2. DEFINITION
• is a rare chronic disorder characterized by diffuse
fibrosis of the skin and internal organs.
• autoimmune
• Symptoms usually appear in the third to fifth decades
• Women are affected two to three times as frequently
as men
• Virtually every organ can be affected
3. FORMS
• two major subsets defined by the pattern of skin involvement and associated
with characteristic clinical and serologic features and natural history
• Diffuse:
• extensive skin induration, starting in the fingers (sclerodactyly) and
ascending from distal to proximal limbs and the trunk.
• progressive skin disease, interstitial lung disease (ILD), and less commonly
acute renal involvement may develop relatively early
• Limited:
• skin involvement remains confined to the fingers, distal limbs, and face,
while the trunk is spared
• Raynaud’s phenomenon generally precedes sclerodactyly and other disease
manifestations, sometimes by years.
• CREST
4. • FIGURE 360-1 Multiorgan
involvement in systemic
sclerosis (SSc). Prominent
complications of SSc:
• red, those more common in
diffuse cutaneous SSc;
• black, those more common in
limited cutaneous SSc;
• blue, complications common in
both SSc subsets.
• GAVE, gastric antral vascular
ectasia; GERD, gastroesophageal
reflux disease; GI,
gastrointestinal
5. INCIDENCE AND PREVALANCE
• acquired sporadic disease with a worldwide distribution and
affecting all races.
• In the United States, the incidence is 9–46 cases per million
per year.
• There are an estimated 100,000 U.S. cases, although this
number may be significantly higher
• reflecting differences in case definition, environmental
exposures, or genetic susceptibility genes
• Age, sex, and ethnicity influence disease susceptibility,
6. EPIDEMIOLOGY
• blacks have higher age-specific incidence rates and
mortality.
• a strong female predominance (4.6:1), which is most
pronounced in the childbearing years and declines after
menopause.
• An additional risk factor for SSc is having an affected
first-degree family member, which increases disease
risk 13-fold.
• blacks with SSc are more likely to have diffuse
cutaneous disease, ILD, and a worse prognosis
7. ETIOLOGY
• Mostly unknown
• Genetic predisposition, autoimmunity and environmental
factors
• autoimmunity and reversible vascular reactivity are early
features of SSc, whereas fibrosis and atrophy occur later in
the disease
9. CLINICAL FINDINGS
• truly a systemic disease that can affect virtually any organ
• limited systemic sclerosis: Raynaud phenomenon is usually
the initial manifestation and can precede other signs and
symptoms by years
• Diffuse systemic sclerosis: Polyarthralgia, weight loss, and
malaise are common early features, but are infrequent in
limited disease.
• Cutaneous disease usually, but not always, develops before
visceral involvement and can manifest initially as non-pitting
subcutaneous edema associated with pruritus.
• With time the skin becomes thickened and hidebound, with
loss of normal folds
10. DIFFUSE PATTERN
• the interval between Raynaud’s phenomenon and onset of other
disease manifestations is typically brief (weeks to months).
• Soft tissue swelling, puffy fingers, and pruritus are signs of the
early inflammatory “edematous” phase.
• The fingers, distal limbs, and face are usually affected first.
• Diffuse hyperpigmentation of the skin, carpal tunnel syndrome,
arthralgias, muscle weakness, fatigue, and decreased joint mobility
are common.
• During the ensuing weeks to months, the inflammatory
edematous phase evolves into the “fibrotic” phase, with skin
induration associated with hair loss, reduced production of skin
oils, and decline in sweating capacity.
11. DIFFUSE PATTERN
• Progressive flexion contractures of the fingers ensue. The wrists,
elbows, knees, and ankles become stiff due to fibrosis of the supporting
joint structures.
• While advancing skin involvement is the most visible manifestation of
early dcSSc, important and clinically silent internal organ involvement
can occur during this stage.
• The initial 4 years from disease onset is the period of most rapidly
evolving and potentially irreversible lung and renal damage.
• If organ failure does not occur during this phase of dcSSc, the systemic
process may plateau and stabilize
12. LIMITED PATTERN
• course of lcSSc tends to be more indolent
• The interval between onset of Raynaud’s phenomenon and
disease manifestations such as gastroesophageal reflux
disease (GERD), cutaneous telangiectasia, ischemic digital
ulcers, or soft tissue calcifications can be as long as years.
• Rarely: Scleroderma renal crisis, significant ILD, and tendon
friction rubs
• PAH and overlap with kerato-conjunctivitis sicca, polyarthritis,
cutaneous vasculitis, and biliary cirrhosis can develop even
many years after disease onset.
14. SYSTEMIC SCLEROSIS SINE
SCLERODERMA
•In some patients, Raynaud’s phenomenon and
characteristic clinical and laboratory features of
SSc occurs in the absence of detectable skin
thickening
•Relatively benign disease subset
16. RAYNAUD’S PHENOMENON
• most frequent extracutaneous complication of SSc, is characterized by
episodic vasoconstriction in the fingers and toes, sometimes also
affecting the tip of the nose and earlobes.
• Attacks are reversible, and can be triggered by a decrease in
temperature, as well as emotional stress and vibration.
• Attacks typically start with pallor of the fingers, followed by cyanosis of
variable duration. Hyperemia ensues spontaneously or with rewarming
of the digit.
