Systemic Sclerosis (ss.pptx):This presentation explores systemic sclerosis (scleroderma)

SYSTEMIC SCLEROSIS
Dr Rawand Alardah
6th
year medical student / HU

What is SSc?
• SSc, commonly referred to as scleroderma, is a rare and
potentially devastating systemic autoimmune disease
• characterized by vasculopathy and organ fibrosis.
• Almost all patients with scleroderma have skin thickening
(“sclero” = thick, “derma” = skin), Raynaud’s phenomenon,
and esophageal reflux or dysmotility.
• ILD and pulmonary HTN are the leading causes of
scleroderma-related death.

Why does classification matter

Classification (localized and Generalized)
• Localized scleroderma: dermal fibrosis without internal organ
involvement.
The two types of localized scleroderma are:
1. Morphea: single or multiple plaques, commonly on the trunk.
2. Linear scleroderma: bands of skin thickening commonly located
on the legs or arms, but sometimes on the face (en coup de sabre)
that typically follow a linear path.
• Generalized scleroderma = SSc.
1. Limited cutaneous SSc (lcSSc, limited scleroderma)
2. Diffuse scleroderma (dcSSc)
3. Systemic sclerosis sine scleroderma (ssSSc)

Classification (localized and Generalized)
Limited cutaneous SSc (lcSSc, limited scleroderma):
• Patients with lcSSc have skin thickening limited to the neck, face, or
distal to the elbows and knees.
• Patients with lcSSc may not come to clinical attention until many
years after symptom onset.
• longstanding Raynaud’s phenomenon and (GERD) and may have
telangiectasia, skin calcifications (calcinosis), and digital edema or
sclerodactyly as their only skin manifestations.
• anti-Scl-70 (anti-topoisomerase) antibody is associated with a
high risk for the development of progressive ILD, and the presence
of anticentromere antibody (ACA) carries the highest risk for PAH.
• Renal crisis is exceedingly rare in lcSSc.

Diffuse scleroderma (dcSSc):
• Patients with dcSSc have skin thickening that extends proximal to
the elbows or knees or with truncal involvement.
• In contrast to lcSSc, patients with dcSSc usually present relatively
abruptly.
• Common presenting symptoms include puffy hands, Raynaud’s
phenomenon, arthritis, carpal tunnel symptoms (due to surrounding
edema or inflammation), fatigue, and rapidly progressive skin
thickening.
• These patients often have the onset of Raynaud’s phenomenon
within a year of developing SSc.
• Patients with dcSSc are at a higher risk for progressive ILD and can
also develop PAH. Patients with diffuse skin thickening and a positive
RNA polymerase III antibody are at highest risk of developing SRC.

Systemic sclerosis sine scleroderma (ssSSc):
• Patients with internal manifestations of SSc along with a
scleroderma-specific antibody (such as a nucleolar-pattern
antinuclear antibody [ANA], ACA, anti-Scl-70 antibody, or anti-
RNA polymerase III antibody), but without evidence of skin
thickening, are described as having ssSSc.
Examples of ssSSc include:
• Raynaud’s, digital edema, ILD, and a positive anti-Scl-70 antibody
• Raynaud’s, GERD, PAH, and a positive ACA
• Raynaud’s, renal crisis, and a positive anti-RNA polymerase III
abs.

What is CREST?
• refers to patients with SSc who have clinical manifestations of
calcinosis, Raynaud’s phenomenon, esophageal dysmotility,
sclerodactyly, and telangiectasia.
• The term is somewhat outdated and often misleading as it
may give the wrong impression that it is distinct from SSc, or
represents a mutually exclusive category of SSc (patients with
lcSSc, and to a lesser degree dcSSc, can both have some or all of
these clinical manifestations).
• It is preferable to categorize patients with SSc in to one of three
subgroups (lcSSc, dcSSc, ssSSc), with clear documentation of
clinical manifestations and autoantibody status.

Systemic Sclerosis (ss.pptx):This presentation explores systemic sclerosis (scleroderma)

The Current ACR/EULAR Classification Criteria For Ssc?

Who gets SSc? What is the cause of SSc?
• Mostly seen in women (F:M = 4:1) aged 35 to 64 years.
• It occurs at a younger age in African– American women than in
European–American women.
• Cause is Unknown.
• The etiology of SSc may involve a complex interplay among a genetically-
susceptible host, sex-related factors, and external triggers.
• Pathophysiological mechanisms that may play a role in disease
development include endothelial disruption, platelet activation, fibroblast
proliferation, and increased transforming growth factor-β. Some
environmental factors, particularly silica dust, have been associated with
an increased risk of SSc.

Effective treatments for SSc
• It depends on which aspect of SSc is considered.
• Effective therapies exist for SSc-associated GERD, SRC, and
SSc-associated PAH. Raynaud’s phenomenon often responds
to vasodilator therapy
• However, there remain large unmet needs with regard to
managing the fibrotic aspects of the disease (especially skin
thickening and progressive lung fibrosis), as well as SSc-
associated calcinosis and GI dysmotility.

