Systemic sclerosis scleroderma

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					Systemic sclerosis (scleroderma)
Author: Doctor Panayiotis G. Vlachoyiannopoulos1
Creation Date: November 2001

Scientific Editor: Professor Haralampos M. Moutsopoulos

1MedicalSchool, Department of Pathophysiology, National University of Athens, 75 Mikras Asias street,
11527 Athens, Greece.

Disease name and synonyms
Excluded diseases
Diagnostic criteria
Differential diagnosis
Clinical description
Clinical findings
Diagnostic methods
Genetic counseling
Antenatal diagnosis
Unresolved questions

Systemic sclerosis (SSc) is an autoimmune systemic disease characterized by small vessel involvement
that leads to tissue ischemia and fibroblast stimulation resulting in accumulation of collagen (fibrosis) in
the skin and internal organs. The peak incidence of the disease is found between the third and fifth
decade of life. The male to female ratio is 5:1. Annual incidence is 14.1 cases per million. Prevalence
ranges from 19 to 75 cases per million. No well-defined treatment has been found. However several types
of treatment exist and can be classified as such A) systemic therapies and B) organ - specific therapies.
Systemic therapies are subdivided into vascular therapies, immunomodulating therapies and antifibrotic
therapies. Organ-specific therapies are subdivided into therapy of pulmonary interstitial fibrosis, therapy of
pulmonary hypertension, therapy of SSc renal crisis. Most of the above-mentioned therapies have been
tested in open clinical trials. Systemic sclerosis is more common in coal and gold miners and miners
exposed to vinyl-chloride, epoxyresins and aromatic hydrocarbons. However, these factors do not explain
the spontaneously developed disease. Recently, CD34 stem cells of child origin were detected in women
with SSc more commonly than in normal women. Furthermore, the SSc women display histocompatibility
in most of the HLA loci with their children.

Systemic scleroderma, fibrosing alveolitis, pulmonary hypertension, renal crisis, heart/lung transplantation

Disease name and synonyms                                         Excluded diseases
Systemic    sclerosis    (SSc),          Scleroderma,             The clinical manifestations of the disease are
Progressive systemic sclerosis.                                   vascular and skin changes. Vascular changes
                                                                  include    Raynaud's     phenomenon,     digital

