Scleroderma, specifically systemic sclerosis, is a complex autoimmune disease characterized by skin hardening and collagen deposition affecting various organs. It has limited and diffuse forms, with varied clinical manifestations including skin tightness, pulmonary hypertension, and gastrointestinal issues. The disease's pathogenesis involves immune dysfunction, collagen deposition, and environmental factors, contributing to its high morbidity and mortality rates.

1. SLERODERMA
Prof Ariyanto Harsono MD PhD SpA(K)

2. Introduction
The term scleroderma is derived from the Greek
words skleros (hard or indurated) and derma
(skin) and it is used to describe a disease
characterized by progressive skin hardening and
induration. Hippocrates first described this
condition as thickened skin.
Prof Ariyanto Harsono MD PhD SpA(K) 2

3. Definition
The term systemic sclerosis is used to describe a
systemic autoimmune disease of unknown origin
characterized by excessive deposition of collagen and
other connective tissue macromolecules in skin and
multiple internal organs, prominent and often severe
fibroproliferative alterations in the microvasculature,
and numerous humoral and cellular immunologic
abnormalities. Although systemic sclerosis is not
inherited, a genetic predisposition plays an
important role in its development.
Prof Ariyanto Harsono MD PhD SpA(K) 3

4.  Systemic sclerosis is a complex and
heterogeneous disease with clinical forms ranging
from limited skin involvement (limited cutaneous
systemic sclerosis) to forms with diffuse skin
sclerosis and severe and often progressive
internal organ involvement (diffuse cutaneous
systemic sclerosis), and occasionally a fulminant
course (fulminant systemic sclerosis).
Prof Ariyanto Harsono MD PhD SpA(K) 4

5.  Limited cutaneous systemic sclerosis involves
areas distal to the elbows and knees but may
involve the face and neck. CREST syndrome
(Calcinosis, Raynaud phenomenon, Esophageal
dysmotility, Sclerodactyly, and Telangiectasias—
although not all are needed for the disorder to
be called CREST) is an older term used to
describe this subset of limited cutaneous
systemic sclerosis.
Prof Ariyanto Harsono MD PhD SpA(K) 5

6.  Diffuse cutaneous systemic sclerosis refers to
skin thickening affecting the trunk and the skin of
the extremities proximal to the elbows and knees
besides involvement of the face. There are rare
cases of typical systemic sclerosis internal organ
involvement in the absence of clinically apparent
cutaneous involvement, a clinical subset known as
“scleroderma sine scleroderma”.
Prof Ariyanto Harsono MD PhD SpA(K) 6

7. Pathophysiology
Systemic sclerosis is a systemic disease that besides the skin
affects numerous organ systems. The pathogenesis of
systemic sclerosis is complex. The clinical and pathologic
manifestations result from three distinct processes:
1) severe fibroproliferative vascular lesions of small arteries
and arterioles,
2) excessive and often progressive deposition of collagen
and other extracellular matrix (ECM) macromolecules in
skin and various internal organs, and
3) alterations of humoral and cellular immunity. It is not
clear which of these processes is of primary importance or
how they are temporally related during the development
and progression of the disease.
Prof Ariyanto Harsono MD PhD SpA(K) 7

8. Overall scheme illustrating a current understanding of SSc pathogenesis. Hypothetical sequence of events involved in tissue fibrosis and
fibroproliferative vasculopathy in SSc. An unknown causative agent induces activation of immune and inflammatory cells in genetically
predisposed hosts resulting in chronic inflammation. Activated inflammatory and immune cells secrete cytokines, chemokines, and growth
factors which cause fibroblast activation, differentiation of endothelial and epithelial cells into myofibroblasts, and recruitment of fibrocytes
from the bone marrow and the peripheral blood circulation. The activated myofibroblasts produce exaggerated amounts of ECM resulting in
tissue fibrosis.
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9. The endothelial cell dysfunction allows the
chemokine- and cytokine-mediated attraction of
inflammatory cells and fibroblast precursors
(fibrocytes) from the bloodstream and bone
marrow and their transmigration into the
surrounding tissues, resulting in the establishment
of a chronic inflammatory process with
participation of macrophages and T and B
lymphocytes, with further production and
secretion of cytokines and growth factors from
these cells.
Prof Ariyanto Harsono MD PhD SpA(K) 9

10. Recent evidence supports the concept that
endothelial dysfunction and fibrosis are closely
related phenomena and it has been suggested
that the vascular alterations, including the
phenotypic conversion of endothelial cells into
activated mesenchymal myofibroblasts, may be
the initiating event and the common
pathogenetic alteration leading to the fibrotic
and chronic inflammatory involvement of
multiple organs.
Prof Ariyanto Harsono MD PhD SpA(K) 10