• The progression of the three color phases reflects the underlying
vasoconstriction, ischemia, and reperfusion. It is important to note that
up to 5% of the general population has Raynaud’s phenomenon.
17. RAYNAUD PHENOMENON
• In the absence of signs or symptoms of an underlying condition,
Raynaud’s phenomenon is classified as primary (Raynaud’s disease),
which represents an exaggerated physiologic vasomotor response to
cold.
• Secondary Raynaud’s phenomenon occurs in SSc and other connective
tissue diseases, hematologic and endocrine conditions, occupational
disordes
18. RAYNAUD’S PHENOMENON
• Ddx of Raynaud’s disease and phenomenon:
• absence of an underlying cause;
• a family history of Raynaud’s phenomenon;
• absence of digital tissue necrosis or ulceration;
• negative ANA test.
• Secondary Raynaud’s phenomenon:
• tends to occur at an older age
• is more severe (episodes are more frequent, prolonged, and painful)
• is frequently complicated by ischemic digital ulcers and loss of digits
• Nail fold capillaroscopy
• 2nd
: distorted, widened and irregular loops, dilated lumen, microhemorrhages
20. SKIN FEATURES
• Bilateral symmetrical skin thickening is the hallmark that
distinguishes SSc from other connective tissue diseases.
• starts in the fingers and characteristically advances from distal
to proximal extremities in an ascending fashion. Some
patients note diffuse tanning in the absence of sun exposure
as a very early manifestation.
• In dark-skinned individuals, vitiligo-like hypopigmentation
may occur.
• Pigment loss sparing the perifollicular areas gives rise to a
“salt-andpepper” appearance of the skin, most prominently on
the scalp, upper back, and chest.
21. SKIN CHANGES
• Dermal sclerosis obliterating hair follicles, sweat glands, and
eccrine and sebaceous glands causes hair loss, decreased
sweating, and xerosis and itching in affected areas of the skin.
• Transverse creases on the dorsum of the fingers disappear
• Fixed flexion contractures of the fingers cause reduced hand
mobility and lead to muscle atrophy. Skin and subjacent
tendon fibrosis accounts for fixed contractures of the wrists,
elbows, and knees.
• Thick ridges at the neck due to firm adherence of skin to the
underlying platysma muscle interfere with neck extension
24. FACIAL CHANGES
• established SSc may show a characteristic “mauskopf” facial
appearance:
• with taut and shiny skin, loss of wrinkles, and occasionally an
expressionless facies due to reduced mobility of the eyelids,
cheeks, and mouth.
• Thinning of the lips with accentuation of the central incisor
teeth and prominent perioral radial furrowing (rhytides)
complete the picture.
• Reduced oral aperture (microstomia) interferes with eating and
oral hygiene.
• The nose assumes a pinched, beak-like appearance.
• In late-stage disease, the skin becomes thin and atrophic and is
firmly bound to the subcutaneous fat (tethering)
25. FACIAL CHANGES
• Dilated skin capillaries 2–20 mm in diameter (telangiectasia), reminiscent of
hereditary hemorrhagic telangiectasia, are frequently on the face, hands, lips,
and oral mucosa
• The number of telangiectasias correlates with the severity of microvascular
disease, including PAH.
• Breakdown of atrophic skin leads to chronic ulcerations at the extensor
surfaces of the proximal interphalangeal joints, the volar pads of the fingertips,
and bony prominences such as elbows and malleoli.
• Ulcers are often painful, heal slowly, and become secondarily infected,
resulting in osteomyelitis.
• Healing of ischemic fingertip ulcerations leaves characteristic fixed digital
“pits.” Loss of soft tissue at the fingertips due to ischemia may be associated
with striking resorption of the terminal phalanges (acro-osteolysis)
29. SKIN CHANGES
• Calcinosis Cutis: Dystrophic calcifications in the skin, subcutaneous, and soft
tissues in the presence of normal serum calcium and phosphate levels occur in
up to 40% of patients, most commonly in those with long-standing anti-
centromere antibody–positive lcSSc.
• Calcific deposits, composed of calcium hydroxyapatite crystals, vary in size
from tiny punctate lesions to large conglomerate masses, and can be readily
visualized on plain radiographs or dual-energy CT.
• These deposits occur when calcium precipitates in tissue damaged by
inflammation, hypoxia, or local trauma. Common locations include the finger
pads, palms, extensor surfaces of the forearms, and the olecranon and
prepatellar bursae
• Large calcific deposits can cause pain and nerve compression and may ulcerate
through the overlying skin with drainage of chalky white material and
secondary infections
• Paraspinal sheet calcifications may cause neurologic complications
32. PULMONARY FEATURES
• ILD
• Pulmonary Vascular disease
• Survival is particularly poor in SSc patients with concurrent presence of
these two processes.
• Less common pulmonary complications of SSc include:
• aspiration pneumonitis complicating chronic gastroesophageal reflux
• pulmonary hemorrhage due to endobronchial telangiectasia
• obliterative bronchiolitis
• pleural reactions
• restrictive physiology due to chest wall fibrosis
• spontaneous pneumothorax
• drug-induced lung toxicity.
• The incidence of lung cancer is increased in SSc
33. ILD
• clinically significant ILD develops in 16–43%; the frequency varies
depending on the detection method used.