Vlachoyiannopoulos PG. Systemic sclerosis (scleroderma). Orphanet encyclopedia, November 2001.                                                                  1
ischemia, ulcers and gangrene. Raynaud's                          mainly against cell nuclear enzymes, like DNA
phenomenon is the episodic, reversible,                           topoisomerase -1 (anti -Topo I) and RNA
sequential expression of pallor, cyanosis,                        polymerases, as well as centromeric proteins,
redness of the digits, ears or nose, due to                       (anticentromere antibodies, ACA).
vasospasm/dilatation repeated attacks, in
response to cold exposure or to emotion. Skin                     Differential diagnosis
changes include puffy or tight and atrophic skin.                 As shown in Table 2, differential diagnosis is
Relying on the vascular changes in scleroderma,                   based on the exclusion of diseases showing
the following diseases should be then excluded:                   vascular, skin and visceral changes similar to
primary Raynaud's phenomenon, systemic lupus                      SSc [2,3]. Physical trauma, chemical exposure,
erythematosus                               (SLE),                drugs and other autoimmune diseases are
dermatomyositis/polymyositis             (DM/PM),                 accompanied by Raynaud's phenomenon and
Sjögren's syndrome (SS), polyarteritis nodosa                     should be excluded by history, physical and
(PN), cryoglobulinemia. Relying on the skin                       laboratory evaluation. Several forms of localized
changes in scleroderma, the following diseases                    scleroderma (i.e without affecting internal
should be then excluded: localized scleroderma,                   organs), constitute a single circumscribed or
undifferentiated connective tissue disease                        linear area of tight skin without signs of visceral
(UCTD), SLE, DM/PM, overlap syndromes of                          involvement, Raynaud's phenomenon or ANAs.
SSc with other autoimmune diseases like SLE,                      Diseases resembling the early phase of
SS, DM/PM, or rheumatoid arthritis (RA); chronic                  scleroderma or overlapping with it should be
graft-versus-host disease (GVHD); POEMS                           recognized on the basis of additional clinical
(polyneuropathy,                  organomegaly,                   signs, the type of organ involvement, the
endocrinopathy, monoclonal gammopathy, skin                       autoantibody profile and biopsy findings. Renal
changes); eosinophilic fascitis, eosinophilia                     biopsy, in particular, allows the distinction
myalgia syndrome and metabolic - genetic                          between       SSc      and      SLE,      vasculitis,
diseases as presented in "differential diagnosis".                cryoglobulinemia, and SS. The analysis of
                                                                  skin/subcutaneous tissue/fascia and muscle
Diagnostic criteria                                               biopsies helps to distinguish between SSc and
In order to include patients into specific clinical               DM/PM or diffuse fasciitis with eoshinophilia or
trials or cohort studies, a person will be classified             eosinophilia - myalgia syndrome. Scleroderma-
as having SSc if one major, two or more minor                     like changes in the skin or in the lung in a patient
criteria are present (see Table 1). [1]                           who underwent bone marrow transplantation are
                                                                  indicative of GVHD. Pulmonary fibrosis in
Table 1: Criteria for the classification of                       scleroderma is associated with antibodies to
systemic sclerosis                                                Topo -I while idiopathic pulmonary fibrosis is not.
A. Major criteria                                                 Furthermore, idiopathic pulmonary fibrosis has a
Proximal scleroderma: symmetric thickening, tightening and        rapidly progressive course. Blood glucose level
induration of the skin of the fingers and the skin proximal to
the metacarpophalangeal or metatarsophalangeal joints.
                                                                  allows the exclusion of diabetes mellitus which is
The changes may affect the entire extremities, face, neck         associated with scleroderma, sclerosis and
and trunk.                                                        arthropathy. Serum protein electrophoresis with
B. Minor criteria                                                 or without immunofixation can rule out
1. Sclerodactyly: the above-mentioned skin changes are            paraproteinemias, like amyloidosis and POEMS.
limited to the fingers.
2. Digital pitting scars or loss of substance from the finger
                                                                  Amyloidosis is diagnosed histologically after
pad. Depressed areas at tips of fingers or loss of digital pad    staining procesure with Congo red, birefringence
tissue as a result of ischemia.                                   characteristic    is   seen     under     polarizing
3. Basilar pulmonary fibrosis: bilateral reticular pattern of     microscopy. Amyloidosis diagnosis biopsy can
linear or lineonodular densities most pronounced in basilar
portions of the lungs on standard chest roentgenogram, not
                                                                  be made on the following biopsies: gingiva, bone
attributable to primary lung disease.                             marrow, rectum, subcutaneous fat, kidney and
                                                                  liver [2,3].
SSc is a multisystemic, autoimmune disease
affecting small arteries, microvessels and
fibroblasts resulting in vascular obliteration,
collagen accumulation and scarring (fibrosis) of
skin and internal organs. This leads to
hidebound skin and damage of gastrointestinal
tract, lungs, heart and kidneys. The serological
specifity of the disease is the presence of
antinuclear antibodies (ANAs) which are directed