What Are The Indications For Immunosuppressive
Immunosuppression in SSc is typically reserved for those
with:
• Progressive skin thickening
• Progressive ILD
• Inflammatory myopathy
• Inflammatory arthritis.
As such, many patients with SSc do not require
immunosuppressive/immunomodulatory therapy.

The Chief Causes Of Mortality In Ssc?
• the chief cause of SSc-associated mortality has
dramatically shifted from renal disease to lung and heart
disease, Why?.
• SSc-related deaths, 35% were attributed to ILD, 26% to
PAH, 26% to cardiac (mainly heart failure and arrhythmias),
and only 4% to renal disease.
• The leading causes of non-SSc-related death included
infections (33%), malignancies (31%), and cardiovascular
causes (29%).

Compare organ system involvement in diffuse and limited
SSc

How is the skin affected in SSc?
• The hallmark of scleroderma is thickened skin, thought to
be due to the excessive production of normal type I collagen
by a subset of fibroblasts along with the accumulation of
glycosaminoglycan and fibronectin in the extracellular
matrix.
• There is loss of sweat glands and hair loss in the areas of
tight skin.
• Skin thickening begins on the fingers and hands in virtually
all cases of SSc.

How is skin thickening treated?
Based on limited data, therapeutic options for skin thickening
primarily include mycophenolate mofetil (MMF), methotrexate, or
cyclophosphamide (CYC).
Low-dose prednisone (<15 mg/day) and benzodiazepines can
provide relief for the pruritus associated with the acute phase of skin
thickening and may supplement conservative management with
topical emollients (alcohol free)
Symptoms of pruritus may also be relieved with agents such as
gabapentin or pregabalin

Raynaud’s Phenomenon
• frequently the first symptom of SSc, is an episodic self-
limited and reversible vasomotor disturbance manifested as
color changes bilaterally in the fingers, toes, and sometimes
ears, nose, tongue, and lips.
• The color changes are pallor, cyanosis and then erythema
(white, blue, and then red) that occur sequentially in
response to environmental cold, emotional stress, or
spontaneously.

With new-onset Raynaud’s phenomenon, what
findings would suggest early SSc?
• Positive SSc-specific Abs (nucleolar-staining ANA, ACA, anti-Scl-70, Pm-
Scl, or RNA polymeraseIII antibody).
• Nailfold capillary abnormalities of capillary drop-out or dilatation.
• Tendon friction rubs.
• Digital edema/puffy hands.
• Digital infarctions or ulcerations.
• Dilated, patulous esophagus (esophageal hypomotility).

How is Raynaud’s phenomenon treated?
• First, keep hands and body warm: gloves, exothermic
reaction bags (chemical heat packs), Repeated soaking in
warm water sometimes helps.
• Cigarette smoking exacerbates Raynaud’s phenomenon.
• Various vasodilators can be used in the treatment of
secondary Raynaud’s phenomenon associated with SSc,
including calcium-channel blockers (first-line therapy), ARBs,
antiadrenergic agents (e.g., prazosin), topical nitrates,
phosphodiesterase type-5 inhibitors (sildenafil), and
prostacyclin analogs. In addition, endothelin antagonists may
be helpful in some patients

• Antiplatelet therapy, anticoagulation, statin medications, and
fluoxetine all have evidence of benefit in the treatment of
Raynaud’s.
• Digital ulcers occur in 30% to 40% patients. All the therapies
listed earlier have been used in an attempt to accelerate healing
and prevent recurrence, with varying levels of success.
Bosentan has been shown to reduce the likelihood of new digital
ulcer formation.
• For cases of digit-threatening ischemia, intravenous
prostacyclin can be instituted.

Why is baseline cardiopulmonary testing important in
patients with scleroderma and what testing is
recommended?
All patients with SSc require initial cardiopulmonary assessments and
longitudinal surveillance for development of lung or heart involvement,
as data suggests better outcomes in patients with earlier stage disease.
Baseline testing includes:
• Thoracic high-resolution computed tomography (HRCT) scan.
• Chest X-ray is inadequate.
• Complete PFTs; lung volumes, spirometry, and diffusing capacity for
carbon monoxide [DLco])
• Echocardiography
• Electrocardiogram (EKG) to screen for conduction system abnormalities.

What types of lung disease do SSc patients get
• ILD and PAH are the two most common types of lung
involvement identified in SSc and are the leading causes of SSc-
associated mortality.
• Airways or pleural disease is rare in SSc.
What is the most common ILD pattern seen in SSc?
• Fibrotic Nonspecific Interstitial Pneumonia (NSIP), identified in
about two-thirds of biopsied cases
• Usual Interstitial Pneumonia (UIP), identified in about one-third
of cases

Which Scleroderma Patients Are At High Risk For Progressive ILD?
Patients at highest risk for progressive ILD are those with:
• Positive anti-Scl-70 antibody
• dcSSc
• Isolated nucleolar-staining ANA—that is a nucleolar-staining ANA with a
negative anti-Scl-70. These patients frequently have an anti–U3 RNP or anti-
Th/To antibody. Pm-Scl antibody is a less common autoantibody but can
result in an isolated nucleolar-staining pattern as well.
Monitoring should not be restricted to those with high-risk features only.
When assessed by thoracic HRCT, approximately 75% patients with SSc
have evidence of bibasilar ILD. Clinically significant ILD in only about 20%
to 30%.
Patients with a positive ACA rarely develop progressive ILD.

