Updated evidence-based (S2e) European Dermatology Forum guideline on topical corticosteroids in pregnancy.

BACKGROUND: Topical corticosteroids may be needed for treating skin conditions in pregnancy. Nevertheless, only limited data on the fetal effects of topical corticosteroids are available. OBJECTIVE: To update an evidence-based guideline on the safe use of topical corticosteroids in pregnancy. METHODS: A guideline subcommittee of the European Dermatology Forum updated the guideline by adding and appraising new evidence. RESULTS: The current best evidence from 14 observational studies with 1 601 515 study subjects found no significant associations between maternal use of topical corticosteroids of any potency and some adverse pregnancy outcomes including mode of delivery, birth defect, preterm delivery and fetal death. However, maternal use of potent/very potent topical corticosteroids, especially in large amounts, is associated with an increase in the risk of low birthweight. CONCLUSION: Mild/moderate topical corticosteroids should be preferred to potent/very potent ones in pregnancy. The well-known topical side-effects of corticosteroids on the mother's side need to be considered as well.

Evidence-based (S3) guideline on topical corticosteroids in pregnancy.

Women with skin conditions may need topical corticosteroids during pregnancy. However, little is known about the effects of topical corticosteroids on the fetus. A guideline subcommittee of the European Dermatology Forum was organized to develop an evidence-based guideline on the use of topical corticosteroids in pregnancy (http://www.euroderm.org/edf/images/stories/guidelines/EDF-Guideline-on-Steroids-in-Pregnancy.pdf). The evidence from a Cochrane Review suggested that the major possible adverse effects on the fetus of topical corticosteroids were orofacial clefts when used preconceptionally and in the first trimester of pregnancy, and fetal growth restriction when very potent topical corticosteroids were used during pregnancy. To obtain robust evidence, a large population-based cohort study (on 84,133 pregnant women from the U.K. General Practice Research Database) was performed, which found a significant association of fetal growth restriction with maternal exposure to potent/very potent topical corticosteroids, but not with mild/moderate topical corticosteroids. No associations of maternal exposure to topical corticosteroids of any potency with orofacial cleft, preterm delivery and fetal death were found. Moreover, another recent Danish cohort study did not support a causal association between topical corticosteroid and orofacial cleft. The current best evidence suggests that mild/moderate topical corticosteroids are preferred to potent/very potent ones in pregnancy, because of the associated risk of fetal growth restriction with the latter.

[Generation of reactive oxygen species in vitro by Malassezia yeasts]. / Bildung von reaktiven Sauerstoffspezies in vitro durch Malassezia-Hefen.

BACKGROUND AND METHODS: Free oxygen species are able to destroy cells due to their cytotoxic effect, which is based on lipid peroxidation, enzyme oxidation and protein oxidation. We analyzed the ability of six different Malassezia (M.) species to generate reactive oxygen species (ROS), using the lucigenin-amplified chemiluminescence. Further investigations showed the effect of different concentrations of terbinafine on ROS generation by M. furfur and M. pachydermatis after 10, 30 and 60 minutes. RESULTS: All of the investigated Malassezia species (M. furfur, M. globosa, M. sympodialis, M. slooffiae, M. obtusa, M. pachydermatis) was able to generate reactive oxygen species. Terbinafine inhibited free radical production by M. furfur and M. pachydermatis. CONCLUSION: Dependent on their cell concentrations, M. species have the ability to generate ROS. The ability of the different Malassezia species to produce ROS should be considered as one further virulence factor of this yeast. The antifungal agent terbinafine (concentrations from 100 microg to 1 microg ml -1) reduced ROS production by M. furfur and M. pachydermatis. Terbinafine acts as oxygen species scavenger. This could be an additional mechanism supporting the classic antifungal effect of this agent, the inhibition of ergosterol synthesis.

Human papillomavirus infections in nonmelanoma skin cancers from renal transplant recipients and nonimmunosuppressed patients.

