Best Practice & Research Clinical Rheumatology

Vol. 21, No. 6, pp. 10931108, 2007

doi:10.1016/j.berh.2007.10.001
available online at http://www.sciencedirect.com

9
The contribution of capillaroscopy to the
differential diagnosis of connective
autoimmune diseases
Maurizio Cutolo *

MD

Professor of Internal Medicine and Rheumatology, Director of Research Laboratory

and Clinical Academic Unit of Rheumatology

Alberto Sulli

MD

Assistant Professor of Rheumatology

Maria Elena Secchi

MD

Postgraduate in Rheumatology

Monica Olivieri

MD

Postgraduate in Rheumatology

Carmen Pizzorni

MD

PhD Staff Member

Research Laboratory and Clinical Academic Unit of Rheumatology, University of Genova, Italy

Raynauds phenomenon (RP) is one of the earliest clinical hallmarks of microvascular involvement in several connective autoimmune rheumatic diseases. The direct observation of the
microvasculature with nailfold videocapillaroscopy (NVC) is useful for an early diagnosis of connective autoimmune diseases (secondary RP) and differentiation from primary (unsymptomatic)
RP. Generally, to detect early pathologic capillaroscopic changes, the following parameters are
considered: presence of enlarged and giant capillaries, haemorrhages, disorganization of the vascular array, ramified/bushy capillaries and loss of capillaries. Careful capillaroscopic analysis of
subjects affected by primary RP can detect the earliest signs of the transition to secondary
RP and thus screening procedures for further differential diagnosis within connective

* Corresponding author. Research Laboratory and Clinical Academic Unit of Rheumatology, Department of
Internal Medicine, University of Genova, Viale Benedetto XV 6, 16132 Genova, Italy. Tel.: 39 010 353 7994;
Fax: 39 010 353 8885.
E-mail address: mcutolo@unige.it (M. Cutolo).
1521-6942/$ - see front matter 2007 Elsevier Ltd. All rights reserved.

1094 M. Cutolo et al

autoimmune diseases can be undertaken. In systemic sclerosis, the recognition of clear and
different NVC morphological patterns (early, active, late) should suggest including this
analysis in the classification criteria of the disease.
Key words: capillaroscopy; connective autoimmune diseases; dermatomyositis; systemic lupus
erythematosus; systemic sclerosis.

RAYNAUDS PHENOMENON
Raynauds phenomenon (RP) (Figure 1) is the clinical hallmark of microvascular involvement in several connective autoimmune rheumatic diseases, and is particularly important in systemic sclerosis (Ssc).1 The occurrence of RP should lead to a prompt
microvascular analysis through a capillaroscopic examination to obtain an early differential diagnosis between primary (uncomplicated) and secondary (disease-associated)
RP.
According to population-based surveys of various ethnic groups, the prevalence of
RP is approximately 35% and geographic variations in prevalence reflect differences in
climate.2,3 Clinical criteria have been suggested to distinguish between patients with
uncomplicated, or primary, RP from those with secondary, disease-associated RP
(mostly connective autoimmune rheumatic diseases). The suggested criteria for primary RP include4:





symmetric attacks
the absence of tissue necrosis
ulceration or gangrene
the absence of a secondary cause (based on medical history and physical examination of the patient)
 a negative test for antinuclear antibodies

Figure 1. Raynauds phenomenon. The microcirculatory effects of vasoconstriction are visible in the fingers
(A-blue and B-white).

Capillaroscopy in the diagnosis of connective autoimmune diseases 1095

 a normal erythrocyte sedimentation rate

 the presence of normal nailfold capillaries.
The mean age at the onset of primary RP is 14 years, with 27% of cases beginning at
the age of 40 years or later.5
A secondary cause of RP is suggested by different findings including6:
 age at onset of more than 30 years
 episodes that appear intense, symmetric, painful and/or associated with ischemic
skin lesions
 clinical aspects suggestive of a connective tissue disease
 presence of specific autoantibodies
 evidence of microvascular alterations as assessed by microscopy of nailfold
capillaries.
A meta-analysis has calculated that in patients with presumed primary RP, a secondary disorder developed in 12.6%, all but 1 of whom had a connective autoimmune disease.7 However, 1520% of patients with RP who have autoantibodies, abnormalities
of nailfold capillaries, or both, and who do not initially meet the criteria for a welldefined connective tissue disease, will ultimately develop such disease within 2 years.8
It is now clear that subversion of the vascular tone, clinically evident as RP, is related to
modification of the function of the endothelium. Recently, new advances on the mechanisms involved in the loss of vascular tone in RP have been identified.
The direct observation of the microvasculature with capillaroscopy is useful both
for an early diagnosis of connective autoimmune diseases in presence of RP and for
functional studies, in particular with several technical modifications and implementations achieved in the past century.1
Capillaroscopic analysis of the microvasculature
Morphologic evaluation of skin capillaries is generally performed at the nailfold because that area is easily accessible for examination and because the major axis of
the capillaries is parallel to the skin surface, whereas in other areas it appears in