Does The Presence Of Ssc-ILD Require Treatment?
• ILD requires treatment only when it is “clinically significant” or
progressive in nature.
• The ILD evaluation includes assessment of breathlessness,
determining extent of disease by thoracic HRCT, complete PFT (lung
volumes, spirometry, and DLco) and assessment for oxygen
desaturation with exercise.
• Research has shown that greater extent of involvement on HRCT
(>20%–50% of lung affected) is associated with an increased risk of
progressive ILD (≥10% drop in forced vital capacity [FVC]) as well as a
more robust response to therapy with cyclophosphamide.

How are PFTs and thoracic HRCT scan useful in the
evaluation of patients with SSc?
• Useful in assessing the degree of respiratory impairment due to ILD
and may provide clues about coexistent PAH as well**
• Patients who decline ≥10% of predicted FVC or ≥15% of predicted
DLco are considered to have progressive disease by PFT.
• In patients with SSc-ILD, pulmonary physiology is a stronger predictor
of survival than underlying histopathologic pattern (FVC < 70%: 5-year
survival 60%–65%).
• Important information relevant to SSc-ILD can also be obtained by
HRCT imaging, including the pattern and extent of disease, and an
assessment of disease progression. Patients with >20% of their lung
affected by ILD on HRCT have a poor prognosis (5-year survival 60%).

What are the therapeutic options for progressive SSc-
ILD?
• Based on Scleroderma Lung Studies I and II and Fibrosing Alveolitis
Trial, either cyclophosphamide (CYC) CYC or mycophenolate
mofetil (MMF) MMF are the drugs of choice for patients with
progressive SSc-ILD.
• CYC can be given by monthly intravenous route or daily oral therapy.
Both MMF and CYC are associated with modest improvements in
FVC, degree of fibrosis on HRCT, health-related quality of life.
• In Scleroderma Lung Study II, treatment with MMF for 2 years was
as effective as treatment with oral CYC for 1 year. MMF was safer
and better tolerated. Furthermore, in contrast to CYC, MMF is a
suitable long-term immunosuppressive agent.

• In refractory cases, rituximab, azathioprine, or calcineurin
antagonists (cyclosporine or tacrolimus) may be considered.
• Treatment with autologous HSCT may have beneficial effects on
the ILD component of SSc but is typically reserved for those with
dcSSc who have failed conventional therapies.
• Pirfenidone and nintedanib were each approved by (FDA) in
2014 for the treatment of (IPF). Both drugs were associated with
slowing of lung function decline in those with IPF. Large,
multicenter clinical trials are underway with each agent for the
treatment of SSc-ILD (and other forms of ILD).
• In September of 2019 the FDA approved the use of nintedanib
(either alone or in combination with MMF) for the treatment of
SSc- ILD.

SSc-PAH and its impact on survival.
• The prevalence is estimated to be 10% to 15%.
• Prior to the availability of PAH-specific therapies, the 5-year
survival was 10% for SSc patients with PAH compared with
80% for SSc patients without PAH.
• The presence of advanced disease (functional class III-IV)
portends a particularly poor outcome.

How is PH classified?
The current classification divides PH into five clinical groups:
Group 1: PAH
Group 2: PH associated with left heart disease
Group 3: PH associated with chronic hypoxia (e.g., PH
associated with ILD)
Group 4: Chronic thromboembolic-associated PH
Group 5: PH with unclear or multifactorial mechanisms (e.g.,
sarcoidosis)

What Types Of PH Are Seen In Ssc?
• Patients with SSc most often have PAH (Group 1), but can also have
other types, particularly PH due to left heart disease (Group 2) or PH-
ILD (Group 3).
• A diagnosis of PAH absolutely requires Right heart Catheterization RHC
• PAH is defined by a mean PAP >25 mmHg, (PCWP) of <15 mmHg, and
pulmonary vascular resistance of >3 Wood units.
• In PH due to left heart disease, the elevated pulmonary pressures are a
result of either systolic or diastolic dysfunction and confirmed by an
increased PCWP >15mmHg on RHC.
• With PH-ILD, the elevated pulmonary pressures are considered to be a
result of chronic hypoxia secondary to underlying lung disease.

What are the presenting symptoms and signs of
PAH?
• Dyspnea and fatigue are the two most common symptoms
of PAH; both are unreliable among patients with scleroderma.
It is important for all scleroderma patients to undergo PAH
screening, including patients who do not report dyspnea.
• There are few signs of early PAH on physical examination, but
several important exam findings suggest advanced PAH (i.e.,
features of right heart dysfunction including lower extremity
edema, the murmur of tricuspid regurgitation, jugular
venous distension, hepatomegaly, and right ventricular
heave).