BACKGROUND: Nonmelanoma carcinomas of the skin represent the most frequent cancers among the Caucasian population worldwide. They occur with high frequency in renal allograft recipient patients after prolonged immunosuppression. PURPOSE: We analyzed tumors obtained from both immunosuppressed and nonimmunosuppressed patients for human papillomavirus (HPV) DNA. METHODS: Twenty-nine specimens of nonmelanoma carcinomas of the skin were obtained from 19 renal allograft recipient patients; these included 20 specimens of squamous cell carcinoma (SCC) from 11 patients, five specimens of basal cell carcinoma (BCC) from four patients, and four specimens of carcinoma in situ (CIS) from four patients. Forty-one specimens of nonmelanoma carcinomas of the skin were obtained from 32 nonimmunosuppressed patients; these included 26 SCC specimens from 19 patients, 11 BCC specimens from nine patients, and four keratoacanthoma (benign epithelial tumor) specimens from four patients. A polymerase chain reaction method involving use of degenerate oligonucleotide primers, in which the conserved region of the open reading frame of the HPV L1 (major capsid protein) gene is amplified, was used to amplify total cellular DNA purified from individual tumors. The DNA of each specimen was subjected to 16 different amplification reactions; different primer combinations were used in order to increase the sensitivity and specificity of HPV detection. Resulting products were probed with a radioactively labeled, degenerate oligonucleotide. HPV-specific DNA was either sequenced directly after elution from the gel or amplified with semi-nested, degenerate primers, after which the products were cloned and sequenced. Sequences were compared with all known papillomavirus sequences. RESULTS: Thirteen (65%) of the 20 SCC specimens and three of the five BCC specimens from immunosuppressed (renal allograft recipient) patients contained identifiable HPV-related sequences, among them 13 putative novel HPV genomes. In addition, all other malignant tumor specimens from this patient group revealed faint signals upon amplification and hybridization; the origin of these signals has not been identified in the present study. In nonimmunosuppressed patients, eight (31%) of 26 SCC specimens and four (36%) of 11 BCC specimens contained sequences of HPV types. Two putative novel HPV sequences could be identified in this group. Faint signals of yet undetermined origin were observed in eight of the SCC specimens and in two of the BCC specimens. Two of four keratoacanthoma specimens contained sequences of known HPV type. (Keratoacanthoma is a nonmalignant lesion for which the natural history has not been defined.) The spectrum of HPV types in both groups of patients differed substantially. CONCLUSIONS: These data point to the frequent presence of HPV sequences in SCCs and BCCs of the skin. The etiologic relationship of these infections to the respective malignant tumors remains to be evaluated. IMPLICATIONS: The presence of HPV DNA in a large percentage of specimens of nonmelanoma carcinomas of the skin from immunosuppressed patients, as well as from nonimmmunosuppressed patients, renders a papillomavirus infection as a possible factor in the etiology of this disease.

A ligand of human thy-1 is localized on polymorphonuclear leukocytes and monocytes and mediates the binding to activated thy-1-positive microvascular endothelial cells and fibroblasts.

Thy-1 is known to be expressed on fibroblasts, nerve cells, and blood stem cells. Previous studies have shown the induction of Thy-1 on phorbol ester stimulated human dermal microvascular endothelial cells in vitro. In situ Thy-1 expression was found on activated endothelium. In this study we were interested in the localization of a Thy-1 ligand and the characterization of the function of Thy-1 on human dermal microvascular endothelial cells and fibroblasts. Human Thy-1 purified from fibroblast extracts was labeled and used as a probe for the detection of a Thy-1 ligand. In cryostat sections of bullous pemphigoid skin a Thy-1 ligand was found on inflammatory cells, whereas the Thy-1 antigen was expressed on the endothelial cells and fibroblasts. By flow cytometry we could show the expression of a Thy-1 ligand on polymorphonuclear leukocytes and monocytes, whereas lymphocytes did not express this Thy-1 ligand. To study whether Thy-1 is involved in cell-cell adhesion we separated Thy-1-positive and Thy-1-negative cells by magnetic cell separation using the monoclonal antibody AS02. Cell adhesion assays and blocking experiments revealed a direct involvement of the Thy-1/Thy-1 ligand interaction in the binding of monocytes and polymorphonuclear leukocytes to Thy-1-positive activated endothelial cells and fibroblasts.

Steady-state mRNA levels of collagens I, III, fibronectin, and collagenase in skin biopsies of systemic sclerosis patients.