• Risk factors for significant ILD include
• male sex, African-American race, diffuse skin involvement, severe
gastroesophageal reflux, and presence of topoisomerase-I (Scl-70)
autoantibodies,
• whereas anti-centromere antibody–positive patients have a reduced risk
of ILD.
• Esophageal dilatation with chronic acid reflux in SSc causes recurrent
micro-aspiration, a risk factor for the development and progression of
ILD.
• The most rapid progression in ILD generally occurs early in the disease
course (within the first 3–5 years), when the FVC can decline by 30% per
34. PULMONARY
• can remain asymptomatic until it is advanced.
• most common presenting respiratory symptoms—
• exertional dyspnea, fatigue, and reduced exercise tolerance—are subtle and slowly
progressive.
• chronic dry cough may be present.
• Physical examination may reveal fine inspiratory “Velcro” crackles at the lung bases.
• (PFT) is relatively insensitive for detecting early pulmonary involvement.
• In patients with established SSc-ILD, PFT typically shows:
• a restrictive ventilatory defect
• reduced total lung capacity (TLC) and diffusing capacity (DLCO).
• reduction in DLCO that is significantly out of proportion to the reduction in lung
volumes should raise suspicion for pulmonary vascular disease but may also be due to
anemia.
• Oxygen desaturation with exercise is common
35. • Chest radiography can be used as an initial screening tool to rule out infection and other causes of
respiratory symptoms in SSc, but compared to HRCT, it is relatively insensitive for detection of early
ILD.
• HRCT
• Characteristic imaging findings include lower lobe subpleural reticular linear opacities and ground-
glass opacifications with an apicobasal gradient, even in asymptomatic patients with normal PFTs
• Additional HRCT findings include mediastinal lymphadenopathy, pulmonary nodules, traction
bronchiectasis, and uncommonly, honeycomb changes. The extent of interstitial changes on chest
HRCT at
baseline is a predictor of ILD progression and mortality.
• bronchoalveolar lavage (BAL) can demonstrate inflammatory cells in the lower respiratory tract and
may be useful for ruling out tuberculosis and other infections, it does not appear to be useful for
SSc diagnosis or for identifying reversible alveolitis.
• Surgical lung biopsy in SSc is indicated only in patients with atypical findings on chest imaging.
37. PAH
• PAH results from vascular remodeling of small (<500 μm) pulmonary arteries.
• PAH develops in 8–12% of patients with SSc as a late complication and can be an
isolated abnormality or associated with ILD.
• MPAP 20 mmHg with a pulmonary capillary wedge pressure 15 mmHg and
≥ ≤
pulmonary vascular resistance >3 Wood units.
• The natural history of SSc-associated PAH is variable but often follows a progressive
course leading to right heart failure.
• The 3-year survival of SSc patients with untreated PAH is <50%.
• Risk factors include limited cutaneous disease, older age at disease onset, high
numbers of cutaneous telangiectasia, and antibodies to centromere, U3-RNP
(fibrillarin), and B23. Mutations in the BMPR2 gene implicated in idiopathic PAH are not
associated with SSc-PAH
38. PAH
• PAH is often asymptomatic in early stages.
• Patients present with exertional dyspnea and reduced exercise capacity.
• With progression, angina, near-syncope, and symptoms and signs of right-sided heart
failure appear.
• Physical examination may show tachypnea, a loud pulmonic component of the S2 heart
sound, pulmonic/tricuspid regurgitation murmur, palpable right ventricular heave,
elevated jugular venous pressure, and dependent edema.
• Doppler echocardiography is a noninvasive screening method for estimating the
pulmonary
arterial pressure.
• In light of the poor prognosis of untreated PAH and better therapeutic response in
patients with early diagnosis, SSc patients should be screened for PAH at initial
evaluation and annually thereafter.
39. • Estimated pulmonary artery systolic pressure >40 mmHg at rest or
tricuspid regurgitation jet velocities >3 m/s suggest PAH.
• Because echocardiography can over- or underestimate pulmonary artery
pressures, cardiac catheterization is required to confirm the diagnosis of
suspected PAH;
• assess its severity, including the degree of right heart dysfunction
• Rule out veno-occlusive disease and other cardiac (postcapillary) causes
of pulmonary hypertension
• provide prognostic parameters.
• Distinguishing PAH in SSc patients from pulmonary hypertension
secondary to pulmonary fibrosis and hypoxia can be difficult.
40. GI
• is the most common internal organ manifestation of SSc
• Variable involvement of the gastrointestinal (GI) tract, which can affect any level,
• seen in up to 90% of SSc patients with both limited and diffuse cutaneous disease
• Severe GI tract involvement is associated with:
• male sex and specific autoantibodies.
• The pathologic findings of GI involvement in SSc include fibrosis, smooth-muscle
atrophy, and obliterative small vessel vasculopathy throughout the length of the GI
tract.
• Together they have major impact on quality of life, malnutrition, and mortality
42. RENAL INVOLVEMENT:
SCLERODERMA RENAL CRISES
• presents with accelerated hypertension accompanied by acute kidney injury and
progressive failure.
• This acute life-threatening complication occurs in <15% of SSc patients, almost always
within 4 years of disease onset.
• Scleroderma renal crisis can occasionally even be the presenting manifestation of SSc.