Vlachoyiannopoulos PG. Systemic sclerosis (scleroderma). Orphanet encyclopedia, November 2001.                                                                       2
Table 2: Differential diagnosis of systemic                       Clinical description
sclerosis                                                         Clinically, the condition may be divided into
Based on the vascular changes                                     different subtypes [4].
                                                                  •          Diffuse cutaneous SSc (dcSSc)
  •   Primary Raynaud's phenomenon                                     The onset of symptoms is more abrupt.
  •   Physical trauma (e.g. jackhammer operator)                       Raynaud's phenomenon is common but may
  •   Chemical        exposure      (vinyl     -      chrolide,        follow       other   features.   The      earliest
      coal/silica/gold/heavy metal miners, organic solvents)           phenomenon is thickening on the trunk and
  •   Drugs/toxins [toxic oil syndrome (ingestion of                   acral skin edema, presence of tendon
      adulterated, rapessed oil, Madrid, 1982), arsenic,               friction rubs, pulmonary fibrosis, oliguric
      bleomycin, cisplatin, ergotamine, beta-blockers (high            renal crisis, diffuse gastrointestinal disease
      dose), 5-hydroxytryptophan, carbidopa]
                                                                       and heart failure or cardiac arrhythmia.
  •   Other autoimmune connective tissue diseases (SLE,
      DM/PM, vasculitis, RA, SS, cryoglobulinemia)                     Antibodies to Topo-I or to RNA-polymerases
                                                                       I, II, III are present while ACA [4] are absent.
                                                                       • Limited Cutaneous SSc (lcSSc)
Based on skin changes
                                                                        Raynaud's phenomenon occurring many
                                                                        years before the onset of skin changes. Skin
  •   Localized scleroderma (morphea, linear scleroderma                induration is limited to hands, face and feet;
      with atrophy of the affected extremity, "en coup de
      sable" with and without facial hemiatrophy).                      pulmonary hypertension, skin calcification
  •   Scleroderma - like skin changes                                   and telangiectasia occuring at a later date,
      o UCTD                                                            ACA are highly prevalent. This subset also
      o Eosinophilic fasciitis with eosinophilia                        includes a subgroup of patients previously
      o Eosinophilia myalgia syndrome                                   classified as patients with CREST syndrome
      o Overlap syndromes (scleroderma, with SLE, or                    (calcinosis,       Raynaud's     phenomenon,
           SS, or DM/PM, or RA)
                                                                        esophageal hypomotility, sclerodactyly,
      o Chronic form of GVHD
                                                                        telangiectasia) [4].
  •   Metabolic - genetic disorders
      o Scleredema/Scleremexedema                                      • Systemic sclerosis sine scleroderma
      o Insulin-dependent diabetes mellitus (scleredema,                     (ssSc)
           digital sclerosis)                                          It is characterized by visceral disease
      o POEMS and other paraproteinemias                               without cutaneous involvement [4].
      o Amyloidosis
                                                                  Clinical findings
Based on visceral involvement                                     Raynaud's phenomenon affects almost all the
                                                                  patients. The skin is initially swollen and
  •   Aging and diabetes mellitus (esophageal hypomotility)       becomes tight later on. Musculoskeletal
  •   Idiopathic pulmonary fibrosis                               involvement is evident in 1/3 to 1/2 of the
  •   Idiopathic (primary) pulmonary hypertension                 patients and is expressed as symmetric
  •   Sarcoidosis                                                 polyarthritis resembling rheumatoid arthritis and
  •   Amyloidosis                                                 muscle weakness. Carpal tunnel syndrome and
  •   Infiltrative cardiomyopathies
                                                                  tendon friction rubs are due to the fibrotic
  •   Malignant hypertension
                                                                  thickening of the tendon sheaths. Muscle
  •   Other autoimmune connective tissue diseases
                                                                  weakness occurs just in 5% of the lcSSc patients
                                                                  but in 50% of the dcSSc patients. It is due to:
                                                                  a) diffuse atrophy with arthralgia and morning
                                                                  stiffness in the majority of patients,
Prevalence                                                        b) scleroderma myopathy non associated with
The disease has a worldwide distribution and                      elevated muscle enzymes
affects all races. It is more frequent and severe                 c) full-blown myositis (6%) with elevated muscle
in young black women. The peak incidence is                       enzymes indistinguishable from PM/DM (overlap
found between the third and the fifth decade of                   of SSc with PM/DM) [2,3,5].
life. The female to male ratio is approximately                   Gastrointestinal manifestations are common in
5:1. Annual incidence is 14.1 cases per million.                  scleroderma (> 50% of patients); they include
Prevalence ranges from 19 to 75 cases per                         gastroesophageal reflux due to hypomotility of
100,000 people. For reasons that have not been                    the distal part of the esophagus, dysphagia,
well understood, the highest prevalence has                       odynophagia, burning pain in the epigastric and
been reported in the Choctaw Native Americans                     retrosternal regions and regurgitation of gastric
in Oklahoma (472/100,000 persons) [3].                            contents, especially when the patient is lying flat
                                                                  or bending over [1-3,5]. Dysmotility of the small
                                                                  intestine may lead to abdominal pain and