Risk Factors For PAH In Ssc.
• lcSSc (especially longstanding disease).
• Duration of Raynaud’s (longer duration = higher risk).
• ACA.
• Isolated nucleolar-pattern ANA.
• Extensive telangiectasia.
• DLco <60% in the absence of extensive ILD or other cause of low
DLco (e.g., emphysema, as described in some SSc patients with
combined pulmonary fibrosis & emphysema).
• FVC%/DLco% ratio > 1.6 (meaning a disproportionately low DLco).

What specific clinical, echo, PFT, and biomarker
findings suggest PAH in a patient with SSc?
• The best predictor for the development of PAH in scleroderma is
declining DLco.
• The DLco is usually very low (<50% predicted) at the time of diagnosis of
SSc-PAH, and this is generally in the absence of significant ILD.
• Restrictive physiology (i.e., reductions in total lung capacity or FVC) is seen
with ILD, while A disproportionate decline in the DLco relative to the
FVC, as demonstrated by FVC%/DLco% ratio > 1.6, is a strong predictor
of PAH development.
• All scleroderma patients should have a baseline set of complete PFTs
including DLco, and these should be repeated yearly in most patients.

• Baseline echocardiogram is recommended in all SSc patients and
should be repeated yearly in most patients.
• Features on echocardiography that suggest the presence of
PH include: right atrial dilation, right ventricular dilation, right
ventricular dysfunction, flattening of the interventricular
septum, pericardial effusion, or elevated estimated right
ventricular systolic pressure (RVSP).
• Echocardiographic views of the right side of the heart can be
limited by technical issues (body habitus, etc.) and up to 15% of
patients do not have a visible tricuspid regurgitation jet, there by
cannot allowing for RVSP estimation.
• Elevated (BNP) and N-terminal-pro-BNP (NT-proBNP) are surrogate
biomarkers for myocardial disease and are frequently elevated in
patients with SSc-PAH.and are associated with a worse prognosis.

What is the “gold standard” test for
confirming PAH?
• RHC is the gold standard test for the diagnosis of PH and is absolutely
required to confirm the diagnosis of PAH.
• If any patient with scleroderma has unexplained dyspnea with an
echocardiogram showing an estimated RVSP >40 mmHg or evidence of
right ventricular dilatation or hypokinesis, RHC should be strongly
considered.
• RHC should also be strongly considered in a scleroderma patient with
any risk factors for PAH, particularly those with a disproportionately low
DLco of <60% or FVC%/DLco% ratio >1.6, with unexplained dyspnea,
findings of right heart compromise on physical examination, oxygen
desaturation on exercise, right heart abnormalities on echocardiogram,
an elevated BNP, or NT-proBNP, even with a normal estimated RVSP.

Are there effective PAH therapies?
• Yes. Conventional therapy for PAH typically includes treatment
with:
• calcium channel blockers
• fluid/volume control (diuretics, fluid restriction, low salt diet)
• supplemental oxygen.
• Chronic anticoagulation with warfarin was classically
administered as an adjunctive therapy for idiopathic PAH, but
its use is controversial in SSc-associated PAH**

PAH-specific therapies
• There are three categories of PAH-specific therapies, each representing a
novel pathophysiologic pathway:
• prostacyclins (inhaled [ilioprost], oral [treprostinil], subcutaneous or
intravenous [epoprostenol, treprostinil])
• oral endothelin receptor antagonists (bosentan, ambrisentan, macitentan)
• nitric oxide potentiators (oral phosphodiesterase-type 5 inhibitors
[sildenafil, tadalafil] or guanylate cyclase stimulator [riociguat]).
• Recent data from the AMBITION trial demonstrated that initial
combination therapy with an endothelin receptor antagonist
(ambrisentan) and a phosphodiesterase-type 5 inhibitor (tadalafil) was
associated with less clinical deterioration than treatment with either agent
alone, without an increase in the side-effect profile.

Heart Involvement In Ssc
• Myocardial, pericardial, or conduction system disease are all potential cardiac
complications associated with SSc.
• Diastolic dysfunction is one of the more common cardiac manifestations of SSc
and can lead to PH due to left heart disease.
• Cardiomyopathy can be difficult to distinguish from ischemic cardiomyopathy;
cardiac MRI SSc-cardiomyopathy typically have evidence of an infiltrative or
fibrotic process.
• Pericardial effusions are almost always asymptomatic, are associated with the
presence of PH, and do not require specific intervention.
• Symptomatic, inflammatory pericarditis is rare and may be treated with NSAID,
low-dose corticosteroids, or colchicine.
• CAD is increased in SSc.
• In general, cardiac disease in SSc is associated with a poor prognosis,
accounting for 26% of all SSc-related deaths and 29% of non–SSc-related deaths.

What is scleroderma renal crisis (SRC)?
• Renal failure, one of the most feared complications of SSc, may
present as acute renal crisis after prolonged hypertension and less
commonly as normotensive renal failure.
• Renal crisis may be the presenting manifestation of SSc and can
sometimes precede skin thickening.
• SRC occurs in up to 5% of the entire SSc population and in 5% to
20% of patients with dcSSc.
• Generally, renal crisis occurs early in the course of the disease,
with a mean onset of 3.2 years and more often in the fall and
winter months.