• While short-term survival in scleroderma renal crisis was <10% prior to the advent of
angiotensin-converting enzyme (ACE) inhibitors, outcomes for this serous complication
have shown great improvement
• Pathogenesis:
• Obliterative vasculopathy of the renal arcuate and interlobular arteries, with
consequent intravascular hemolysis
• Progressive reduction in renal blood flow, aggravated by vasospasm, leads to
increased juxtaglomerular renin secretion and angiotensin II generation, with further
renal vasoconstriction resulting in a vicious cycle that culminates in accelerated
hypertension
43. SCLERODERMA RENAL CRISES
• Risk factors:
• African-American race
• male sex
• diffuse or progressive skin involvement.
• Up to 50% of patients with scleroderma renal crisis have antibodies to anti-RNA
polymerase III,
whereas patients with anti-centromere antibodies appear protected.
• Palpable tendon friction rubs, pericardial effusion, new unexplained anemia, and
thrombocytopenia may be harbingers of impending scleroderma renal crisis.
• High-risk patients with early-stage SSc should monitor their blood pressure daily.
• Because glucocorticoid use is associated with scleroderma renal crisis, prednisone in
high-risk SSc
patients should be taken only when absolutely required and at low doses (<10 mg/d)
44. RENAL CRISES
• characteristically present with accelerated hypertension (generally >150/90
mmHg) and progressive oliguric renal insufficiency.
• However, ~10% of patients present with blood pressure in the normal range.
Normotensive renal crisis is generally associated with a poor outcome.
• Headache, blurred vision, congestive heart failure, and pulmonary edema may
accompany elevation of blood pressure.
• Moderate thrombocytopenia and microangiopathic hemolysis with fragmented
red blood cells can be seen,
and urinalysis typically shows mild proteinuria, granular casts, and microscopic
hematuria.
• Progressive oliguric renal failure over several days generally follows.
45. • Scleroderma renal crisis is sometimes misdiagnosed as thrombotic
thrombocytopenic purpura (TTP) or other forms of thrombotic
microangiopathy. In such cases, renal biopsy and determination of
serum von Willebrand factor–cleaving protease activity may be of
benefit.
• The presence of oliguria or a creatinine >3 mg/dL at initial presentation
predicts poor outcome (permanent hemodialysis and mortality), as do
vascular thrombosis and glomerular ischemic collapse on renal biopsy
• Crescentic glomerulonephritis in the setting of SSc has been described
and may be associated with myeloperoxidase-specific antineutrophil
cytoplasmic antibodies (ANCAs).
• Membranous glomerulonephritis may occur in patients treated with D-
penicillamine. Asymptomatic renal impairment can occur in up to half of
SSc patients, is commonly associated with other vascular
manifestations, and rarely progresses to end-stage renal failure
47. CARDIAC INVOLVMENT
• Although it is often silent, cardiac involvement is detected in 10–50% of
SSc patients screened with sensitive diagnostic tools.
• more frequent in dcSSc than in lcSSc and may be primary or secondary
to PAH, ILD, or renal involvement.
• is associated with poor outcomes. The endocardium, myocardium, and
pericardium may each be affected separately or together.
• Pericardial involvement
• pericarditis, pericardial effusions, constrictive pericarditis, and rarely,
cardiac tamponade.
48. • Conduction system fibrosis is common and may be silent or manifested
by heart block.
• Other arrhythmias include premature ventricular contractions, atrial
fibrillation, and supraventricular tachycardia.
• Microvascular involvement, recurrent vasospasm, and ischemia-
reperfusion injury contribute to patchy myocardial fibrosis, and the
resulting systolic or diastolic left ventricular dysfunction may progress to
overt heart failure.
• Acute or subacute myocarditis leading to left ventricular dysfunction may
occur, best diagnosed by cardiac magnetic resonance imaging or
endomyocardial biopsy.
49. MSK INVOLVEMENT
• are commonly seen in SSc.
• Carpal tunnel syndrome may be a presenting disease manifestation
• generalized arthralgia and stiffness are prominent in early disease.
• Large joint contractures occur in patients with dcSSc and are frequently
accompanied by tendon friction rubs.
• These are characterized by coarse leathery crepitation heard or palpated upon
passive joint movement and are caused by fibrosis and adhesion of the tendon
sheaths and
fascial planes at the affected joint.
• The presence of tendon friction rubs is associated with increased risk for renal
and cardiac complications and reduced survival.
50. MSK INVOLVMENT
• Synovitis seen on ultrasound or MRI is common; occasional SSc patients
develop erosive polyarthritis in the hands
• some may have a seropositive rheumatoid arthritis overlap.
• Muscle weakness is common and multifactorial; deconditioning, disuse
atrophy, malnutrition, inflammation, and fibrosis may all contribute.
• A chronic noninflammatory form of myopathy characterized by atrophy
and fibrosis with mildly elevated muscle enzymes occurs in late-stage
SSc.
• Bone resorption in the terminal phalanges causes the characteristic loss
of the distal tufts (acro-osteolysis) (Fig. 360-5).
• Resorption of the mandibular condyles can lead to bite difficulties.