Vlachoyiannopoulos PG. Systemic sclerosis (scleroderma). Orphanet encyclopedia, November 2001.                                                                         3
malabsorption and muscular atrophy of the large                   patients [1-3,5]. It affects mainly male patients
bowel wall which may lead to wide-mouth                           with dcSSc who have antibodies to RNA
diverticula. Pulmonary involvement occurs in                      polymerase III and who also suffer from cardiac
25% of the lcSSc and in more than 50% of the                      involvement (especially pericarditis) or take
dcSSc patients. It has mainly three forms:                        prednisolone at levels of 25mg daily or higher.
a) pulmonary interstitial fibrosis (PIF),                         Renal involvement takes the form of
b) pulmonary hypertension and isolated                            scleroderma renal crisis, which is defined as
reduction of diffusing capacity of the lung                       follows: «a rise in diastolic blood pressure above
[expressed as isolated impairement of carbon                      110 mmHg and decreasing clearance during the
monoxide transfer factor for whole lung (TLCO)].                  final week of observation associated with
Pulmonary alveolitis precedes PIF and can be                      hematuria or proteinuria or retinal hemorrhages
detected       by     high-resolution      computed               or microangiopathic hemolytic anemia or
tomography (HRCT) of the lung as increased                        papilledema». Occasionally, renal crisis may
lung density or patchy air-space opacification                    occur with normal blood pressure. Creatinine
with reticular and nodular patterns (ground                       levels above 3mg/dL, during the episode, male
glass). It can also seen by bronchoalveolar                       sex and older age at disease onset are
lavage (BAL), which recovers increased                            associated with poor outcomes. Incidence and
numbers of alveolar macrophages, neutrophils,                     poor outcome of renal crisis have been reduced
eosinophils and CD8 positive T lymphocytes.                       after the introduction of treatment with
PIF can be evident by chest X-ray or HRCT as                      angiotensin converting enzyme (ACE) inhibitors
linear and reticular densities, leading to honey-                 [1-3].
combing appearance affecting prominently the
lower two thirds of the lung (reticular pattern).                 Management
PIF is associated with the dcSSc and anti-Topo-I                  It can be divided into two major parts:
antibodies [5-7]. PH affects a small number of                    A) Systemic therapy,
patients with lcSSc and ACA [5]. The most                         B) Organ-specific therapies.
common symptom is exertional dyspnea and/or                       Systemic therapy can be divided into: vascular
dry, non productive cough. On clinical                            therapy, immunomodulation and antifibrotic
examination bilateral basilar rales may be                        therapy.
present. In the case of PIF, spirometric                          Organ-specific therapies can be divided into the
evaluation reveals decreased forced vital                         therapy of PIF; PH; peripheral vascular disease;
capacities (FVC) and decreased total lung                         cardiac disease; renal crisis; gastrointestinal
capacities (TLC), while in case of PH, only the                   involvement; skin involvement; musculoskeletal
TLCO and the partial pressure of blood oxygen                     involvement [9].
are decreased. PH leads to right-sided heart
failure, which has very poor prognosis. Clinically                Systemic therapies
evident cardiac involvement occurs in nearly
10% of the lcSSc patients and more than 20% of                    Vascular therapy
the dcSSc patients, it is mainly due either to                    Smoking is completely prohibited. Drugs, such
abnormalities of the intra-myocardial circulation                 as ß-blockers, which aggravate vasoconstriction
(common) or to cardiomyopathy resulting from                      and Raynaud's phenomenon should be avoided.
myocardial fibrosis (rare). It is manifested as:                  Calcium chanel blockers reduce cellular uptake
a)       conduction       system       abnormalities              of calcium and therefore inhibit the contraction of
(arrhythmias) [8],                                                smooth muscle cells. Nifedipine at doses 10 mg
b) left-sided heart failure,                                      tid (ter in die) or in the tablets retard (40-60 mg
c) pericardial effusion (usually silent).                         daily, divided into two doses) may reduce the
However, ultrasound, electrophysiologic and                       frequency and the severity of the ischemic
thallium scanning studies revealed that                           attacks. Frequent adverse affects include
arrhythmia, or reperfusion abnormalities of the                   tachycardia, nausea, flushing, headaches,
intra-myocardial circulation occur in respectively                pretibial edema. The doses for the other drugs of
80%       and     95%      of     patients   [1-3,8].             the same category are diltiazem (60mg, tid),
Hypoxia/reperfusion injury due to vasospasm of                    nicardipine (20mg, tid), amlodipine (5 mg per
distal coronary vessels («cardiac» Raynaud's                      day) [10].
phenomenon), leads to the areas of contraction                    Prostaglandins         and      their    analogues:
band necrosis. Cardiac involvement has a poor                     prostaglandins are derived from arachidonic acid
prognosis. For reasons not fully understood,                      (AA), which is released primarily from the
pericarditis is a precipitating manifestation of                  phospholipids         phosphatidylinositol      and
renal crisis. Renal involvement occurs in nearly                  phosphatidylcholine of the cell membrane, via
2% of the lcSSc and 6%-30% of the dcSSc                           the enzyme phospholipase A2. Once released,

