exclusion Criteria Uncontrolled arrhythmia, left ventricular

ejection fraction (LVEF) <50% or mean PAP >50 mmHg measured by ECHO

DLCO <45% of predicted, creatinine clearance <20 ml/min

Platelets <80 000/mm3, hemorrhagic cystitis, HIV or HTLV1 seropositivity, malignancy, pregnancy, a cardiac or vascular prosthesis, and no vascular access

After a median follow-up of 5.2 (1–7.5) years, death from disease progression occurred in 2 patients (8%): both from relapse at 18 months after transplantation, one after initial PR and the other after initial MR. A third patient, a heavy smoker, died from small cell

lung cancer 64 months after HSCT.

Among the others showed 35% (n=9) sustained MR, 50% (n=13) sustained PR, and 3% (n=1) progressed after PR.

Event-free survival (EFS) for the patients with at least 6 months of follow-up after autologous HSCT was 64.3% (95% CI 47.9–86.3%) at 5 years and 57.1% (95% CI 39.3–83.1%) at 7 years

ResultsResults The WHO performance status improved

throughout the follow up, from baseline values at median 2.12 (0–4, n=26) to 0.60 (0– 2, n=15 p,0.05) after 5 years of follow-up (fig 2).

A significant fall in mRSS was observed up to 7 years after HSCT with faster regression within the first year and sustained fall thereafter.

In comparison with baseline values for all patients, there was no significant change in FEV1 or DLCO during follow-up. Cardiac and renal function remained stable during follow-up

Benefits and SurvivalBenefits and Survival After a median follow-up of 5.3 (1–7.5) years 81%

(n=21/26) of the patients demonstrated a clinically beneficial response.

The Kaplan–Meier estimated survival at 5 years was 96.2% (95% CI 89–100%) and at 7 years 84.8% (95% CI 70.2–100%) and event-free survival, defined as survival without mortality, relapse or progression of SSc, resulting in major organ dysfunction was 64.3% (95% CI 47.9–86%) at 5 years and 57.1% (95% CI 39.3–83%) at 7 years.

The positive effect of HSCT on survival rate needs to be interpreted with care, due to a wide range in the duration of patients’ follow-up and the uncontrolled nature of this study, but the results are encouraging.

Agents to inhibit fibrosisAgents to inhibit fibrosis

Gamma interferonsGamma interferons Interferon alphaInterferon alpha D-penicillamineD-penicillamine RelaxinRelaxin

Prevention of vascular Prevention of vascular damagedamage

Prostacyclin analogProstacyclin analoge: poprostenol and treprostinil, benefit exercise capacity, dyspnea score, cardiopulmonary hemodynamics, and survival. The inhaled form of Iloprost, another prostacyclin

derivative, is also available in the United States. Data supporting the use of Iloprost in SSc PAH are

mostly symptomatic

Bosentan: Bosentan: oral mixed endothelin A/B antagonist, which improves PAH because it antagonizes endothelin-1, a potent vasoconstrictor and smooth muscle mitogen. Two randomized, placebo-controlled studies have

shown that bosentan improves exercise capacity, cardiopulmonary hemodynamics, decreased pulmonary vascular resistance, and decrease pulmonary artery pressure.

Prevention of vascular Prevention of vascular damagedamage

Sildenafil: Sildenafil: phosphodiesterase-5 inhibitor causes preferential pulmonary vasodilation, decreases pulmonary vascular resistance index, and improves gas exchange in patients with severe lung fibrosis and secondary pulmonary hypertension

ACE-I: ACE-I: despite rising serum creatinine concentrations while taking an ACE inhibitor, the drug should be continued as part of the antihypertensive therapy.

These treatments, and those being These treatments, and those being tested in current research trials, tested in current research trials, may provide significant benefit to may provide significant benefit to patients with lung disease in patients with lung disease in scleroderma.scleroderma.

The basic process of fibrosis awaits proven effective therapy.

Case ReportCase Report 65-yr-old Korean female visited the 65-yr-old Korean female visited the

Rheumatology Clinic due to the thickening of Rheumatology Clinic due to the thickening of hand and facial skin with digital pallor and hand and facial skin with digital pallor and cyanosis on cold exposure x 2 mo.cyanosis on cold exposure x 2 mo.

On the first visit, BP 130/80 mmHgOn the first visit, BP 130/80 mmHg PE: skin thickening on the fingers of both PE: skin thickening on the fingers of both

hands, and on the right hand dorsum and hands, and on the right hand dorsum and right forearm. right forearm.

She was diagnosed with systemic sclerosis of She was diagnosed with systemic sclerosis of the limited cutaneous subsetthe limited cutaneous subset

J Korean Med Sci. 2006 Dec;21(6):1121-1123.A Case of Renal Crisis in a Korean Scleroderma Patient with Anti-RNA polymerase I and III Antibodies

WBC 8.39×109/L, Hgb 12.1 g/dL, platelets WBC 8.39×109/L, Hgb 12.1 g/dL, platelets 240×109/L240×109/L

ESR 8 mm/hr, ALT 21U/L, AST 18 U/L, total ESR 8 mm/hr, ALT 21U/L, AST 18 U/L, total bilirubin 0.6 mg/dL, albumin 3.7 g/dL, BUN 11 bilirubin 0.6 mg/dL, albumin 3.7 g/dL, BUN 11 mg/dL, and creatinine 0.7 mg/dL. mg/dL, and creatinine 0.7 mg/dL.