Figure 2. Nailfold videocapillaroscopic analysis. See text for details of the procedure.

1096 M. Cutolo et al

a perpendicular status. Each subject must remain in the room where the analysis is being conducted for a minimum of 15 minutes before the nailfold analysis; the constant
room temperature should be 2022  C. After placing a drop of immersion oil on the
nailfold bed to improve the image resolution, the nailfolds of all ten fingers should be
examined in each patient. Fingers affected by recent local trauma should not be
analysed.
Nailfold capillary microscopy has an impressive cost/effectiveness ratio: it is simple,
non-invasive, and inexpensive (Figure 2). In clinical practice, the skin capillaries are
generally observed through an incident light microscope. However, nailfold capillary
microscopy can be performed by means of a series of instruments, including the
ophthalmoscope, the stereomicroscope, the photomacrography, and more recently
the videocapillaroscopic systems.
Currently, videocapillaroscopic analysis is considered the most sophisticated tool
to for investigating the microvasculature and can also detect the blood flow at the level
of the microvessels. Handle videocapillaroscopic devices are available. Recently, the
handheld dermatoscope analysis of the nailfold gave interesting results, which were
comparable to those described with other more sophisticated instruments.9 As a general rule, all fingers should be evaluated, as already discussed. However, the most accurate morphologic assessments are commonly performed at the 4th and 5th fingers,
because of the greater transparency of the skin at these levels. Generally, to detect
early capillaroscopic changes in connective autoimmune diseases, the following parameters are considered, according to previous classifications: presence of enlarged and
giant capillaries, haemorrhages, disorganization of the vascular array, ramified/bushy
capillaries, loss of capillaries.1
Capillaroscopic microvascular morphology in Raynauds phenomenon
In normal conditions or in primary RP (excluding during the cold-exposure test) the
normal nailfold capillaroscopic pattern shows a regular disposition of the capillary
loops along with the nailbed (Figure 3). However, in patients suffering from secondary

Figure 3. The normal nailfold capillaroscopic pattern, showing the regular disposition of the capillary loops
along with the nail bed (magnification 200, M. Cutolo).

Capillaroscopy in the diagnosis of connective autoimmune diseases 1097

Figure 4. Homogeneously enlarged microvascular loops (giant capillaries). Note the characteristic, symmetrical shape of these ectasias (arrow) (magnification 200, M. Cutolo).

RP, one or more of the following capillaroscopic findings should alert the physician to
the possibility of a connective autoimmune disease not yet detected.
Enlarged capillaries (giant capillaries)
The detection of homogeneously enlarged microvascular loops (giant capillaries) represents the earliest and striking features of secondary RP (Figure 4). These ectasias
have a characteristic symmetrical shape, which distinguishes them from those observed in other pathological conditions, such as diabetes mellitus and acrocyanosis.
Capillaries with normal shape and diameter might coexist in most instances, together
with enlarged or giant loops. Even the detection of a single loop with a circumscribed

Figure 5. Local microhaemorrhages (magnification 200, M. Cutolo).