Vlachoyiannopoulos PG. Systemic sclerosis (scleroderma). Orphanet encyclopedia, November 2001.                                                                     4
AA can be converted into prostaglandins (PGs),                    morbidity such as cough, asthma, alveolitis and
thromboxanes (TXs) or leukotrienes (LTs),                         interstitial fibrosis.
depending       on     tissue      type,   enzyme                 Photophoresis is based on the inhibition of the
concentrations and cytokine milieu. Biologically                  activated        T     cells   by     extracorporeal
active PGs are PGD2, PGI2, (prostacyclin),                        photoactivated 8-methoxypsoralen. The patients
PGE2, and PGF2a. They act via cell - surface                      receive the photosensitizing component 8-
receptors and have important vasoactive                           methoxypsoralen            and     then      undergo
properties. Stimulation of PGE2, PGI2 and                         leukophoresis. Peripheral blood in an extra
PGD2 receptors leads to smooth muscle cell                        corporeal flow system is exposed to ultraviolet A
relaxation while stimulation of PGF2a, and TXA2                   (UVA). T lymphocytes sensitized by 8-
receptor     activates    smooth      muscle   cell               methoxysporalen are sensitive to UVA and their
contraction [10]. The short half-life of PGs made                 function. The results of various studies are
their pharmacologic use difficult and led to the                  conflicting       regarding    the     efficacy   of
discovery of prostaglandin analogues with longer                  photophoresis. Controlled studies are currently
half-life.                                                        in progress [9].
Carboprostacyclin      (iloprost),    a   synthetic               Autologous stem cell transplantation aims at
analogue of prostacyclin, has proven to be                        eliminating the active (including autoreactive) T
useful in reducing severe ischemia which can                      lymphocytes and «reprogramming» the immune
lead to digit amputation. The drug should be                      system by infusing their progenitor cells, known
used on an inpatient basis by slow intravenous                    as CD34 positive stem cells. Improvement in
infusion at doses ranging from 0.5 to 2 ng/kg/min                 skin score in 69% of the cases was reported.
for 6 hours per day for 4 weeks [11]. In addition                 Lung function was not improved in a recent
to vasodilatation, the drug inhibits platelet                     study while 17% of the patients died from the
aggregation, decreases blood viscosity and                        procedure [16]. This procedure still remains an
alters neutrophil function [9]. For the                           experimental therapy.
management of Raynaud's phenomenon [12],
oral iloprost shows the same efficacy than                        Antifibrotic therapy
placebo.                                                          D-Penicillamine [17], interferons (α-and - ß) [9],
Antagonists of angiotensin II receptor, type 1;                   recombinant human relaxin [18] have been
Losartan compared with nifedipine in a                            tested in controlled trials which did not show any
randomized, parallel group, controlled trial was                  benefit.
shown to be effective as a short-term treatment
of Raynaud's phenomenon [13].                                     Organ specific therapies

Immunomodulation                                                  Pulmonary Interstitial fibrosis (fibrosing alveolitis)
Activation of the immune system plays a key-role                  Prednisolone, cyclophosphamide, either per os
at disease onset and on the disease-related                       or in intraveinous (IV) pulses, azathioprine and
organ damage.                                                     home oxygen have been used with limited
Cyclosporine A suppresses cell-mediated                           success. Their efficacy has not been tested in
immunity and collagen synthesis by activated                      controlled trials. Spirometry and PIF score on
SSc derived fibroblasts. The major response                       HRCT are response parameters.
parameter evaluated in open studies was the                       Cyclophosphamide either as monthly IV
severity and the extent of skin involvement,                      injections at a dose of 0.750 g to 1 g/m2 or as a
known as «skin score» [14]. Hypertension,                         50mg to 125 mg oral daily dose has shown
hypertrichosis and deterioration of renal function                some benefit in open studies [19]. Controlled
are common side effects. Arteriolar hyalinization                 studies are in progress. Many experts add small
and interstitial fibrosis have been reported in the               doses of prednisolone, (20 mg daily or less) to
kidney of patients treated with cyclosporine. In                  the above-mentioned regimen.
addition, endothelial cell stimulation of                         Corticosteroids have been widely used for the
endothelin production by cyclosporine was                         treatment of interstitial lung disease with
described. Relying on these findings, this drug                   conflicting results [9].
should not be recommended for the treatment of                    Azathioprine at a daily dose of 2.4 mg/kg has
SSc [9].                                                          been used following a 3-month induction phase
Methotrexate, 15mg per week, reduces the                          with cyclophosphamide, especially in females
extent of skin involvement. However, its effect is                who are at child bearing age [9].
not sufficient to consider the drug as significantly              Therapy is required for PH, especially when
effective for the treatment of dcSSc [15]. In                     pulmonary artery pressure is above 50 mmHg
addition, methotrexate may induce pulmonary                       and TLCO < 70%. Evidence for long-term