What is scleroderma renal crisis (SRC)?
• Patients with early diffuse skin thickening, especially patients
with RNA polymerase III antibody positivity, are at highest risk
for SRC and vigilant surveillance is indicated.
• Serologically, RNA polymerase III antibody conveys a higher risk
of SRC (present in 50% of cases of SRC, but <20% of SSc overall).
• SRC typically presents with an abrupt onset of arterial
hypertension (>150/90; although 10% are normotensive),
appearance of grade III (flame-shaped hemorrhages and/or
cotton-wool exudates) or grade IV (papilledema) retinopathy, and
the rapid deterioration of renal function (within a month).
Pericardial effusion is frequently present.

• Abnormal laboratory tests include elevated renal function tests,
proteinuria, consumptive thrombocytopenia, microangiopathic
hemolysis (schistocytes; 50%), elevated renin levels (twice the
upper limit of normal or greater), and normal or only mildly
decreased ADAMTS 13 levels (>20% of normal). This latter test may
be important given the similar clinical presentation of TTP/HUS and
SRC.
• In addition, a subset of patients with SSc may suffer acute renal
failure secondary to an (ANCA)-associated glomerulonephritis,
another potential mimicker of SRC***.
• Approximately 50% of patients who develop SRC will require
dialysis, but nearly half of these patients will be able to discontinue
dialysis after 3 to 18 months on ACE inhibitor therapy.
• Five-year mortality is still significant and ranges from 20% to 40% in
the literature.

How we avoid renal failure in patients with
SSc?
• The use of ACE inhibitors has dramatically changed the
outcome of renal involvement in SSc.
• Captopril and enalapril are the most studied ACE inhibitors
in scleroderma, but probably any of the ACE inhibitors are
effective.
• Angiotensin II receptor antagonists have not been proven
effective in treating SRC.
• There is no data to support prophylactic ACE inhibitor
therapy in patients with SSc***.

What Are Risk Factors For SRC?
• Early diffuse scleroderma (first 1–4 years after diagnosis).
• Tendon friction rubs.
• Corticosteroid (prednisone > 20 mg/day or prolonged low
dose) or cyclosporine use.
• Anti-RNA polymerase III antibody (50%–60%).

How is SRC treated?
• Patients with SRC should be hospitalized.
• They should be put on a short-acting ACE inhibitor with the goal of
decreasing systolic blood pressure by 20 mmHg within the first 24
hours. Hypotension should be avoided.
• The ACE inhibitor should then be maximized to normalize the blood
pressure.
• Up to 30% of patients will have continued blood pressure elevation on
ACE inhibitors. These patients should have calcium channel blockers
added as second-line therapy, followed by angiotensin-receptor
blockers.
• Endothelin receptor antagonists and prostacyclins have also been tried.

What Are Poor Prognostic Signs?
• Poor prognostic factors include: (1) male gender, (2) initial
creatinine > 3mg/dL, (3) normotensive at onset, and (4)
cardiac involvement with myocarditis or arrhythmias.
• Approximately 50% to 60% patients will require dialysis
within the first 24 months, with half of those recovering
enough renal function to stop dialysis. Therefore, ACE
inhibitor therapy should be continued indefinitely even in
patients who have progressed to dialysis, and kidney
transplantation should be delayed at least 24 months.

What are the GI manifestations of SSc?
• Upper GI tract: GERD (heartburn), hypomotility, dysphagia,
nausea, stricture formation, risk of Barrett’s esophagus (10%–
15%), gastric antral vascular ectasia (GAVE). Cough due to
aspiration is a common symptom associated with GERD.
Calcium channel blockers used to treat Raynaud’s can make
GERD worse.
• Lower GI tract: Hypomotility, bloating, nausea, small
intestinal bacterial overgrowth (manifested by fluctuating
constipation and diarrhea), malabsorption, intestinal pseudo-
obstruction, loss of rectal sphincter tone with resultant fecal
incontinence, and rectal prolapse.

Discuss the pathophysiologic
progression of GI involvement in SSc.
• First, there is neural dysfunction thought to be due to
arteriolar changes of the vasa nervorum leading to
dysmotility.
• Second, there is smooth muscle atrophy.
• Third, there is fibrosis of the smooth muscle.

How are upper GI tract manifestations assessed in
patients with SSc?
• Esophageal dysmotility may be documented by manometry,
barium swallow.
• A dilated, patulous esophagus is a frequent incidental finding
noted on thoracic CT scans of patients with SSc.
• Endoscopy is used to assess reflux esophagitis, candidiasis,
Barrett’s esophagus, and strictures of the lower esophageal area.
Patients who develop Barrett’s esophagitis are at risk for
developing adenocarcinoma and will need surveillance
endoscopies every 1 to 2 years depending on the presence of
dysplasia.
• GERD treatment??