1098 M. Cutolo et al

or homogeneous diameter >50 microns should be considered as a potential marker of

microangiopathy related to an early scleroderma spectrum disorder. It has been suggested that microvascular dilatation (enlarged capillaries) represents a local autoregulatory response to tissue hypoxia.10 In recent studies, enlarged capillaries have been
found in 100% of Ssc patients, 86% of patients affected by dermatomyositis (DM)
and 56% of patients affected by undifferentiated connective tissue disease (UCTD).1
Local microhaemorrhages
Local microhaemorrhages are associated with early vascular damage. The appearance
of microhaemorrhages represents the bridge between the presence of megacapillaries and the subsequent loss of capillaries (Figure 5). The shape of microhaemorrhages
is totally variable.
Angiogenesis
A wide range of morphologic features of capillary neoformation can be observed in
patients with the secondary RP.11 Highly tortuous and arborized capillary loop clusters, often surrounded by dropout of normal capillary loops are a characteristic feature of angiogenesis (Figure 6). The main morphologic hallmark of angiogenesis is
the clustering of tortuous capillaries with a pronounced shape heterogeneity, including
thin or large meandering and bushy capillaries (ramified capillaries).11 Moreover, coiled
capillaries are the morphologic hallmark of angiogenesis in the elongated papillae of
psoriatic plaque.12 These aspects are also frequently observed in DM.
Loss of capillaries and/or avascular areas
A decreased number of loops (<30 over 5 mm in the distal row of the nailfold) should be
considered highly specific for secondary RP.12 Loss of capillaries can be relevant in determining critical tissue hypoxia (Figure 7). It has been estimated that the number of normal

Figure 6. Tortuous and arborized capillary loop clusters (magnification 200, M. Cutolo).

Capillaroscopy in the diagnosis of connective autoimmune diseases 1099

Figure 7. A decreased number of capillary loops (magnification 200, M. Cutolo).

capillaries might be reduced to perhaps only 20% in Ssc patients.13 The extensive disappearance of capillaries might generate large avascular areas with a desert-like appearance of the nailbed. In patients with even recent onset of the RP, the appearance of
rapidly progressive capillary loss might represent the first dramatic capillaroscopic
evidence of severe Ssc. Progressive loss of capillaries has been associated with more
extensive skin involvement and with a poor.14,15
Architectural derangement of the nailfold microvascular network
Modification of the normal architectural arrangement represents an early morphological feature in Ssc and other connective autoimmune diseases (Figure 8). Interestingly,
in patients with recent-onset secondary RP, these changes might be patchy, unilateral
or expressed in a single finger.

Figure 8. Modified normal architectural arrangement in Ssc (magnification 200, M. Cutolo).

1100 M. Cutolo et al

Enlarged loops, haemorrhages, angiogenesis, loss of capillaries and avascular areas,

and architectural disorganization characterize more than 95% of patients with overt
Ssc. The term scleroderma pattern includes all the sequential capillaroscopic changes
typical of the microvascular involvement in Ssc and represents an important diagnostic
criterion.16 The capillaroscopic aspects observed in DM and UCTD are generally
reported as having a scleroderma-like pattern.
The scleroderma pattern
The peripheral microvascular damage in Ssc is mainly characterized by increasing
structural alterations of the capillaries with progressive decrease of their density.
Blood flow is also altered, with reduced blood flow and increased periods of stasis.17,18
Previous studies have partially graded the morphological aspects of the vascular damage in patients with Ssc, as assessed by nailfold capillaroscopy, and two major patterns
within the term of scleroderma pattern have been recognized from the beginning:
namely the active and the slow patterns (Figure 9).19
New classifications have been proposed recently. These relate to selected characteristics of the disease progression and aim to improve the diagnostic and prognostic
power of the capillaroscopic analysis.20,21 In a recent study, microvascular alterations
as detected by NVC in patients with Ssc were reclassified in three different patterns
(see Figure 6).22 The three NVC patterns identified within the scleroderma pattern
have been called early, active and late.

Figure 9. The scleroderma pattern: early, active and late NVC patterns. See text for details (magnification 200, M. Cutolo).