11. Etiology
The exact etiology of systemic sclerosis is not known. Systemic
sclerosis is not inherited, although a genetic predisposition plays
an important role in its development. Environmental factors (eg,
triggers or accelerators) may contribute to the development of
systemic sclerosis in the proper genetic background. These include
the following:
 Silica exposure
 Solvent exposure (vinyl chloride, trichloroethylene, epoxy resins,
benzene, carbon tetrachloride)
 Radiation exposure or radiotherapy
 Cytomegalovirus, human herpesvirus 5, and parvovirus B19 have
been proposed as viral accelerating factors.
Prof Ariyanto Harsono MD PhD SpA(K) 11

12. Complications
Complications of systemic sclerosis include the following:
o Digital infarctions
o Pulmonary hypertension
o Myositis
o Renal failure
o Wound infections
Prof Ariyanto Harsono MD PhD SpA(K) 12

13. Mortality/morbidity
Systemic sclerosis has the highest case-specific mortality among the systemic
autoimmune diseases. Pulmonary hypertension, pulmonary fibrosis
(interstitial lung disease), and scleroderma renal crisis are the most
frequent causes of mortality.
Survival has improved in recent decades and correlates best with the clinical
disease subtype (diffuse cutaneous vs limited cutaneous) and with the
extent of organ involvement. Five-year survival among patients with
diffuse cutaneous systemic sclerosis has improved significantly, from 69%
in the 1990–1993 cohort to 84% in the 2000–2003 cohort. Five-year
survival among the patients with limited cutaneous systemic sclerosis
remained very high and unchanged for the same periods (93% and 91%,
respectively).
Mortality associated with scleroderma renal crisis has declined significantly
during the last decades, as use of angiotensin-converting enzyme (ACE)
inhibitors. In contrast, pulmonary involvement (interstitial lung disease
and/or pulmonary arterial hypertension) has become the most common
cause of death in patients with systemic sclerosis.
Prof Ariyanto Harsono MD PhD SpA(K) 13

14. Clinical Manifestations
 Skin manifestations
Skin manifestations of systemic sclerosis are as follows:
o Progressive skin tightness and induration, often preceded by swelling and
puffiness (edematous stage) that does not respond to diuretic therapy
o Skin induration initially affects the fingers (sclerodactyly) and extends proximally.
o Tightening of the skin in the face, with a characteristic beaklike facies and paucity
of wrinkles.
o Tightening of the skin in the face is often noted very early in the course of the
disease
o Sclerodactyly with digital ulceration, loss of skin creases, joint contractures, and
sparse hair.
o Prominent skin pigmentary changes both hyperpigmentation and
hypopigmentation
o Anterior chest demonstrating salt-and-pepper hypopigmentation and diffuse
hyperpigmentation in a white woman.
o Diffuse pruritus
Prof Ariyanto Harsono MD PhD SpA(K) 14

15.  Vascular manifestations
o Raynaud phenomenon is part of the initial presentation in 70% of
patients with systemic sclerosis; 95% eventually develop it during the
course of their disease. Raynaud phenomenon may precede obvious
systemic sclerosis features by months or even years.
Raynaud phenomenon that is not associated with systemic sclerosis
or other autoimmune diseases is known as primary Raynaud
phenomenon. It occurs in 5-15% of the general population. The
female-to-male ratio is 4:1, with onset occurring usually during
adolescence.
Other vascular manifestations of systemic sclerosis include the
following:
o Healed pitting ulcers in fingertips
o Large fingertip ulcers may lead to finger amputation
o Cutaneous and mucosal telangiectasias
o Evidence of macrovascular involvement including non-atherosclerotic
myocardial infarction 15

16.  Gastrointestinal manifestations
GI findings in systemic sclerosis include the following:
o Gastroesophageal reflux caused by lower esophageal sphincter (LES)
incompetence and decreased or absent peristalsis in the lower two
thirds of the esophagus (may lead to hoarseness, dysphagia and
aspiration pneumonia)
o Dyspepsia, bloating, and early satiety
o Intestinal pseudo-obstruction
o Constipation alternating with diarrhea from bacterial overgrowth
(may lead to malabsorption)
o Fecal incontinence
o Malnutrition from inadequate caloric intake
o Chronic iron deficiency anemia from occult blood loss
Prof Ariyanto Harsono MD PhD SpA(K) 16

