Phototherapy,photodynamic therapy and photophoresis in the treatment of connective‐tissue diseases: a review

Connective‐tissue disorders, which include lupus erythematosus, morphoea/scleroderma and dermatomyositis, are characterized by cutaneous manifestations that are sometimes resistant to conventional therapy. Light treatments, which include phototherapy, photodynamic therapy (PDT) and photopheresis, are routinely utilized in the treatment of dermatological conditions and may provide unique mechanisms of action in the treatment of these connective‐tissue disorders. The objective of this study is to conduct a review of the literature that describes the use of phototherapy, PDT and photopheresis in the treatment of lupus erythematosus, morphoea/scleroderma and dermatomyositis. A MEDLINE search was conducted to find articles that discuss treatment of connective‐tissue diseases with light therapies and more than 30 publications that discuss light therapy for these diseases were identified. These range in design from case reports to randomized, prospective trials. Study outcomes and details were summarized and presented within each connective‐tissue disease by light therapy modality, which includes phototherapy, PDT and photopheresis. Although there is a known association between photosensitivity and connective‐tissue diseases, light therapies, when used appropriately, may be legitimate therapeutic options for recalcitrant cutaneous manifestations in lupus erythematosus, morphoea/scleroderma and dermatomyositis.     

COLLAGEN-LIKE PROTEIN IN SERUM OF PATIENTS WITH CONNECTIVE TISSUE DISORDERS

Collagen-like protein (CLP) was demonstrated in the serum of normal human individuals and of patients with connective tissue disorders. The average amount of CLP in normals was 9.1 ± 0.2 μg/ml, whereas in systemic scleroderma, circumscribed scleroderma, and systemic lupus erythematosus the amounts were significantly lower. Serum CLP levels were also found to be decreased in pseudoxanthoma elasticum, striae atrophicae, and impetigo herpetiformis, but variable in dermatomyositis, and within normal limits in pyoderma gangrenosum. There seemed to be a relationship between the behavior of collagen-like protein and the severity of clinical manifestations in systemic scleroderma and systemic lupus erythematosus.     

Photosensitivity in collagen vascular diseases

Clinically, photosensitivity is clearly part of both lupus erythematosus and dermatomyositis, but the prevalence of this reaction varies. Photosensitivity does not appear to be part of the disease spectrum of scleroderma or part of the clinical picture of vasculitis. Implications of photosensitivity in both lupus erythematosus and dermatomyositis are systemic. The pathogenesis of photosensitivity in lupus erythematosus and dermatomyositis is not fully understood. The presence of photosensitivity has therapeutic implications.     

Physical therapy possibilities in the treatment of collagen diseases

We report about the rank of physiotherapy in the treatment of connective tissue diseases with special emphasize on scleroderma. Based upon therapeutic aim physiotherapeutic approaches for lupus erythematosus, dermatomyositis, and scleroderma are pointed out.     

Extensive calcinosis cutis with systemic lupus erythematosus

Calcinosis cutis is a common clinical feature of dermatomyositis and scleroderma but is only rarely reported in association with systemic lupus erythematosus (SLE). We describe three patients with long-standing systemic lupus erythematosus in whom extensive calcinosis cutis developed. We identify characteristics our patients share in common with 23 previously described patients.     

Clinical pearls and therapeutic challenges in connective tissue disease

ABSTRACT: The management of autoimmune skin disease is extremely challenging. This article provides the clinician with clinical pearls and highlights novel/anecdotal treatments for the management of recalcitrant discoid lupus erythematosus, lupus profundus, calcinosis cutis associated with dermatomyositis and scleroderma, and intractable pruritus in autoimmune disease. The disfigurement that occurs as a result of autoimmune skin diseases may be great. This article includes a discussion of the cosmetic and psychosocial concerns of patients. Lastly, wounds and wound care in autoimmune diseases are addressed along with practical management of challenging cases such as digital ulcers in Raynaud's disease, pyoderma gangrenosum, and ulcerating striae and leg ulcers in scleroderma and dermatomyositis.     

Chromosomal breakage in systemic sclerosis and related disorders.

Chromosome aberrations such as gaps and breaks of one or both chromatids, acentric fragments, dicentrics, ring chromosomes and other abnormal chromosomes are observed in lymphocyte and fibroblast cultures as well as in direct bone marrow preparations from patients with systemic sclerosis. A serum factor producing chromosome breaks in mitoses from healthy donors was observed in 37 of 42 scleroderma patients. The biochemical nature of this breakage factor is still undefined. Increased breakage is also noted in a high percentage of healthy family members of scleroderma patients. It is also a common feature of related disorders such as lupus erythematosus, dermatomyositis, periarteritis nodosa and rheumatoid arthritis. An increase in chromosome breaks and rearrangements is also present in NZB mice developing spontaneously an autoimmune disorder that has been extensively studied by workers interested in lupus erythematosus. The similarity of the cytogenetic findings provides the opportunity to use these mice as an experimental model to investigate relationships between immunological perturbations and chromosomal aberrations.     