Capillaroscopy in the diagnosis of connective autoimmune diseases 1101

The early NVC pattern contains few enlarged/giant capillaries, few capillary haemorrhages, relatively well-preserved capillary distribution and no evident loss of capillaries. The active NVC pattern involves frequent giant capillaries, frequent capillary
haemorrhages, moderate loss of capillaries, mild disorganization of the capillary architecture and absent or mild ramified capillaries. The late NVC pattern includes irregular enlargement of the capillaries, few or absent giant capillaries and haemorrhages,
severe loss of capillaries with extensive avascular areas, disorganization of the normal
capillary array and ramified/bushy capillaries.
The study confirmed previous observations, indicating enlarged and giant capillaries, together with haemorrhages, as the earliest NVC finding in Ssc22; these abnormalities become rare in the late stage of the disease. However, as already reported by
other authors, the early stage is also characterized by the coexistence of normaldiameter microvessels and a few enlarged capillaries. These early-phase nailfold
changes must be investigated carefully, on all fingers.23
Ssc patients with an active pattern show a marked increase in such nailfold changes.
Loss of capillaries, together with vascular architectural disorganization and ramified
capillaries were found to be rare in the early stages of Ssc, whereas they seem to increase
with the progression of the fibrotic phase of the disease (active and late patterns).
A significant and gradual increase of these latter vascular abnormalities is observed during the Ssc progression and the three NVC patterns have been found to correlate with both
RP and Ssc duration, reflecting at least the possible evolution of the disease process.24
An increased vascular permeability and a reduced blood flow is observed in all NVC
groups confirming previous studies.3 Furthermore, NVC in Ssc allows observation of
the prolonged phases of reduced or ceased capillary perfusion as a result of coldinduced peripheral vasospasm.
Whereas in healthy control subjects and in patients with primary RP the morphologic
features of the nailfold microvascular bed might remain unchanged for a long time, patients with RP associated with scleroderma-spectrum disorders might show a higher degree of morphologic variability, even after a few days. The NVC patterns have been
correlated with different clinical aspects and manifestations of Ssc, as well as to the
effects of treatment contributing to the overall study of the disease.2529
Capillaroscopic patterns and connective autoimmune rheumatic diseases
The presence of megacapillaries and a decreased capillary density are the hallmarks of the
scleroderma capillary pattern, which can be detected by nailfold Capillaroscopy. A large
recent study of 186 patients with RP investigated 65 patients with undifferentiated connective tissue disease (UCTD), 47 with systemic lupus erythematosus (SLE), 26 with dermato-/polymyositis, 14 with rheumatoid arthritis and 7 with primary Sjogrens syndrome.
In addition; 102 patients with Ssc were investigated.30 Of the 16 patients with diffuse cutaneous Ssc and the 86 limited cutaneous Ssc cases, 14 (87.5%) and 53 (61.6%) showed
the scleroderma capillary pattern, respectively. Nine of the 65 (13.8%) cases with UCTD
and 24 of the 186 (12.9%) cases with RP also exhibited a pattern very similar. Seven of the
26 (26.9%) with dermato-/polymyositis and no patients with rheumatoid arthritis or
Sjogrens syndrome exhibited the scleroderma-like pattern.
The conclusion is that the scleroderma pattern is often present in Ssc and dermato-/polymyositis, and that patients with RP and UCTD might also occasionally exhibit this pattern. Capillaroscopy therefore seems to be a useful tool for the early
selection of those patients who are potential candidates for developing scleroderma
spectrum disorders.

1102 M. Cutolo et al

DERMATOMYOSITIS
A defined pattern has been reported in patients affected by dermatomyositis.31 This
pattern, often associated with aspects of the scleroderma pattern, includes the presence of two or more of the following findings in at least two nailfolds: enlargement of
capillary loops, loss of capillaries, disorganization of the normal distribution of
capillaries, budding (bushy) capillaries and capillary haemorrhages (Figure 10).32
SYSTEMIC LUPUS ERYTHEMATOSUS
The SLE pattern generally includes morphological alterations of capillary loops, venular
visibility and sludging of blood with variability of capillary loop length (Figure 11).33,34 A
recent study evaluated the association between the nailfold capillary abnormalities frequently observed in patients with SLE and the presence of RP, anti-U1RNP and anticardiolipin (aCL) antibodies.35 One hundred SLE patients were studied. Wide-field nailfold
capillaroscopy was considered abnormal according to five criteria. Intercapillary distance, capillary width and capillary length were registered by videomorphometry in
two fingers in 100 patients and in four fingers in 40 of these patients. Both the presence
of altered capillaroscopy and the presence of the scleroderma pattern, characterized by
the presence of avascular areas and enlarged or giant loops, were associated with the isolated presence of RP (P < 0.001) or anti-U1RNP antibodies (P < 0.01), as well as with the
simultaneous presence of RP and anti-U1RNP antibodies (P < 0.001). Higher figures for
the videomorphometric parameters capillary width, intercapillary distance and capillary
length were observed in patients with RP. Patients presenting both RP and anti-U1RNP
antibodies showed higher figures for intercapillary distance and capillary width. This
study demonstrated significant association between nailfold capillaroscopic abnormalities and either RP or anti-U1RNP antibodies in patients with SLE. The association of
RP, anti-U1RNP antibodies and scleroderma-like findings on nailfold capillaroscopy
(the scleroderma pattern) in patients with SLE might suggest a new SLE subset with
subclinical features of Ssc.