17. Respiratory manifestations
Respiratory compaints in systemic sclerosis include
the following:
o Progressive dyspnea
o Chest pain (precordial) due to pulmonary artery
hypertension
o Dry persistent cough due to restrictive lung
disease
Prof Ariyanto Harsono MD PhD SpA(K) 17

18. Musculoskeletal manifestations
Musculoskeletal complaints in systemic sclerosis
include the following:
o Arthralgia
o Myalgia
o Loss in joint range of motion and joint flexion
contractures
o Tendon friction rubs
o Symptoms of carpal tunnel syndrome
o Muscle weakness
Prof Ariyanto Harsono MD PhD SpA(K) 18

19.  Cardiac manifestations
Cardiac signs and symptoms in systemic sclerosis include the
following:
o Dyspnea due to congestive heart failure or myocardial
fibrosis
o Palpitations, irregular heart beats, and syncope due to
arrhythmias or conduction abnormalities
o Symptoms of congestive heart failure or right sided heart
failure
o Systemic sclerosis is an independent risk factor for acute
myocardial infarction
Prof Ariyanto Harsono MD PhD SpA(K) 19

20. Renal manifestations
Renal signs and symptoms in systemic sclerosis
include the following:
o Hypertension
o Renal crisis
o Chronic renal insufficiency
o History of high dose corticosteroid use.
Prof Ariyanto Harsono MD PhD SpA(K) 20

21. Genitourinary manifestations
Patients with systemic sclerosis may present with
the following:
o Erectile dysfunction
o Bladder fibrosis
o Dyspareunia (if introitus is affected)
o Vaginal narrowing, dryness and pain caused by
vaginal fibrosis
Prof Ariyanto Harsono MD PhD SpA(K) 21

22.  Eyes, ears, nose, and throat manifestations
Patients may present with the following:
Sicca syndrome
o Poor dentition secondary to sicca syndrome
o Loosening of dentition caused by alterations in the tooth
suspensory ligament and thickening of the periodontal
membrane
o Hoarseness due to acid reflux with vocal cord
inflammation or fibrosis
o Decreased oral aperture
o Blindness caused by retinal artery occlusion
Prof Ariyanto Harsono MD PhD SpA(K) 22

23. Neurologic/psychiatric manifestations
Patients may present with the following:
o Facial pain and decreased sensation due to
trigeminal neuralgia
o Hand paresthesias and weakness due to carpal
tunnel peripheral entrapment neuropathy
o Headache and stroke during hypertensive renal crisis
o Depression and anxiety
Prof Ariyanto Harsono MD PhD SpA(K) 23

24. Constitutional manifestations
Constitutional complaints in systemic sclerosis
include the following:
o Fatigue
o Weight loss
o Loss of appetite
Prof Ariyanto Harsono MD PhD SpA(K) 24

25. Physical Examination
 Skin
The skin of the hands may be edematous or swollen early in systemic
sclerosis and the patient may initially report these changes as
puffiness. This edematous stage precedes the indurated sclerotic
stage. Slow progression of the sclerotic phase is associated with a
better prognosis, whereas a rapid progression of cutaneous sclerosis
indicates a worse prognosis and more extensive and severe visceral
organ involvement with an increased risk of renal crisis or interstitial
lung disease and higher mortality.
In the sclerotic phase, the skin appears tight and shiny (see image
below), with a characteristic loss of hair, decreased sweating, and
loss of the ability to make a skin fold. This process of skin thickening
usually begins distally on the fingers (sclerodactyly) and progresses
proximally in a continuous symmetrical fashion.
Prof Ariyanto Harsono MD PhD SpA(K) 25

26. Reduced oral aperture (microstomia) caused by perioral fibrosis
(assessed by measurements of the incisor-to-incisor distance)
Prof Ariyanto Harsono MD PhD SpA(K) 26

27. Tightening of the skin in the face, with a characteristic beaklike facies and
paucity of wrinkles.
Prof Ariyanto Harsono MD PhD SpA(K) 27

28. Sclerodactyly with digital ulceration, loss of skin creases, joint contractures,
and sparse hair.
Prof Ariyanto Harsono MD PhD SpA(K) 28

29. Skin pigmentary changes include a salt-and-pepper appearance, with areas of
hyperpigmentation and hypopigmentation, or an overall appearance of darkened skin
not related to sun exposure
Anterior chest demonstrating salt-and-pepper hypopigmentation and diffuse
hyperpigmentation in a white woman.
Prof Ariyanto Harsono MD PhD SpA(K) 29

30. Calcinosis may develop in the fingers and extremities, most commonly in the
finger tips, the extensor surface of the forearms and in the prepatellar regions;
however, any area of the body can be affected. Occasionally, large calcium
deposits with the appearance of tumoral calcinosis may occur
A radiograph of the distal digits demonstrating calcinosis and distal phalanx reabsorption (acral
osteolysis).
Prof Ariyanto Harsono MD PhD SpA(K) 30