Total RNA was extracted from skin biopsies of nine patients suffering from systemic sclerosis (SSc). Steady-state mRNA levels of collagen alpha 1(I) and alpha 1(III), collagenase, fibronectin, and beta-actin were studied using specific cDNA probes and compared to those of 12 sex- and age-matched healthy individuals. There was a more than three-fold elevation of collagen I mRNA levels in SSc skin compared to controls. No difference was found, however, for collagen III, collagenase, and fibronectin mRNA levels in SSc and control biopsies. The selective increase of collagen alpha 1(I) mRNA levels indicates a specific alteration of fibroblast metabolism in scleroderma. Analysis of mRNA levels in skin biopsies might not only offer a direct approach to the understanding of the pathophysiology of SSc, but also facilitate the monitoring of fibrotic activity in SSc patients during therapeutic trials.

Novel fibroblast-specific monoclonal antibodies: properties and specificities.

Specific detection of fibroblasts has been one of the unsolved problems in cell biology. Because monoclonal antibodies (MoAbs) might provide an easy and reproducible method of fibroblast detection, we have produced a panel of MoAbs raised against cell surface proteins of human dermal fibroblasts. Using flow cytometry and immunohistochemistry, we have shown that two of these MoAbs, FibAS01 and FibAS02, react exclusively with human fibroblasts. They do not react in vitro with human keratinocytes, endothelial cells, or blood cells. Immunohistologic experiments investigating the binding pattern of the MoAbs FibAS01 and FibAS02 in cryostat sections of different tissues confirmed the flow cytometric results. In human skin, the antibodies exclusively labeled fibroblasts. In other human tissues such as lymph nodes, placenta, kidney, muscle, thyroid gland, gall bladder, cartilage, and tendon, the specificity for fibroblasts was borne out. Neither antibody reacts with fibroblasts from mouse, rat, or pig. The isotype was defined as an IgG1 for both. By western blot analysis, both antibodies detected a molecule of 60-65 kDa under reducing and nonreducing conditions. By immunoelectron microscopy, we observed the antigens on the cell surface without any clustering at specific sites. These data demonstrate that the two MoAbs, FibAS01 and FibAS02, exclusively recognize human fibroblasts.

Transforming growth factor-beta controls cell-matrix interaction of microvascular dermal endothelial cells by downregulation of integrin expression.

Transforming growth factor-beta (TGF-beta) is a pleiotropic regulatory factor of tissue remodeling. Angiogenesis, a prerequisite of tissue repair and tissue expansion, is induced by TGF-beta in vivo, while proliferation and migration of cultured endothelial cells are inhibited by TGF-beta. Indirect mechanisms stimulating angiogenesis and modification of TGF-beta effects by cell-matrix interaction have been postulated to account for this paradigm. Because cellular behavior in tissue remodeling is decisively determined by cell-matrix interactions, which in turn is mediated via integrins, we investigated the effect of TGF-beta on matrix-dependent endothelial cell functions. Integrin expression of human dermal microvascular endothelial cells (HDMEC) was measured by Northern blot and fluorescence-activated cell sorter analysis after TGF-beta treatment and correlated to cell-matrix interactions, which were studied in a colorimetric cell attachment assay as well as the Boyden chamber chemotaxis assay. We found a cell-specific downregulation of integrin expression in HDMEC on the level of mRNA as well as on the cell surface. This effect correlated well with the reduction of integrin-dependent cell adhesion to several matrix proteins, in particular to fibronectin. Moreover, TGF-beta decreased fibronectin-induced chemotaxis of HDMEC. Thus, TGF-beta controls cell-matrix interaction of HDMEC by down-regulation of integrin expression. This effect of TGF-beta reflects direct and cell-specific control mechanisms on microvascular cells that may be critical for the coordinated process of angiogenesis requiring a balance of stimulatory and inhibitory factors.

Chemokine release from activated human dermal microvascular endothelial cells--implications for the pathophysiology of scleroderma?

Long-term exposure to silica (SiO2) may induce silicosis as well as extrapulmonary diseases such as scleroderma. Infiltration of mononuclear cells and release of proinflammatory cytokines from these cells have been suggested to play a role in the development of inflammatory and immunological events typical of scleroderma as well as of silica-induced scleroderma. We showed that silica is able to directly activate cytokine expression in blood monocytes, collagenase expression in cultured dermal fibroblasts and ICAM-1 expression in human dermal microvascular endothelial cells. In the study reported here we found that silica and TNFalpha induce mRNA and protein of the chemokines RANTES and MCP-1 in endothelial cells. In addition, we demonstrated that culture supernatants of silica-treated endothelial cells are chemotactic for mononuclear cells from peripheral blood, suggesting that activation of endothelial cells may contribute to the chemotactic gradient necessary for extravasation of inflammatory blood cells into the surrounding tissue found in early scleroderma. However, a polyclonal anti-RANTES antibody failed to block chemotaxis suggesting that other proteins are involved in this phenomenon. We also studied the expression of RANTES in situ in the skin of systemic sclerosis patients and of healthy individuals. We found abundant RANTES mRNA expression in the skin of SSc patients, whereas in control skin no expression was found. From our data we conclude that RANTES and MCP-1 induction by silica may be an initiating event in inflammatory infiltration, whereas TNFalpha-mediated inflammation may propagate the disease more efficiently.