Vlachoyiannopoulos PG. Systemic sclerosis (scleroderma). Orphanet encyclopedia, November 2001.                                                                        5
efficacy for the regimens described below is                      Cardiac involvement
lacking.                                                          It is treated on an empirical basis, depending
Calcium chanel blockers and ACE inhibitors.                       upon its type.
Short- and medium- term efficacy has been
shown for nifedipine and captopril, as detected                   Etiology
by a decrease in mean pulmonary vascular                          SSc is rather common in coal and gold miners
resistance [9].                                                   and in workers exposed to vinyl-chloride,
Carboprostacyclin (Iloprost) has been used by                     epoxyresins      and aromatic hydrocarbons.
direct infusion into the pulmonary artery, then by                Individuals taking pentazocin, bleomycin and
oral and inhaled delivery. One of the main                        products containing L-tryptophan develop SSc-
problems is the need for sustained drug release                   like features [2,3,9]. However, all these factors
for years and the decreasing of systemic                          do not explain the spontaneously developed
vascular resistance which may precipitate a fall                  disease. The activation of the immune system is
in cardiac output [9].                                            an outstanding disease feature. Autoantibodies
Prostacyclin (epoprostenol) in continuous,                        and perivascular lymphocytic (mainly CD4
intravenous infusion improves the exercise                        positive T lymphocytes) infiltrates indicate
capacity of the patients after 12 weeks of                        activation of the immune system. The CD4
therapy compared to conventional therapy alone                    positive T cells can be activated by endothelial
[20].                                                             basement membrane components like laminine
Warfarin increases survival in primary PH, but                    and type IV collagen. Consequently, these cells
the drug has not been tested in PH secondary                      secrete an endothelial cytotoxic factor, named
to SSc.                                                           granzyme, as well as tumor necrosis factor
Oxygen was shown to reduce pulmonary                              (TNF) which activates endothelial cells and
vascular resistance for a short period of time.                   transforming growth factor - β (TGF-β) which
Single lung or heart/lung transplantation is still                activates fibroblasts to express TGF- β and
an experimental therapy, although there are                       platelet-derived growth factor (PDGF). PDGF
encouraging results from a small number of                        activates fibroblasts to secrete increased
transplanted patients [9].                                        amounts of collagen. The chronic form of GVHD
                                                                  (a T-cell dependent disease) shares clinical
Renal disease                                                     features with SSc. This observation supported
Management of renal disease requires a high                       the hypothesis that alloreactive T cells derived
index of suspicion, especially the first 4 years [9].             from the child survive for a long time in the
Doses of prednisolone above 20mg daily should                     mother's body and vice-versa. This phenomenon
be avoided. Blood pressure should be controlled                   is called «microchimerism». Chimeras may
by ACE inhibitors. In case of renal crisis the                    survive longer if histocompatibility exists
patient should be hospitalized and high doses of                  between mother and fetus [3,9]. Recently, CD34
captopril or endlapril should be prescribed with                  stem cells of child origin were detected in
the aim to reduce both, systolic and diastolic                    women with SSc more commonly than in normal
blood pressure. Short-term hemodialysis should                    women. Furthermore the SSc women display
be considered if necessary. The degree of                         histocompatibility on most of the HLA loci with
microangiopathic hemolytic anemia should be                       their children [3].
monitored carefully [9].
                                                                  Diagnostic methods
Gastrointestinal manifestations                                   Only clinical examination allows the diagnosis of
H2-blockers and proton pump inhibitors are                        scleroderma.
important therapeutic agents to eliminate
dysphagia, odynophagia and gastroesophageal                       Genetic counseling
reflux symptoms. The hypomotility of the small                    Genetic counseling cannot be carried out.
intestine responds to long-acting somatostatine
analogue octreotide and also to metoclopramide.                   Antenatal diagnosis
Therapeutic measures for malabsorption include                    Antenatal diagnosis cannot be carried out.
antibiotics, nutritional supplements, vitamins and
low-residue diets. Pseudo-obstruction of the                      Unresolved questions
large bowel should be treated carefully, after                    Regarding etiology, pathogenesis and         the
hospitalizing the patient and giving fluids                       therapeutic potential of various regimens.
intravenously [9].
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