• Osteolysis can also affect the ribs and distal clavicles
52. LESS RECOGNIZED DISEASE
MANIFESTATIONS
• Dry Mouth and dry Eye Sicca: ddx with sjogren (Bx: fibrosis vs
lymphocytic infiltration)
• Hypothyroidism (Graves or Hashmato’s thyroiditis part. In lcsS)
• Unilateral or bilateral trigeminal neuralgia
• ED
• Sexual performance is also adversely affected in women. fertility is not
impaired in SSc
• Pregnancy with most fetal adverse outcomes, cardiac compliations and
renal crises
• Lung cancer and esophageal adenocarcinoma: long-standing ILD or
GERD
• Paraneoplastic Syndrome: breast, lung and ovarian cancer
53. LAB
• Antinuclear autoantibodies are detected in almost all patients
with SSc.
• Anti-topoisomerase I (Scl-70) and anti-centromere antibodies:
highly specific for SSc.
• Topoisomerase I (Scl-70) antibodies are associated with
increased risk of ILD and poor outcomes.
• Anti-centromere antibodies are associated with PAH, but only
infrequently with significant cardiac, pulmonary, or renal
involvement.
54. LAB
• Nucleolar immunofluorescence pattern may indicate antibodies to U3-
RNP (fibrillarin), Th/To, or PM/Scl, whereas speckled
immunofluorescence indicates antibodies to RNA polymerase III,
associated with increased risk of scleroderma renal crisis and
malignancy
• Anti-RNA polymerase III antibodies develop in 10–20% of systemic
sclerosis patients overall and are associated with rapidly progressive
skin disease, renal crisis, and a higher risk of concomitant solid cancers,
especially breast cancer
55. LAB
• Mild microcytic anemia is frequent and may indicate recurrent GI
bleeding caused by GAVE or chronic esophagitis.
• Macrocytic anemia may be caused by folate and vitamin B12
deficiency due to small bowel bacterial overgrowth and
malabsorption or by drugs such as methotrexate.
• Microangiopathic hemolytic anemia caused by mechanical
fragmentation of red blood cells during their passage through
microvessels coated with fibrin or platelet thrombi is a hallmark of
scleroderma renal crisis.
• The erythrocyte sedimentation rate (ESR) is generally normal in
SSc; an elevation may signal coexisting myositis or malignancy
56. DX, STAGNING & MONITORING
• made primarily on clinical grounds and is generally straightforward in
patients with established disease.
• Diagnostic criteria developed for classification are >90% specific and
sensitive for Sc.
• The presence of skin induration with a characteristic symmetric
distribution pattern associated with typical visceral organ manifestations
establishes the diagnosis with a high degree of certainty.
• In lcSSc, a history of Raynaud’s phenomenon and GERD symptoms,
coupled with sclerodactyly and nail fold capillary changes, often in
combinations with cutaneous telangiectasia and calcinosis cutis, helps to
establish the diagnosis
57. • Primary Raynaud phenomenon: vs early SS
• nailfold capillaries are normal
• Early-stage SSc might be initially misdiagnosed as arthritis, SLE, myositis, or,
most commonly, undifferentiated connective tissue disease leading to delays in
diagnosis.
• Within weeks to months, Raynaud’s phenomenon and advancing skin
induration appear.
• SSc-specific autoantibodies provide a high degree of diagnostic certainty.
• Patients with a new diagnosis of SSc should be screened for ILD, followed by
regular pulmonary monitoring for several years
58. • Raynaud’s phenomenon with fingertip ulcerations or
other evidence of digital ischemia, coupled with
telangiectasia, distal esophageal dysmotility,
unexplained ILD or PAH, or accelerated hypertension
with renal failure in the absence of clinically evident
skin induration, suggests the diagnosis of SSc sine
scleroderma.
59. DIFFERENTIAL DIAGNOSIS
• Early in disease course:
• SLE
• MCTD
• Inflammatory myopathies
• Primary Raynaud
• Nail fold microscopy
60. MANAGEMENT
• General principles:
• Prompt and accurate diagnosis
• Patient sub-classification and risk stratification based on
clinical, radiologic, and laboratory evaluation, including
autoantibody profiles and prognostic and predictive
biomarkers
• Early recognition of organ-based complications and
assessment of their extent, severity, and likelihood of
deterioration;
• Regular monitoring for disease progression, new
complications, and response to and side effects of therapy;
• Adjusting therapy
61. MANAGMENT
• no therapy has been shown to significantly alter the natural
history of SSc
• numerous interventions are effective in
• alleviating the symptoms
• slowing the progression of the cumulative organ damage
• reducing disability.
• Moreover, a significant decrease in disease-related mortality
has been noted during the past 25 years
63. IMMUNOSUPPRESSIVE THERAPY
• Glucocorticoids:
• alleviate stiffness and aching in early inflammatory-stage dcSSc
• do not influence the progression of skin or internal organ involvement.
• their use is associated with an increased risk of scleroderma renal crisis, glucocorticoids
should be given only:
• when absolutely necessary
• at the lowest dose possible
• for brief periods only
• Oral and intravenous cyclophosphamide:
• have been shown to reduce the progression of SSc-associated ILD, with stabilization and,
rarely, modest improvement of pulmonary function, HRCT findings, respiratory symptoms,
and skin induration.