Lymphocytotoxic autoantibodies in progressive systemic sclerosis.

In 53 patients with progressive systemic sclerosis (PSS) the lymphocytotoxic activity of their serum was measured in a microlymphocytotoxicity assay. In 21 of the 53 patients the test reacted distinctly positively in the heterologous system, and in 9 of these 21 also in the autologous system. After preparation of the immunoglobulins from these positive sera, whole cytotoxic activity was detected only in the IgM fraction but not in the IgG fraction. When using prepared T lymphocytes as target cells in the microlymphocytotoxicity test, the cytotoxic activity of the positive PSS sera showed itself to be directed against this lymphocyte population. Further analysis using the Western-blot technique showed that the IgM autoantibody in PSS sera reacted with the cell surface of CD4+ lymphocytes. The cross reactivity with extractable nuclear antigens was rather improbable. These results suggest that lymphocytotoxic autoantibodies may play a role in immunological disturbances in PSS.

The monoclonal antibody AS02 recognizes a protein on human fibroblasts being highly homologous to Thy-1.

Recently, we described a novel fibroblast-restricted monoclonal antibody (mAb AS02) that recognizes a membrane-bound antigen. Characterization and isolation of the corresponding antigen showed that mAb AS02 recognized a protein on human fibroblasts that is highly homologous or identical to human Thy-1 antigen (CD90). Partial amino acid sequencing of the corresponding mAb AS02 antigen and comparison with known proteins revealed a 100% homology of the sequenced peptides to the human Thy-1 antigen. Cross-immunodepletion studies with mAb AS02 and an anti-Thy-1 antibody confirmed these results. Utilizing two-dimensional (2D) gel electrophoresis of fibroblast cell extracts and purified antigen, mAb AS02 and the anti-Thy-1-antibody recognized identical protein spots. Furthermore, we demonstrated many identical biochemical properties of the corresponding AS02 antigen and Thy-1 antigen, such as the molecular weight of the core protein and deglycosylation products and the detection of a GPI anchor. In functional assays, the attachment of fibroblasts to collagen I and fibronectin was increased after incubation of fibroblasts with mAb AS02. Therefore, the Thy-1 antigen appears to be involved in the regulation of the adherence of human dermal fibroblasts.

Serum levels of soluble Fas/APO-1 receptor are increased in systemic sclerosis.

It has been suggested that rheumatic diseases may result from a deficit in Fas-mediated T-cell apoptosis. Recent studies have demonstrated increased soluble Fas in sera from lupus erythematosus patients. We were interested to determine whether elevated soluble Fas levels are associated with systemic sclerosis. Soluble Fas levels were retrospectively assayed using a sandwich enzyme-linked immunosorbent assay in serum from 30 patients with systemic sclerosis and 15 normal controls. Hospital medical records were retrospectively reviewed for clinical and laboratory characteristics of the patients. Soluble Fas levels were analysed in subsets of patients with limited (lcSSc) versus diffuse cutaneous systemic sclerosis (dcSSc) and correlated with inflammatory activity. In systemic sclerosis soluble Fas serum levels (lcSSc, 2.19 +/- 0.71 ng/ml, dcSSc 2.53 +/- 1.37 ng/ml) were significantly higher than in normal controls (1.26 +/- 0.36 ng/ml). However, there were no significant differences in soluble Fas levels between lcSSc and dcSSc and poor correlation between soluble Fas levels and inflammatory activity status. Detection of elevated soluble Fas might serve as a clinical marker for immunological dysregulation in systemic sclerosis, but not for inflammatory disease activity.

Interleukin-2 receptor expression and interleukin-2 production in bullous pemphigoid.