What is a “watermelon stomach”?
• Watermelon stomach is a descriptive
term for GAVE and is the result of
extensive and prominent telangiectasia
involving the gastric mucosal surface.
• This can be a cause of chronic iron
deficiency anemia and acute upper GI
bleeding in scleroderma.
• Laser treatment or argon plasma
coagulation are effective treatments for
GAVE.

Patients with SSc may have small and large bowel
involvement.
• Involvement of the small intestine (17%–57% patients) and colon (10%–50%
patients) is common.
• The major manifestations are due to diminished peristalsis with resulting stasis
and dilatation. can lead to bacterial overgrowth . Later, malabsorption can be a
major problem (low albumin, low B6/B12/folate/25-OH vit D, high fecal fat, high INR
due to low vitamin K).
• Patients may report abdominal distention and pain due to dilated bowel,
obstructive symptoms from intestinal pseudo-obstruction, or diarrhea from
bacterial overgrowth or malabsorption
• Patients with large bowel involvement affecting the anorectum can suffer from
debilitating fecal incontinence. This may be due to a neuropathy more than
sphincter atrophy/fibrosis.
• Atrophy and thinning of the muscular wall in the colon can lead to “wide mouth”
diverticulae. It should be emphasized that barium studies are relatively
contraindicated in SSc patients with poor GI motility owing to the risk of barium
impaction. Rectal prolapse has also been reported.

Management of small and large bowel problems?
Intestinal dysmotility/constipation
• Stimulation of gut motility with domperidone, metoclopramide, or
erythromycin can be given 30 minutes before meals to stimulate gut
motility. .
• Injectable octreotide may help in severe or refractory cases.
• Fiber may help colonic dysmotility. dietary fiber intake through 100%
whole grain products, fruits, and vegetables is generally safe and
recommended.
• Maintaining exercise may help move food through the digestive tract.

Diarrhea
Diarrhea is commonly treated initially as if it were due to bacterial overgrowth.
• An antibiotic is given that can partially decrease the gut flora, such as rifaximin (550 mg
thrice a day [TID]), ciprofloxacin (500 mg twice a day [BID]), amoxicillin-clavulanic acid
(875 mg BID), or metronidazole (500 mg TID) for 10 days.
• Agents that slow intestinal motility, such as paregoric or loperamide, should be avoided.
• If the diarrhea persists, a malabsorption work-up should be pursued. Most patients with
malabsorption can be treated with supplemental vitamins, minerals.
• Dietary modification (for symptoms of bloating, alternating diarrhea, and constipation):
patients may consider removing specific food that may be more difficult to digest (e.g.,
gluten and lactose). A food diary may allow patients to identify specific triggers.
• Some patient advocacy groups suggest a low FODMAP (fermentable, oligosaccharides,
disaccharides, monosaccharides, and polyols) diet.

Rectal involvement
• Fecal incontinence is treated with sacral nerve stimulation (limited
data on tibial nerve stimulation), and/or surgical repair.
• Rectal prolapse includes management of constipation and
possibly surgical correction.

What Is Calcinosis?
• Calcinosis consists of cutaneous deposits of basic calcium
phosphate that characteristically occur in the hands (especially
over the PIP joints and fingertips), periarticular tissue, and over
bony prominences elbows and knees), but can occur anywhere
on the body.
• The deposits of calcium are firm, irregular, and generally
nontender, ranging in diameter from 1 mm to several
centimeters.
• They can become inflamed, infected, or ulcerated and may
discharge a chalky white material.
• Calcinosis can be persistent for years. It is extremely difficult
to treat, and no therapy is consistently successful.

What are telangiectasia?
• Telangiectasia are dilated venules, capillaries, and arterioles.
• In SSc they tend to be oval or polygonal macules 2 to 7 mm
in diameter found on the hands, face, lips, and oral mucosa.
• They are seen more commonly with limited SSc.
• Telangiectasia are usually harmless but can be a cosmetic
problem. They may disappear spontaneously over time.
• Laser therapy has been used to remove them with some
success, but commonly they will return.
• In the GI mucosa (called “watermelon stomach” or GAVE).

The Bone And Articular Involvement In
Ssc.
• Bone involvement is usually demonstrated by resorption of bone.
Acrosclerosis with osteolysis is common.
• Arthralgias and morning stiffness are relatively common, but
erosive arthritis is rare.
• Hand deformities and ankylosis are seen, but these are usually
attributed to the tethering effects of skin thickening instead
of joint involvement.
• Tendon sheaths can become inflamed and fibrinous, mimicking
arthritis. Tendon friction rubs can be palpated typically over the
wrists, ankles, and knees and are found primarily in patients with
diffuse SSc (50%–65%).

The Three Types Of Muscle Abnormalities In Ssc.
1. Mild proximal weakness due to a noninflammatory benign
myopathy. On histology: normal or shows a type 2 muscle fiber
atrophy. This pattern also seen with inactivity and steroid use. The
muscle enzymes are typically normal.
2. Mild elevation of muscles enzymes with waxing and waning of
symptoms. Muscle biopsy; interstitial fibrosis and fiber atrophy.
Minimal inflammatory cell infiltration. Should not be treated with
corticosteroids.
3. Inflammatory type of myopathy with elevated muscle enzymes (as
seen with polymyositis). These considered to have an overlap
syndrome, and many fit the definition of MCTD. Should be treated with
immunosuppressive therapy.