ANA+, but anti-centromere and anti-SCL-7- negative. ANA+, but anti-centromere and anti-SCL-7- negative.

PFTs: FVC 73%; forced expiratory volume in 1 sec, PFTs: FVC 73%; forced expiratory volume in 1 sec, 79%; and DLCO 121%. 79%; and DLCO 121%.

High resolution CT of the lungs revealed old TB in the High resolution CT of the lungs revealed old TB in the right lower lobe with pleural thickening and right lower lobe with pleural thickening and calcifications without evidence of interstitial lung calcifications without evidence of interstitial lung disease. disease.

Prazosin 1 mg/day was administered for Raynaud's Prazosin 1 mg/day was administered for Raynaud's phenomenon and intermittent antihistamines for skin phenomenon and intermittent antihistamines for skin pruritus.pruritus.

Twenty- two months after the diagnosis of limited SSc, Twenty- two months after the diagnosis of limited SSc, her skin thickening began to rapidly progress above her skin thickening began to rapidly progress above elbows and knees, and finally involved the trunk. elbows and knees, and finally involved the trunk.

Blood pressure was in the normal range. Blood pressure was in the normal range.

The diagnosis was converted to SSc of the diffuse The diagnosis was converted to SSc of the diffuse cutaneous subset and she was started on D-cutaneous subset and she was started on D-penicillamine 250 mg/day. penicillamine 250 mg/day.

A month later, she visited the emergency room due to A month later, she visited the emergency room due to the sudden onset of facial edema and severe dyspnea. the sudden onset of facial edema and severe dyspnea. Her blood pressure was 220/134 mmHg, heart rate Her blood pressure was 220/134 mmHg, heart rate

120 beats/ min, respiration rate 48/min, and body 120 beats/ min, respiration rate 48/min, and body temperature 35℃.temperature 35℃.

She reported that the dyspnea had begun 10 days She reported that the dyspnea had begun 10 days previously and that her urine output had decreased previously and that her urine output had decreased markedlymarkedly. .

A physical examination revealed facial and pre-tibial A physical examination revealed facial and pre-tibial edema, and pulmonary rales in the whole lung field. edema, and pulmonary rales in the whole lung field.

Laboratory data showed hemoglobin at 9.9 g/dL, LDH Laboratory data showed hemoglobin at 9.9 g/dL, LDH 703 IU/L, total bilirubin 2.9 mg/dL, indirect bilirubin 703 IU/L, total bilirubin 2.9 mg/dL, indirect bilirubin 1.8 mg/dL, and 1.8 mg/dL, and schistocytes with schistocytes with polychromasia on peripheral blood smear, polychromasia on peripheral blood smear, suggesting intravascular hemolysissuggesting intravascular hemolysis. .

Antineutrophil cytoplasmic antibody was negative. Antineutrophil cytoplasmic antibody was negative.

Urinalysis and microscopic examination showed mild Urinalysis and microscopic examination showed mild proteinura (1+), hematuria (≥100 RBC per high proteinura (1+), hematuria (≥100 RBC per high power field with dysmorphic RBC >90%), and pyuria power field with dysmorphic RBC >90%), and pyuria (20-29 white blood cells per high power field). (20-29 white blood cells per high power field).

Urine culture grew no organisms. Urine culture grew no organisms.

Azotemia was also detected with a BUN of 31 Azotemia was also detected with a BUN of 31 mg/dL and a creatinine of 2.2 mg/dL. mg/dL and a creatinine of 2.2 mg/dL.

CXR: cardiomegaly and bilateral hilar CXR: cardiomegaly and bilateral hilar infiltrates consistent with pulmonary edema. infiltrates consistent with pulmonary edema.

She was transferred to intensive care unit, She was transferred to intensive care unit, intubated, and assisted with a mechanical intubated, and assisted with a mechanical ventilator. ventilator.

Under a diagnosis of scleroderma renal Under a diagnosis of scleroderma renal crisis, captopril was begun, but failed to crisis, captopril was begun, but failed to reverse a deteriorating renal function despite reverse a deteriorating renal function despite successful blood pressure control within 2 successful blood pressure control within 2 days. days.

Renal biopsy showed severe fibrinoid necrosis Renal biopsy showed severe fibrinoid necrosis with luminal obliteration in interlobar arteries with luminal obliteration in interlobar arteries and arterioles, strongly suggesting scleroderma and arterioles, strongly suggesting scleroderma renal crisisrenal crisis

Immunofluorescence staining showed no Immunofluorescence staining showed no evidence of immune complex or autoantibody evidence of immune complex or autoantibody deposition. deposition.

Because scleroderma renal crisis has been Because scleroderma renal crisis has been reported to be associated with anti-RNAP I or III reported to be associated with anti-RNAP I or III antibodies, pt was tested and, anti-RNAP I/III antibodies, pt was tested and, anti-RNAP I/III antibodies were detectedantibodies were detected

Hemodialysis was started and has been Hemodialysis was started and has been continued for 3 yr without renal recovery.continued for 3 yr without renal recovery.