• These benefits of cyclophosphamide need to be balanced against its potential toxicity,
including bone marrow suppression, opportunistic infections, hemorrhagic cystitis and
bladder cancer, premature ovarian failure, and late secondary malignancies
64. IMMUNOSUPPRESSIVE THERAPY
• Methotrexate: had modest effect on SSc skin involvement
• Mycophenolate mofetil: Both skin induration and ILD improved in
patients treated with mycophenolate mofetil, and the drug was well
tolerated.
• Tocilizumab, a monoclonal antibody that blocks IL-6 receptor signaling,
also showed benefit on both skin and lung involvement in randomized
SSc trials.
• Open-label studies and small clinical trials provide some support for
rituximab, a monoclonal antibody directed against the mature B-cell
marker CD20, along with extracorporeal photopheresis, IV
immunoglobulin, and abatacept, a fusion protein that inhibits T-cell co-
stimulation and function
65. IMMUNOSUPPRESIVE THERAPY
• The use of cyclosporine, azathioprine, hydroxychloroquine (Plaquenil),
thalidomide, and rapamycin for SSc therapy is currently not well supported
by the literature.
• Intensive immune ablation using high-dose chemotherapy, followed by
autologous hematopoietic stem cell reconstitution therapy (HSCT), was
associated with durable remission and improved long term survival in
multiple randomized clinical trials.
• Currently, HSCT is indicated for selected patients with severe SSc but carries
potential morbidity and mortality, as well as significant cost. Additional forms
of potentially disease-modifying cellular therapies are under investigation.
66. ANTI-FIBROTIC THERAPY
• tissue fibrosis underlies organ damage
• D-penicillamine was shown to:
• stabilize skin induration
• prevent new internal organ involvement
• improve survival
• However, a randomized controlled clinical trial in early active SSc found
no difference in the extent of skin involvement between patients treated
with standard-dose (750 mg/d) or very low-dose (125 mg every other
day) D-penicillamine.
• Recent clinical trials show benefit of the tyrosine kinase inhibitor
nintedanib,
alone or in combination with mycophenolate, in patients with SSc-ILD,
with significant slowing of the loss of lung function
67. VASCULAR THERAPY
• Goal of Raynaud’s therapy is to:
• control episodes,
• prevent and enhance the healing of ischemic complications
• slow the progression of obliterative vasculopathy.
• Patients should dress warmly, minimize cold exposure, and avoid drugs
that precipitate or exacerbate vasospastic episodes.
• Extended-release dihydropyridine calcium channel blockers such as
amlodipine and nifedipine, as well as diltiazem, ameliorate Raynaud’s
phenomenon, but their use is often limited by side effects (palpitations,
dependent edema, worsening gastroesophageal reflux).
• While ACE inhibitors do not reduce the frequency or severity of
episodes, angiotensin II receptor blockers such as losartan are effective
and well tolerated
68. • Patients with Raynaud’s phenomenon unresponsive to these therapies
may require the addition of α1-adrenergic receptor blockers (e.g.,
prazosin), phosphodiesterase-5 inhibitors (e.g., sildenafil), topical
nitroglycerine, and intermittent IV infusions of prostaglandins.
• Endothelin-1 receptor antagonist bosentan reduces the risk of new
ulcers.
• There is limited evidence-based information for the treatment of cardiac
complications of SSc, which should be guided by specialists experienced
in their diagnosis and management.
• While selective beta blockers such as metoprolol can precipitate
vasospasm, nondihydropyridine calcium channel blockers can be used
for rate control in atrial arrhythmias, and nonselective alpha/ beta
blockers such as carvedilol can be used for improving myocardial
perfusion and left ventricular systolic function.
69. SSC-ILD
• ILD is a leading cause of death in patients with SSc.
• it is important to identify patients who are at high risk for disease
progression
• The extent of ILD on HRCT and the FVC at initial evaluation and the
decline in FVC during the preceding 12-month period are helpful in
identifying these patients.
• Male sex, older age at initial presentation, progressive skin involvement,
and myocardial disease may be risk factors for ILD progression.
• Patients at high risk for ILD should be monitored by performing PFTs
every 6 months
• serial HRCT imaging is not recommended
70. SSC-ILD
• Cyclophosphamide, given IV or orally for 6–12 months, and
mycophenolate mofetil slow the decline in lung function and improve
respiratory symptoms, but cyclophosphamide is associated with more
frequent side effects.
• The efficacy and optimal duration of antifibrotic therapy with nintedanib,
which was recently approved for SSc-associated ILD, are currently under
investigation.
• In patients who show continued progression of ILD despite medical
therapy, lung transplantation might be considered as a lifeprolonging
procedure, although significant GERD contributing to organ rejection is
a concern in SSc.
• Recurrence of SSc-ILD in transplanted lung allografts has not been
reported
72. TX OF GI CX
• regular dental care is recommended : Because decreased oral aperture, decreased
saliva production, gum recession, periodontal disease, and teeth loss, are
• Gastroesophageal reflux is very common in SSc and may occur in the absence of
symptoms:
• Patients should be instructed to elevate the head of the bed,
• eat frequent small meals
• avoid alcohol, caffeine, known reflux exacerbants, and meals before bedtime.
• Proton pump inhibitors to reduce acid reflux may need to be given in relatively
high doses.
• Prokinetic agents such as metoclopramide, erythromycin (a motilin agonist), and
domperidone may occasionally be helpful in SSc but are frequently associated with
side effects.