What clinical characteristics help separate
conditions that mimic scleroderma from SSc?
- Lack of Raynaud’s phenomenon.
- Lack of nailfold capillary abnormalities including dilatation and
dropout.
- Lack of positive antinuclear antibody (90%–95% of SSc).
- Lack of progression of cutaneous sclerosis in a centripetal
(“center-seeking”) fashion (e.g., finger and toe involvement first,
spreading proximally).
- Lack of characteristic organ involvement associated with SSc
(e.g., patulous esophagus, interstitial lung disease, cutaneous
telangiectasia).

MORPHEA (LOCALIZED SCLERODERMA)
• Localized scleroderma is a local fibrosing condition that
commonly lacks systemic organ involvement and as such
should not be considered part of the spectrum of SSc.
• The term morphea may be preferred over the term localized
scleroderma to help avoid potential confusion.
• Do patients with morphea commonly evolve into SSc? No.

Clinical Features Often Differ By Disease
Category:
Circumscribed:
• most frequent subtype; comprises most
cases of adults with morphea.
• Can present initially as a well-
circumscribed lesion surrounded by an
erythematous border. Later, the central
portion may become indurated and
sclerotic.
• The lesions can be shiny and may lack hair
and exocrine glands similar to SSc.
• some lesions can present as pink or
hyperpigmented macules and patches that
do not become indurated (superficial
morphea).
.

Clinical Features Often Differ By Disease
Category:
Generalized:
• defined as four or more lesions (>3 cm in
size) that involve two or more anatomic
sites.
• Lesions are often symmetrical and may
coalesce over time.
• Disabling pansclerotic morphea is a
subtype of the generalized morphea
category. This rare subtype occurs in
childhood and can be rapidly progressive,
involving deeper structures to the level of
the bone and resulting in skin necrosis,
open ulcers, muscle atrophy, and joint
contracture. It is associated with an
elevated risk of cutaneous squamous-cell
carcinoma.

• Deep: rarest variant (accounts for 5% of localized
scleroderma); involvement extends beyond epidermis and
dermis, potentially including layers of fat, fascia, and
muscle. Often symmetric; located on the extremities. More
common in childhood.
• Linear (linear scleroderma): most common category among
children. May affect a unilateral limb or less commonly the
scalp and face (en coup de sabre; most commonly in the
region between the eyebrow and the hairline). Linear
scleroderma can extend beyond the skin to fascia, muscle, and
bone leading to tissue atrophy.

+: Commonly reserved for disease that is unresponsive to topical therapy, that extends beyond the dermis, or that
carries risk of
functional impairment.
++: Lesions that are deep but localized may be treated with intralesional steroids.

What is scleredema?
• Scleredema is characterized by firm, nonpitting skin edema
(“woody”) that typically begins on the neck and upper back and
spreads to the shoulders and trunk.
• The face and extremities (typically upper) can also be involved.
The hands and feet are spared.
• The onset of skin involvement can be abrupt.
• Skin biopsy typically shows normal epidermis but thickened
dermis with broad bands of collagen that appear separated on
histology due to mucin deposition between the collagen
bundles.

There are three subtypes of scleredema based on the underlying
cause:
• Type I: scleredema adultorum and scleredema neonatorum
follow an infection or febrile illness, with resolution occurring in
months to years. Female predominance (2:1) with age of onset
commonly <20 years.
• Type II: scleredema with no preceding febrile illness and a
slow, progressive course. There is a female predominance (2:1).
Frequently associated with paraproteinemia (most commonly IgG,
IgA). Progression to multiple myeloma has been reported in 25% to
45% of patients.
• Type III: scleredema diabeticorum occurs in association with
poorly controlled diabetes mellitus (type I or II). There is a male
predominance (10:1), and prevalence of 2% to 10% has been
reported among patients with diabetes.

What is scleromyxedema?
• Scleromyxedema (papular mucinosis) is characterized by a wide-spread
eruption of small (2–3 mm), nonpruritic, waxy papules on the face,
neck, upper trunk, distal forearms, and dorsal surface of the hands
(sparing the palms). Involvement of skin overlying the eyebrows and
forehead can give rise to leonine facies.
• Over 80% of individuals have an IgG monoclonal protein (usually IgG
lambda), with 10% developing multiple myeloma. Thyroid studies are
normal.
• The typical age of onset is 30 to 80 years and men and women are
affected equally.
• Skin biopsies reveal a normal epidermis, a perivascular mononuclear
cell infiltrate, mucin deposition in the papillary dermis, fibroblast
proliferation, and fibrosis. Extracutaneous disease can be common, with
concurrent myopathy, arthralgia/arthritis, and dysphagia, as well as
neurologic, cardiac, pulmonary, and renal involvement.

Eosinophilic Fasciitis (Diffuse Fasciitis With Eosinophilia)
• The mean age of onset is 40 to 50 years, with a slight male
predominance more commonly among Caucasians.