31.  Eyes, ears, nose, and throat
o Salivary production may be decreased and spontaneous
sublingual pooling of saliva may be absent.
o Xerostomia and xerophthalmia may be part of the
examination findings. A confirmatory minor salivary gland
biopsy may show fibrosis without the pronounced
lymphocytic aggregates that would be expected with
primary Sjögren syndrome. Furthermore, patients with
systemic sclerosis typically do not harbor anti-Ro and anti-
La antibodies.
o Funduscopic examination during the hypertensive episodes
of scleroderma renal crisis may reveal exudates and
vascular alterations. Retinal artery occlusion causing acute
loss of vision has been described in rare instances.
Prof Ariyanto Harsono MD PhD SpA(K) 31

32. Vascular changes
Raynaud phenomenon results in characteristic color
changes of pallor, cyanosis, and then erythema
(white, blue, red) in the fingers, toes and other acral
body parts, and is usually accompanied by numbness,
tingling, or pain. These events are triggered by cold
exposure, smoking, or emotional stress. Subintimal
hyperplasia, typically present in systemic sclerosis
vessels, can cause a severe reduction of their luminal
diameter, limiting blood flow. The baseline reduction
in vessel lumen coupled to an exaggerated response
to vasoconstricting stimuli accounts for the severity of
Raynaud phenomenon in systemic sclerosis.
Prof Ariyanto Harsono MD PhD SpA(K) 32

33.  Other manifestations of vascular involvement are as follows:
o Infarction and dry gangrene of the fingers and toes may be
caused by severe vasospasm superimposed to structural fibrotic
and fibroproliferative vascular narrowing
o Some studies suggest that patients with systemic sclerosis have an
increased risk of coronary atherosclerosis, peripheral vascular
disease, and cerebrovascular calcification compared with healthy
individuals, and may develop non-atherosclerotic myocardial
infarction
Prof Ariyanto Harsono MD PhD SpA(K) 33

34. Nail-fold capillary microscopy demonstrates fewer capillaries than normal (ie,
capillary loop drop) and numerous dilated and tortuous capillary loops
Fingernail capillary bed demonstrating capillary dropout with large dilated
vessels.
Prof Ariyanto Harsono MD PhD SpA(K) 34

35. Diagnosis
 Approach Considerations
The diagnosis of systemic sclerosis is based on the clinical manifestations.
Nevertheless, a number of tests and procedures may be used in the initial
diagnosis (eg, to exclude alternative diagnosis), the assessment of organ
involvement, and monitoring of disease progression.
Laboratory testing may include the following:
o Complete blood cell count (CBC)
o Serum muscle enzyme levels
o Erythrocyte sedimentation rate
o N-terminal pro-brain natriuretic peptide
o Autoantibody assays: Fibrillarin antibodies and antibodies to ribonucleoprotein
(RNP) may be present. Anti-RNP is present mostly in patients with diffuse
disease with overlap syndromes and in patients with MCTD. These antibodies
are more common in patients with skeletal muscle involvement and pulmonary
disease.
o Assessment of gastrointestinal involvement
Prof Ariyanto Harsono MD PhD SpA(K) 35

36. Atrophy of smooth muscle and submucosal fibrotic changes leading to decreased
peristalsis throughout the gastrointestinal (GI) tract cause gastroesophageal reflux
disease [GERD], gastroparesis, severe constipation, and pseudo-obstruction.
Barium swallow demonstrating reflux into the distal esophagus, as well as an accordion
appearance in the duodenum.
Prof Ariyanto Harsono MD PhD SpA(K) 36

37. Electrocardiograms (ECGs) should be performed
routinely to identify arrhythmias and conduction
defects. ECGs can identify early changes of right
ventricular strain caused by pulmonary
hypertension, and in advanced states, right atrial
hypertrophy. Perform 24-hour ambulatory
Holter monitoring to evaluate arrhythmias and
serious conduction defects.
Prof Ariyanto Harsono MD PhD SpA(K) 37

38. Histologic Findings
The histopathological findings in the skin include
marked thickening of the dermis with massive
accumulation of dense collagen causing
epidermal atrophy, flattening of the rete pegs,
and replacement of sebaceous and sweat glands,
as well as hair follicles. A prominent
inflammatory infiltrate is often present at the
dermal-adipose tissue interphase, especially in
early lesions. The small vessels of the lower
dermis show fibrous thickening but evidence of
vasculitis is absent.
Prof Ariyanto Harsono MD PhD SpA(K) 38