73. • Botulinum toxin injection sometimes ameliorates impaired gastric
emptying.
• Antireflux procedures such as Nissen fundoplication can result in
secondary achalasia and generally should be avoided.
• Episodic bleeding from GAVE (watermelon stomach) may be treated with
endoscopic ablation using laser or argon plasma photocoagulation,
although it commonly recurs.
• In some patients, enteral feeding and/or decompression via
percutaneous gastrostomy or jejunostomy may become necessary.
74. • Small intestinal bacterial overgrowth secondary to gut dysmotility causes
abdominal bloating and diarrhea and may lead to malabsorption and severe
malnutrition.
• Short courses of rotating broad-spectrum antibiotics such as metronidazole,
erythromycin, and rifaximin can eradicate bacterial overgrowth.
• Small bowel hypomotility may respond to octreotide, but pseudo-obstruction
is difficult to treat.
• Fecal incontinence, a frequent but underreported complication, may respond
to antidiarrheal medication, biofeedback, sphincter augmentation, and sacral
neuromodulation.
• Potential malnutrition should be routinely assessed
75. PAH
• PAH carries an extremely poor prognosis and accounts for 30% of
deaths.
• Because PAH is asymptomatic until advanced, patients with SSc should
be screened at initial evaluation and
regularly thereafter.
• Treatment is generally started with an oral endothelin-1 receptor
antagonist such as bosentan or a phosphodiesterase-5 inhibitor such as
sildenafil.
• Recently, the soluble guanylate cyclase stimulator riociguat, which acts
by increasing the production of nitric oxide, and the selective IP
prostacyclin receptor agonist selexipag were shown to improve PAH
symptoms and survival.
• Patients may also require diuretics and digoxin.
76. • If hypoxemia is documented, supplemental oxygen should be
prescribed in order to avoid secondary pulmonary vasoconstriction.
• Prostacyclin analogues such as epoprostenol or treprostinil can be given
by continuous IV or SC infusion or via intermittent nebulized inhalations.
• Combination therapy with different classes of agents acting additively or
synergistically is often necessary.
• Lung transplantation remains an option for selected SSc patients with
PAH who fail medical therapy, and 2-year survival rates (64%) are
comparable to those of idiopathic ILD or PAH
77. MANAGEMENT OF RENAL CRISIS
• represents a medical emergency.
• Since its outcome is largely determined by the extent of renal damage at the time that
aggressive therapy is initiated, prompt recognition of impending or early scleroderma
renal crisis is essential, and efforts should be made to avoid its occurrence.
• High-risk SSc patients
• early disease
• extensive and progressive skin involvement
• Tendon friction rubs,
• anti-RNA polymerase III antibodies)
should be instructed to monitor their blood pressure daily and report significant
alterations immediately.
• Potentially nephrotoxic drugs should be avoided, and glucocorticoids should be used
only when absolutely necessary and at low doses.
• Patients presenting with scleroderma renal crisis should be immediately hospitalized.
78. • Once other causes of acute renal disease are excluded,
treatment should be started promptly with titration of short-
acting ACE inhibitors, with the goal of rapid normalization of
the blood pressure.
• In patients with persistent hypertension, addition of
angiotensin II receptor blockers, calcium channel blockers,
endothelin-1 receptor blockers, prostacyclins, and direct renin
inhibitors should be considered.
• In light of evidence for intrarenal complement pathway
activation in some patients with scleroderma renal crisis,
addition of eculizumab to ACE inhibitors may be considered.
79. • Up to two-thirds of patients with scleroderma renal crisis
necessitate dialysis.
• Substantial renal recovery can occur following an episode of
scleroderma renal crisis, and renal replacement therapy can
be ultimately discontinued in 30–50% of patients. Kidney
transplantation is appropriate for patients unable to
discontinue dialysis after 2 years.
• Survival of transplanted SSc patients is comparable to that of
other diseases, and recurrence of renal crisis is rare.
80. SKIN CARE
• skin involvement in SSc is never life-threatening and stabilizes, and may
even regress spontaneously, disease management should not be
dictated by its cutaneous manifestations.
• The inflammatory symptoms of early skin involvement can be controlled
with antihistamines and short-term use of low-dose glucocorticoids (<5
mg/d of prednisone).
• Cyclophosphamide and methotrexate have modest effects on skin
induration.
• skin is dry, the use of hydrophilic ointments and bath oils is encouraged,
and regular skin massage is helpful.
81. • Telangiectasia, which presents a cosmetic problem, especially on the
face, can be treated with pulsed dye laser.
• Ischemic digital ulcerations should be protected by occlusive dressings
to promote healing and prevent infection.
• Infected skin ulcers are treated with topical antibiotics and surgical
debridement.
• While no therapy has been shown to be effective in preventing soft-
tissue calcific deposition or promoting its dissolution, reports support
the use of minocycline, bisphosphonates, and topical or IV sodium
thiosulfate (STS).
• Additional approaches include carbon dioxide laser treatment,
extracorporeal shock-wave lithotripsy, and surgical high-speed
microdrilling
82. TREATMENT OF
MUSCULOSKELETAL
COMPLICATIONS
• Arthralgia and joint stiffness are very common and distressing
manifestations in early-stage disease.