What Are The Three Stages Of EF?
• Stage I: pitting and edema. Disease onset is commonly acute, with
simultaneous involvement of affected areas and rapid spread of skin
disease. The most frequent pattern of involvement includes
bilateral arms and legs (most commonly the calves and
forearms) in a symmetrical fashion with sparing of the fingers
and toes.
• Stage II: the initial manifestations of EF are followed by the
development of severe induration of the skin and subcutaneous
tissues of affected sites. These histologic changes manifest clinically
as a “woody”, firm texture of involved skin, with a coarse orange-
peel appearance (peau d’orange)

What Are The Three Stages Of EF?
The groove sign is an indentation caused by tethering of the dermis
to the fascial and muscular tissue layers along the tract of superficial
veins, and is best seen with elevation of the extremity. Although the
induration often remains confined to the extremities, it may variably
affect extensive areas of the trunk and face. Inflammatory and fibrotic
disease extends to the muscle and can result in a low-grade myositis,
although (CPK) levels are commonly normal.
• Stage III: because of the involvement of the fascia, carpal tunnel
syndrome is an early feature in many patients. Flexion contractures of
the digits and extremities may occur as a consequence of the fascial
involvement. Muscle atrophy can be prominent. Sclerodactyly and
nailfold capillary abnormalities do not occur.

What laboratory and radiographic abnormalities
usually occur in patients with EF?
• Peripheral eosinophilia is present in 80% of patients.
• An elevated erythrocyte sedimentation rate, high C-reactive protein, and a
polyclonal hypergammaglobulinemia are usually present.
• Aldolase can be elevated, whereas CPK is normal in a significant number of
patients.
• (MRI) shows fascial thickening and enhancement of the fascia with
gadolinium.
• It is important to note that as many as 20% of patients with EF do not have
peripheral eosinophilia, and other lab tests may be nondiagnostic as well.
• As such, the diagnosis of EF is a clinical diagnosis based upon the pattern of
skin thickening and confirmed by the presence of fasciitis on full thickness
biopsy. (the biopsy may or may not demonstrate eosinophilic infiltration).

• the diagnosis of EF is confirmed histologically By performing a
full thickness, deep wedge biopsy of an involved area. The
biopsy should be deep enough to acquire skin, subcutis, fascia,
and muscle for the study.
• Although inflammation and fibrosis are generally found in all
layers (except for the epidermis which is normal), they are usually
most intense in the subcutis and fascia****.
• If untreated, fascial inflammation will lead to joint contractures in
85% of patients. In addition, the skin that is initially indurated will
frequently become bound down and develop a peau d’orange
appearance.
• In some patients, the illness is self-limited with spontaneous
improvement. Occasionally, complete remission can occur even
after ≥2 years. Young age at onset and trunk involvement are
poor prognostic signs.

Effective Therapies In Patients With EF
• High-dose prednisone (40–60 mg/day) often results in marked
and rapid improvement in the eosinophilia and gradual
improvement in the fasciitis and contractures in more than
70% of treated patients.
• aim for early initiation of corticosteroids followed by a gradual
taper over 12 to 18 months.
• Some patients may be refractory to prednisone therapy and
require early initiation of immunosuppressive therapy.
• Methotrexate is most often used for treatment-resistant cases
• Physical therapy to minimize flexion contractures is important.

Nephrogenic Systemic Fibrosis
• NSF is a progressive fibrosing disorder occurring in patients
with severe renal disease who have received gadolinium-
containing contrast during an MRI procedure.
• Most patients are dialysis-dependent or have a glomerular
filtration rate of <15 mL/minute (stage 5 chronic kidney disease
[CKD]).
• Rarely, patients may develop NSF with less severe kidney
disease.

• NSF typically presents within 2 to 4 weeks of an at risk patient
receiving gadolinium-containing contrast during MRI.
• Cutaneous features first involve lower extremities and extend proximally.
The face is not involved.
• Patients first experience itching or burning, followed by development of
papules and plaques. Skin may develop a peau d’orange appearance and
“cobblestone” texture over the upper arms, back, and thighs. Skin is very
indurated and may develop hyperpigmentation.
• Flexion deformities of fingers, elbows, and knees are commonly disabling.
Fibrosis of any visceral organ can occur and may be symptomatic.
Raynaud’s phenomenon does not occur

The Therapy And Prognosis Of NSF.
• The best therapy for NSF is prevention.
• Patients with stage 4 and 5 CKD should not receive gadolinium-containing
contrast during MRI.
• In patients with milder forms of renal insufficiency, use of lower-risk
gadolinium-based contrast agents is recommended (macrocyclic chelates)
as they may result in lower concentrations of free gadolinium (Gd+3) ions.
• Once NSF is present, there is no effective therapy. Early renal
transplantation has helped some patients.
• Phototherapy with UVA1, extracorporeal photopheresis, plasmapheresis,
and oral imatinib mesylate have been anecdotally reported as being
effective.
• Patients with NSF have a three-fold increased mortality.

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