Figure 10. The dermatomyositis pattern. See text for details (magnification 200, M. Cutolo).

Capillaroscopy in the diagnosis of connective autoimmune diseases 1103

Figure 11. The SLE pattern (magnification 200, M. Cutolo).

A previous study evaluated the relationship between aCL (found in 4050% of patients suffering from SLE) and skin microcirculatory changes or vascular symptoms in
51 consecutive SLE patients.36 Twenty-two patients (43.1%) had positive. aCL (IgG 22
(560) GPL; IgM 5 (316.5) MPL; median titre and range) and 12 (54.5%) of them had
abnormal capilloscopic findings. By contrast, among the 29 patients without aCL, only
six (20.7%) had an abnormal capillaroscopy (P 0.027). There was no correlation
between either aCL or capillaroscopy and RP. These results showed a relationship
between aCL and nailfold capillary changes in patients with SLE, suggesting a direct
damage of the vascular endothelium by aCL.
ANTIPHOSPHOLIPID SYNDROME
Interesting microvascular alterations have been observed in patients affected by antiphospholipid syndrome (APS). One study reported symmetrical microhaemorrhages

Figure 12. The antiphospholipid syndrome pattern (magnification 200, M. Cutolo).

1104 M. Cutolo et al

at the nailfold analysis; these were found to be particularly significant in patients with
both serum IgG and IgM aCL (Figure 12).37 Marked microcirculatory damage was
found to be related to the occurrence of thrombotic manifestations in patients with
APS in other studies, confirming the pattern.38
A more recent study confirmed that nailfold capillary morphology is altered in patients
with APS, but these changes could not be correlated to impairment of functional parameters.39 Although uncommon, the occurrence of small-vessel occlusions (thrombotic microangiopathy) in association with antiphospholipid antibodies (aPL) affecting, for example,
the retinal vessels, the nailfold, the skin or major intrabdominal organs such as the kidney,
the liver or the bowel, is well documented and defined as microangiopathic APS.40
GREN SYNDROME
SJO
Capillaroscopic changes have been observed in primary Sjogren syndrome (SS).41 Forty
patients with SS (14 without RP, 16 with RP, 10 with aCL), 20 patients with Ssc (10
with limited and 10 with diffuse disease) (disease control group) and 40 healthy controls
(control group) were evaluated by nailfold capillaroscopy. Capillaroscopic abnormalities in
SS ranged from non-specific findings (crossed capillaries) to more specific findings (confluent haemorrhages and pericapillary haemorrhages) or scleroderma-type findings. SS
patients with RP presented capillary abnormalities in higher frequency than patients without RP. The majority of SS patients with aCL (80%) presented scleroderma-type findings.
Nailfold capillaroscopy can be used as a simple non-invasive method to evaluate the microvascular abnormalities in SS patients, especially in those with RP and those with aCL.42
OTHER DISEASES
Patients with mixed cryoglobulinaemia show a variety of microcirculatory changes, often clustered in a characteristic pattern of abnormally oriented, short capillaries and
neoangiogenetic phenomena. Capillary changes are more numerous in nephritic
patients.43 Altered microvasculature has also been reported in psoriasis and psoriatic
arthritis.44 A large study showed a significant decrease in capillary loop density in patients with either psoriasis plus nail disease (14.5  5.7 capillaries per 3-mm field) or
psoriasis plus nail and distal interphalangeal (DIP) joint disease (14.3  5.0) compared
with controls (19.2  3.8).45 Patients with psoriatic arthritis affecting the DIP joints
demonstrated a statistically significant decrease in arterial and venous capillary limb
diameters; this was also seen in those with arthritis associated with nail changes. However, there was no difference in capillary dimensions between patients with psoriasis
and/or nail changes when compared with normal controls.
Capillaroscopic abnormalities have been reported also in rheumatoid arthritis
patients and familial Mediterranean fever.46,47
TRANSITION FROM PRIMARY TO SECONDARY RAYNAUDS
PHENOMENON: THE ROLE OF NAILFOLD
VIDEOCAPILLAROSCOPY
Nailfold videocapillaroscopy is a tool that allows us to distinguish between primary and
secondary RP and that allows, through the recognition of the early microvascular pattern, the early differential diagnosis at least of Ssc.48 The recognition of different NVC
morphological patterns (early, active,late), and a significant and gradual increase