Update on connective tissue diseases in dermatology

Recent advances in understanding the pathogenesis of autoimmune diseases, including lupus erythematosus, dermatomyositis, and scleroderma, have allowed for reorganization of the classification of these disorders. With these novel stratifications, early identification of rheumatic skin diseases with systemic implications and consistency in designing and executing therapeutic trials will be enhanced. This review will provide a compilation of updates on epidemiology, pathology, evaluation, and classification with a predominant focus on therapeutics, reflecting the growth is this area.     

Connective tissue panniculitis: lupus panniculitis,dermatomyositis, morphea/scleroderma

Panniculitis is an uncommon cutaneous manifestation of connective tissue diseases. Our discussion will include panniculitis occurring in the setting of lupus erythematosus, dermatomyositis, and scleroderma/morphea. These subtypes of panniculitis are unified by an active inflammatory stage of the disease that can progress to develop scarring, atrophy, and calcifications. Treatment is most effective if initiated during the active phase of the disease and often requires systemic therapy because of the location of the inflammation. Antimalarials are the initial treatment of choice for most cases of lupus erythematosus panniculitis, whereas corticosteroids in combination with other steroid‐sparing immunosuppressive agents are the first‐line treatment for panniculitis in patients with dermatomyositis. The appropriate treatment for panniculitis in the setting of morphea/scleroderma varies based on clinical severity.     

Diffuse soft tissue calcifications (calcinosis cutis) in a patient with discoid lupus erythematosus

Soft tissue calcification is known to occur in dermatomyositis, systemic scleroderma and CREST syndrome, but rarely in systemic lupus erythematosus (SLE). Diffuse soft tissue calcifications have not been reported in discoid lupus erythematosus (DLE). In a patient with discoid lupus erythematosus, calcinosis cutis developed about 20 years after the onset of the disease. During the follow-up time of 25 years, manifestations suggestive of a systemic disease were observed in our patient. However, no specific diagnosis could be established. The clinical, light and electron microscopic as well as immunohistochemical findings of our patient are reported. On the basis of electron microscopic findings it is suggested that intracellular calcification occurred in this case.     

Current Treatment Strategies: Collagen Vascular Diseases in Children

Of the various collagen vascular diseases seen in pediatric age group, discoid lupus erythematosus, systemic lupus erythematosus, neonatal lupus erythematosus, juvenile dermatomyositis and childhood scleroderma are common and of practical importance to clinicians. Various treatment modalities of these conditions have been discussed at length. Of these, some are conventional and routine,while others are used in challenging situations of these diseases. Autologous stem cell transplant, biological therapies, intravenous immunoglobulin and narrow band ultraviolet B are among the latest therapeutic options for these difficult-to-treat conditions in children.     

The relation between nailfold bleeding and capillary microscopic abnormality in pateints with connective tissue diseases

Background Patients with connective tissue diseases, mainly scleroderma, show nailfold bleeding and nailfold capillary abnormality. An attempt was made to determine the possible relation between nailfold bleeding and nailfold capillary abnormality.
Methods The correlation between nailfold bleeding and nailfold capillary abnormality was studied using quantitative nailfold capillary microscopy.
Results The frequencies of nailfold bleeding in scleroderma, mixed connective tissue disease, dermatomyositis/polymyositis, and secondary Raynaud's phenomenon were significantly higher than those of normal controls. The distributions of abnormal values of capillary parameters in scleroderma, mixed connective tissue disease, dermatomyositis/polymyositis, systemic lupus erythematosus, primary Sjögren's syndrome, secondary Raynaud's phenomenon, primary Raynaud's phenomenon, and diabetes mellitus were significantly higher than those of normal controls. In normal controls, scleroderma, mixed connective tissue diseases, dermatomyositis/polymyositis, systemic lupus erythematosus, primary Sjögren's syndrome, primary Raynaud's phenomenon, and diabetes mellitus, all nailfold bleeding was observed in subjects with nailfold capillary abnormality. The distribution of nailfold bleeding in secondary Raynaud's phenomenon with abnormal values of capillary parameters was significantly higher than that with normal values.
Conclusions There is a close relationship between nailfold bleeding and nailfold capillary abnormality.     