• Short courses of nonsteroidal anti-inflammatory agents,
methotrexate, and cautious use of lowdose glucocorticoids
alleviate symptoms.
• Physical and occupational therapy can be effective for
preventing loss of musculoskeletal function and joint
contractures and should be initiated early.
83. DISEASE COURSE
• The natural history of SSc is highly variable and difficult to predict, especially in early
stages of the disease.
• dcSSc tend to have a more rapidly progressive course and worse prognosis than those
with lcSSc.
• Inflammatory symptoms of early dcSSc, such as fatigue, edema, joint pain, and
pruritus, subside, and skin thickening reaches a plateau at 2–4 years after disease
onset.
• It is during the early edematous/inflammatory stage that life-threatening visceral
organ involvement may develop.
• While existing visceral organ involvement, such as ILD, may progress even after skin
involvement peaks, new organ involvement is rare.
• Scleroderma renal crisis generally occurs within the first 4 years of disease. In late-
stage disease (>6 years), the skin is usually soft and atrophic.
84. DISEASE COURSE
• Skin regression characteristically occurs in an order that is the reverse of initial
involvement, with softening on the trunks followed by proximal and finally distal
extremities; however, sclerodactyly and fixed finger contractures generally persist.
• Relapse or recurrence of skin thickening after peak skin involvement has been
reached is uncommon.
• Patients with lcSSc follow a clinical course that is markedly different than that of
dcSSc.
• Raynaud’s phenomenon typically precedes other disease manifestations by years
or even decades.
• Visceral organ complications such as PAH generally develop late and progress
slowly.
85. PROGNOSIS
• SSc confers a substantial increase in the risk of premature death. Age- and gender-
adjusted mortality rates are five- to eightfold higher compared to the general
population, and more than half of all patients with SSc die from their disease.
• In one population-based study of SSc, the median survival was 11 years.
• The prognosis correlates with the extent of skin involvement, which itself is a
surrogate for visceral organ involvement.
• Major causes of death are PAH, pulmonary fibrosis, GI involvement, and cardiac
disease.
• Scleroderma renal crisis is associated with a 30% 3-year mortality.
• Lung cancer and excess cardiovascular deaths also contribute to increased
mortality.
86. • Markers of poor prognosis
• male gender
• African-American race
• older age at disease onset,
• extensive skin thickening with truncal involvement
• palpable tendon friction rubs
• evidence of significant or progressive visceral organ involvement.
87. PROGNOSIS
• The advent of ACE inhibitors in scleroderma renal crisis had a
dramatic impact on survival, increasing survival from <10% at
1 year in the pre–ACE inhibitor era to >70% 3-year survival at
the present time.
• Moreover, 10-year survival in SSc improved from <60% in the
1970s to >66–78% in the 1990s, a trend that reflects both
earlier detection and better management of complications.
89. MIXED CONNECTIVE TISSUE
DISORDERS
• Patients who have lcSSc coexisting with features of SLE, polymyositis, and rheumatoid
arthritis may have mixed connective tissue disease (MCTD).
• This overlap syndrome is generally associated with the presence of high titers of
autoantibodies to U1-RNP.
• The characteristic initial presentation is Raynaud’s phenomenon associated with puffy
fingers and myalgia. Over time, sclerodactyly, soft-tissue calcinosis, and cutaneous
telangiectasia may appear.
• Skin rash suggestive of SLE (malar erythema, photosensitivity) or dermatomyositis
(heliotrope
rash on the eyelids, erythematous rash on knuckles) occurs.
• Arthralgia is common, and some patients develop erosive polyarthritis. Pulmonary
fibrosis and isolated or secondary PAH may develop.
• Other manifestations include esophageal dysmotility, pericarditis, Sjögren’s syndrome,
and renal disease, especially membranous glomerulonephritis.
90. • Laboratory evaluation shows elevated ESR and
hypergammaglobulinemia.
• While anti-U1RNP antibodies are detected in high titers, SSc-
specific autoantibodies are absent.
• In contrast to SSc, MCTD often responds to glucocorticoids,
and the long-term prognosis is better than that of SSc.
Whether MCTD is truly a distinct entity or is a subset of SLE or
SSc remains controversial
91. EOSINOPHILIC FASCIITIS (DIFFUSE
FASCIITIS WITH EOSINOPHILIA)
• Eosinophilic fasciitis is a rare idiopathic disorder of adults associated
with abrupt skin induration.
• The skin characteristically shows a coarse cobblestone “peau d’orange”
appearance.
• In contrast to SSc, Raynaud’s phenomenon and SSc-associated internal
organ involvement and autoantibodies are absent.
• Furthermore, skin involvement spares the fingers.
• Full-thickness biopsy of the lesional skin reveals fibrosis of the
subcutaneous fascia, with variable inflammation and eosinophil
infiltration.
92. • In the acute phase of the illness, peripheral blood eosinophilia may be
prominent. MRI appears to be a sensitive tool for the diagnosis of
eosinophilic fasciitis.
• Eosinophilic fasciitis can occur in association with, or preceding, various
myelodysplastic syndromes or multiple myeloma.
• Although glucocorticoids cause prompt resolution of eosinophilia, the
skin shows slow and variable improvement.
• The prognosis of patients with eosinophilic fasciitis is generally good.