39. Skin biopsy showing severe fibrosis. The fibrosis reflects a widening of collagen
bundles in concert with an increase in the number of collagen fibers. Note the
superimposed deposition of the newly synthesized delicate collagen bundles
interposed between the preexisting collagen bundles, the latter appearing
wide and manifesting a hyalinized morphology.
Prof Ariyanto Harsono MD PhD SpA(K) 39

40. Lung biopsy demonstrating severe interstitial fibrosis and medial fibrosis and
smooth muscle hyperplasia of a pulmonary arteriole compatible with
pulmonary hypertension.
Prof Ariyanto Harsono MD PhD SpA(K) 40

41. Lung biopsy demonstrating expansion of the interstitium of the lung by fibrous
tissue along with chronic inflammatory cells.
Prof Ariyanto Harsono MD PhD SpA(K) 41

42. Treatment
 Approach Considerations
Current treatment of systemic sclerosis is directed toward
managing complications and providing symptomatic relief.
In addition, a range of disease-modifying treatments have
been investigated.
Disease-modifying treatment aims at inhibiting tissue fibrosis
and vascular and immune system alterations, which are the
three crucial components of disease pathogenesis. To date,
however, the US Food and Drug Administration (FDA) has
not approved any disease-modifying therapies for systemic
sclerosis.
Prof Ariyanto Harsono MD PhD SpA(K) 42

43. o No placebo-controlled studies have
demonstrated clear superiority for any drug
except for a modest benefit from use of
methotrexate. Numerous uncontrolled
prospective and retrospective trials along with
post-hoc analysis have suggested a beneficial
effect from mycophenolate mofetil.
o Retrospective uncontrolled studies also
supported a beneficial role for D-penicillamine,
but a large high-dose versus low-dose controlled
trial failed to demonstrate benefits of the higher
dose versus the lower dose.
Prof Ariyanto Harsono MD PhD SpA(K) 43

44. o Sildenafil, an inhibitor of phosphodiesterase 5
(PDE-5), has been approved for treatment of
pulmonary hypertension. In addition, it has been
shown to be effective and well tolerated in
patients with Raynaud phenomenon.
Treatments for gastrointestinal symptoms of
systemic sclerosis include the following:
o Antacids
o Histamine 2 (H2) blockers
Prof Ariyanto Harsono MD PhD SpA(K) 44

45. Pulmonary Fibrosis/Alveolitis
Although there is some controversy regarding the
beneficial effects of immunosuppressive therapy
in idiopathic pulmonary fibrosis, numerous
studies support the use of these agents in
systemic sclerosis–associated interstitial lung
disease. Pulmonary fibrosis in systemic sclerosis
has been successfully treated with
o cyclophosphamide, either orally or in intravenous
pulses. Several recent nonrandomized studies
have also shown benefit from
o mycophenolate mofetil.
Prof Ariyanto Harsono MD PhD SpA(K) 45

46. Myositis may be treated cautiously with steroids
(first choice), or with methotrexate or
azathioprine in corticosteroid-resistant cases or
when there are contraindications to
corticosteroid use. Doses of prednisone greater
than 40 mg/d are associated with a higher
incidence of scleroderma renal crisis.
Prof Ariyanto Harsono MD PhD SpA(K) 46

47. Prognosis
Survival in patients with diffuse cutaneous disease has improved
significantly; currently, the 5-year survival is estimated to be
about 80%. Five-year survival in patients with limited cutaneous
disease is approximately 90%.
Factors associated with a more severe prognosis are as follows:
o Younger age
o African descent
o Rapid progression of skin symptoms
o Greater extent of skin involvement
o Anemia
o Elevated erythrocyte sedimentation rate (ESR)
o Pulmonary, renal, and cardiac involvement
Prof Ariyanto Harsono MD PhD SpA(K) 47

48. Patient Education
To minimize the risk of Raynaud phenomenon
flare, instruct patients to maintain their core
body temperature; strongly encourage smoking
cessation in patients who smoke, and advise all
patients to avoid exposure to cigarette smoke.
Instruct the patient to avoid digital or skin
trauma and prolonged cold exposure.
Prof Ariyanto Harsono MD PhD SpA(K) 48

49. Reference
Jimenez SA; Chief Editor: Diamond HS:
Sleroderma.
http://emedicine.medscape.com/article/3318
64-overview, Accessed 3-Oct, 2014.
Prof Ariyanto Harsono MD PhD SpA(K) 49

50. Thank you
Prof Ariyanto Harsono MD PhD SpA(K) 50