Expression of interleukin-2 (IL2) receptors was studied on peripheral blood lymphocytes (PBLs) in 25 patients with bullous pemphigoid. Analysis was carried out by flow cytometry. Without immunosuppressive therapy expression of IL2 receptors only on T cells (CD5) was significantly increased as shown by double staining (11.9% +/- 7.8% vs 2.1% +/- 1% in controls). After 2-3 weeks under immunosuppressive treatment with prednisolone and azathioprine, however, BP lymphocytes did not exhibit any IL2 receptors. PBLs of 18 BP patients showed an increase in IL2 production (1027.4 +/- 670.5 U/ml vs 270 +/- 100 U/ml in controls) during the acute stage of the disease after stimulation with phytohaemagglutinin (PHA)/phorbol myristate acetate (PMA). On the contrary, IL2 production of the same cells in five patients was only in the lowest range of control values after PHA stimulation without PMA (12.5 +/- 29.6 U/ml vs 40 +/- 20 U/ml in controls). Under treatment with immunosuppressants the IL2 production normalized after PHA/PMA stimulation and slightly decreased following PHA stimulation. From these results we conclude that a T-cell activation via activation antigens, as IL2 receptors, and the production of the specific ligand, IL2, may play a role in the pathogenesis of bullous pemphigoid, especially in the earliest stages, and serve as a marker of disease activity.

Origin of the enhanced activity of lysosomal beta-galactosidase in serum and skin in progressive systemic sclerosis.

In 14 patients with progressive systemic sclerosis (PSS) the activities of acid lysosomal glycosidases (alpha-, beta-galactosidase, beta-glucosidase, beta-glucuronidase, and beta-N-acetyl-glucosaminidase) were determined fluorometrically in serum, leukocytes, and skin tissue. The beta-galactosidase was the only enzyme which exhibited a significantly elevated activity in PSS serum and skin but not leukocytes, as compared to the control. The activity patterns of the studied glycosidases in serum were similar to those found in skin, but differ from the distribution of glycosidase activities in leukocytes. In cultured dermal fibroblasts derived from PSS patients, an elevated intracellular activity of beta-galactosidase was detected. These results suggest that the increased beta-galactosidase activity in the serum originates from the skin fibroblasts.

Pemphigus vulgaris in association with silicosis.

We report on a sixty-seven year old miner with pemphigus vulgaris characterised clinically by a three month history of relapsing oral lesions and blisters/erosions on the trunk, axillae and extremities, histologically by suprabasal cleavage due to acantholysis, immunologically by the epidermal intercellular net-like pattern due to deposits of IgG- and IgM-antibodies and complement C3 in the direct immunofluorescence as well as by serum antibodies to desmoglein 3 (130 KD) and plakoglobin (85 KD) by immunoblotting analysis. Silicosis has already been known for 6 years. In addition, antinuclear antibodies, anti-ssDNA-antibodies and anti-topoisomerase antibodies were found. Clinical improvement and clearing of skin symptoms could be achieved by systemic steroids in combination with cyclophosphamide. However, the patient died of sepsis deriving from recalcitrant pneumonia. Although the association of silicosis with various autoimmune diseases such as systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis and dermatomyositis has been reported many times, our patient is, to the best of our knowledge, the second case with features of the two diseases: pemphigus vulgaris and silicosis.

Cyclosporine A delays wound healing and apoptosis and suppresses activin beta-A expression in rats.

Cyclosporine A is a powerful immunosuppressive agent which is widely used for the prevention of allograft rejection and for the treatment of autoimmune diseases. Clinical and experimental data show that it may also act on connective tissue. We investigated the influence of cyclosporine A on granulation tissue formation and wound healing. Using an in vitro approach, we followed the time course of rat dermal fibroblasts during wound repair. Granulation fibroblasts were compared to dermal fibroblasts flow cytometrically and by mRNA analysis with respect to the expression of procollagen alpha1(I), integrin beta1, interleukin-6, transforming growth factor beta1, keratinocyte growth factor and activin betaA. The most pronounced effect in cyclosporine-treated rats was the strong down-regulation of activin beta expression. In cryo-sections of granulation tissue from the same rats, the distribution and expression intensity of intercellular adhesion molecule and its receptors were investigated by immunohistology. Clearly, a time course was detectable. Tissue from CsA-treated animals showed a delay of three days compared to untreated animals. Apoptosis was also delayed in CsA-treated rats by around three days. Furthermore, we investigated the effect of CsA on the expression of collagen alpha1(I), fibronectin and matrix metalloprotease 1 genes in dermal fibroblasts from untreated donors. No changes in the mRNA steady state levels of these genes were revealed after direct addition of different doses of CsA to fibroblast cultures. Our data suggest that CsA may interfere with the complicated net of interactions between connective tissue and the immune system by down-regulation of the inflammatory phase by modulation of cytokines and a subsequent delay of tissue repair.