Capillaroscopy in the diagnosis of connective autoimmune diseases 1105

of these latter microvascular abnormalities, are observed during the disease and seem to
reflect the possible evolution of the pathophysiologic process.24 In a recent study, 20% of
patients initially diagnosed as having primary RP were found to have transitioned to either
suspected secondary RP or secondary RP based on identifying an associated disease during the follow-up period of 10 years.49 The annual incidence of transition to suspected
secondary RP was 2%, and the annual incidence of transition to secondary RP was 1%.
Although vital capillary microscopy was considered in this study, its relevance for the diagnosis was partially underestimated. In a more recent study, 129 subjects initially referred at the NVC analysis as primary RP were evaluated.50 Based on the appearance
of the well-assessed NVC patterns, 14.6% of patients were classified as secondary RP
over a mean follow-up of 29.4  10 months. Interestigly, 4.6% of these patients showed
at baseline a normal NVC pattern (transition from normal to altered pattern in 42  30
months) and 10% showed at baseline minimal and non-significant microvascular changes
(transition to altered pattern in 25  15 months). The duration of RP from the beginning
up to the transition to secondary RP was 58  10 and 29  10 months, respectively, for
the two groups that were formed by the 80% of Ssc patients who showed the wellassessed scleroderma pattern. Positivity for an ANA titer >160 was observed later during follow-up (29.4  10 months) in almost 85% of the Ssc patients. The initial prevalence
of secondary RP, following the extended screening programme, was 11% in the study by
Hirsch; however, during the follow-up period of 11.2  3.9 years the prevalence shifted
to 14.9%.49 In the more recent capillaroscopic investigation, following a careful NVC
analysis, a similar prevalence for secondary RP (14.6%) was defined during a follow-up
of 29.4  10 months. The comparison between the two studies showed that the transition from primary to secondary RP should be supported by both clinical/laboratory parameters and microvascular change investigations. However, more than 90% of Ssc
patients and 85% of patients with mixed connective tissue disease (MCTD) present
with RP as an early symptom. The detection of scleroderma patterns (or of the scleroderma-like pattern in case of MCTD and dermatomyositis) by NCV allows a definite differential diagnosis between primary and secondary RP.51 In conclusion, we suggest
a careful, twice yearly capillaroscopic analysis of the subjects affected by primary RP to
detect the transition to secondary RP as early as possible and to extend the screening
procedures for further differential dignosis within connective autoimmune diseases.52
Practice points
 Capillaroscopy is the best and most reliable method of distinguishing between
primary and secondary Raynauds phenomemon.
 Nailfold capillary microscopy has an impressive cost/effectiveness ratio; it is
simple, non invasive, and inexpensive.
 The presence, on capillaroscopic analysis, of giant capillaries and microhaemorrhages is sufficient to identify the scleroderma pattern (early).
 In normal conditions or in primary RP (excluding during the cold-exposure
test), the normal nailfold capillaroscopic pattern shows a regular disposition
of the capillary loops along with the nailbed.
 The diagnosis of dermatomyositis is defined also by the presence of a welldefined capillaroscopic pattern (scleroderma-like).
 The follow-up by nailfold capillararoscopy (analysis every 6 months) is suggested in presence of Raynauds phenomenon.

1106 M. Cutolo et al

Research agenda
 Large, controlled studies are needed to evaluate (through capillaroscopy) the
rate of transition from primary to secondary Raynauds phenomenon.
 The results of the capillaroscopic analysis must be included in the classification
criteria of systemic sclerosis at least.
 The employment of handle capillaroscopes might induce a greater use of the
study of the miscrovasculature in connective autoimmune rheumatic diseases.
 Controlled studies should finally define if the microvascular abnormalities observed during systemic sclerosis and detected by capillaroscopy, might reflect
at least the possible evolution of the pathophysiologic process and therapeutical effects.

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