Pulmonary nocardiosis with cutaneous involvement mimicking a metastasizing lung carcinoma in a patient with chronic myelogenous leukaemia.

We report a unique case of a man suffering from chronic myelogenous leukaemia who presented with clinical symptoms, X-ray, and bronchoscopical findings consistant with a bronchopulmonary space-occupying process which was suspected to be a central lung carcinoma as a secondary de novo malignancy. In addition, the patient developed several subcutaneous nodular livid red lesions on the left forearm which were considered to be cutaneous metastases of the presumptive lung malignancy. Treatment was started with percutaneous radiation of the mediastinum over a period of ten days with a total dose of 25 Gray. The patient died from circulatory and respiratory failure. Only post mortem pathological examination was indicative of a nocardiosis of the lungs with haematological spread to eosophagus, pleura, and subcutaneous skin of the left forearm. Unfortunately, diagnosis of nocardiosis could not finally proven by culture or molecular biological methods. A lung carcinoma or an infiltrate of residual or relapsing chronic myelogenous leukemia in the lung could be definitely ruled out.

Cutaneous breast angiosarcoma after conserving treatment of breast cancer.

Cutaneous angiosarcoma is a rare malignancy that sometimes occurs as a late sequela of breast conservation therapy. We report on a 79-year-old female who developed well-differentiated angiosarcoma in a lymphedematous left breast 5.5 years after surgery and radiotherapy for early invasive ductal breast cancer. The initial appearance was very similar to late radiation dermatitis, and histologically interpreted as scar tissue with atypical vascular lesion. The lesion progressed further, and was clinically suspicious for angiosarcoma. Thus, a second biopsy was taken which confirmed the diagnosis. A complete mastectomy removed all the tumor with clear margins. However, within a period of 16 months she presented four local recurrences which were treated by wide local excision. At present, the patient is free of locally recurrent tumour for 7 months. The few cases of breast angiosarcoma after breast conservation therapy reported so far demonstrate that these lesions are difficult to diagnose due to their rarity and their highly variable and benign appearance, which sometimes may mimic radiation-induced cutaneous changes. Since chronic lymphedema possibly contributes to the development of angiosarcoma, long-term clinical surveillance of these patients is recommended. Biopsies should be taken if new skin lesions occur.

[Livedo racemosa with ulcerations. Cyclic therapy with iloprost infusions]. / Livedo racemosa mit Ulzerationen. Zyklische Therapie mit Iloprost (Ilomedin)-Infusionen : Zyklische Therapie mit Iloprost (Ilomedin)-Infusionen.

A 43 year old woman suffered from an intermittent painful livedo racemosa at the back since her childhood. Her clinical course was complicated by ulcerations. In careful clinical investigations no signs of an underlying disease could be found, in particular a Sneddon syndrome could be excluded. By means of both conservative and surgical treatments, initial healing of the ulcerations was achieved but relapses occurred. Cyclic infusions of iloprost achieved long-term clearing of the ulcerations and disappearance of the pain. To the best of our knowledge the effectiveness of this treatment has not been described for this disease in the literature.

Systemic sclerosis-scleroderma.

Systemic sclerosis is a clinically heterogeneous, systemic disorder which affects the connective tissue of the skin, internal organs and the walls of blood vessels. It is characterized by alterations of the microvasculature, disturbances of the immune system and by massive deposition of collagen and other matrix substances in the connective tissue. This review discusses epidemiology and survival, clinical features including subsets and internal organ involvement, pathophysiology and genetics, microvasculature, immunobiology, fibroblasts and connective tissue metabolism and environmental factors. Early diagnosis and individually tailored therapy help to manage this disorder, which is treatable, but not curable. Therapy involves immunomodulation as well as the targeting of blood vessel mechanics and fibrosis. Physical therapy and psychotherapy are also important adjunctive therapies in this multifactorial disease.