Novel autoantibody to Cu/Zn superoxide dismutase in patients with localized scleroderma

Abnormal production of reactive oxygen species (ROS) induces tissue damage and superoxide dismutase (SOD) that converts superoxide radicals to hydrogen peroxide functions as defense against ROS. Cu/Zn SOD administration has been shown to be effective for various fibrotic conditions by inhibiting the fibrogenic effects of ROS. We hypothesized that autoimmune background in localized scleroderma induced anti-Cu/Zn SOD autoantibodies that inhibited SOD activity and thereby contributed to fibrosis by increasing ROS. ELISA using human purified Cu/Zn SOD revealed that IgG or IgM anti-Cu/Zn SOD Ab was detected in the serum of 89% of localized scleroderma patients, especially 100% of patients with generalized morphea, the severest form of localized scleroderma, but was positive only in the serum of less than 15% of patients with other autoimmune disorders, including systemic sclerosis, systemic lupus erythematosus, dermatomyositis, and autoimmune bullous disorders. The immunoblotting analysis confirmed the presence of IgG anti-Cu/Zn SOD Ab in sera from localized scleroderma patients. Remarkably, anti-Cu/Zn SOD autoantibody could inhibit Cu/Zn SOD enzymatic activity. Collectively, these results indicate that anti-Cu/Zn SOD Ab is a novel, major autoantibody in localized scleroderma, and also suggest that the autoantibody may play a role in the development of fibrosis by directly inhibiting SOD activity.     

Calcinosis cutis in systemic lupus erythematosus: a case report and review of the published work

Calcinosis cutis is a common clinical feature of dermatomyositis and scleroderma but rarely reported in association with systemic lupus erythematosus (SLE). Calcinosis cutis in SLE occurs without calcium and phosphorus metabolic abnormalities and may be localized or generalized. The pathophysiology remains unclear and no effective therapy is currently available. We report a 30-year-old woman with a 13-year history of SLE who developed multiple calcinosis cutis around both knees and we review the relevant published work.     

The handheld dermatoscope as a nail-fold capillaroscopic instrument

BACKGROUND: The presence of nail-fold capillary abnormalities may be useful in diagnosing several connective tissue disorders, including scleroderma, dermatomyositis, and mixed connective tissue disease, and in differentiating primary Raynaud phenomenon from Raynaud phenomenon due to scleroderma and mixed connective tissue disease. Capillaroscopy, however, usually requires special equipment and may be time consuming.Purpose To investigate the potential use of the unmodified common handheld dermatoscope as a capillaroscopic instrument.Subjects The study included 106 patients who were consecutively referred and a control group of 170 healthy subjects or patients with unrelated skin disorders. METHODS: A nail-fold capillaroscopic examination using a standard handheld dermatoscope was performed on all fingers of each subject. A scleroderma-dermatomyositis pattern was defined as the presence of 2 or more of the following findings in at least 2 nail folds: enlargement of capillary loops, loss of capillaries, disorganization of the normal distribution of capillaries, "budding" ("bushy") capillaries, twisted enlarged capillaries, and capillary hemorrhages (extravasates). RESULTS: A scleroderma-dermatomyositis pattern was found in 19 (70.4%) of 27, 7 (63.6%) of 11, and 4 (50%) of 8 patients with scleroderma, dermatomyositis, and mixed connective tissue disease, respectively. These frequencies were statistically significantly higher than a null percentage of scleroderma-dermatomyositis pattern in the control group (P<.001) and a scleroderma-dermatomyositis pattern in only 1 (4.5%) of 22 patients with systemic lupus erythematosus as well as in 2 (5.3%) of 38 patients with Raynaud phenomenon but without evidence of a connective tissue disorder (P<.01). CONCLUSIONS: The capillaroscopic results obtained with the dermatoscope are comparable to those described with other instruments. Therefore, the unmodified hand-held dermatoscope may be used as a capillaroscopic instrument to detect a scleroderma-dermatomyositis pattern and to help the dermatologist in the clinical diagnosis of connective tissue disorders.     

Associations of tumor necrosis factor alpha and HLA polymorphisms with adult dermatomyositis: implications for a unique pathogenesis

We recently reported that the -308A tumor necrosis factor alpha promoter polymorphism is associated with the photosensitive disorder subacute cutaneous lupus erythematosus and mediates an exaggerated tumor necrosis factor alpha response to ultraviolet B. We now sought to examine the association of this polymorphism with adult dermatomyositis, a photosensitive disease that exhibits some features in common with subacute cutaneous lupus erythematosus. Fifty adult patients with dermatomyositis and 239 healthy, race-matched controls were examined for the -308A tumor necrosis factor alpha polymorphism and the more common -308G allele. The frequency of the -308A allele was 0.27 in the entire dermatomyositis group, versus 0.14 in the controls (p = 0.003, chi2 2 x 2 table). Caucasians were the only racial/ethnic group in our study large enough to allow separate statistical analysis (47 dermatomyositis, 223 controls). The frequency of the -308A allele was 0.26 for dermatomyositis and 0.14 for controls (p = 0.014). Caucasians are known to exhibit a linkage disequilibrium between -308A and HLA-DR3, which we previously found to be significantly enhanced in subacute cutaneous lupus erythematosus patients. In contrast, we now found no increase in the association of -308A and HLA-DR3 in Caucasians with dermatomyositis compared to controls. Consistent with this observation, the association of these two genes in dermatomyositis was significantly less than we previously reported in Caucasians with subacute cutaneous lupus erythematosus (p = 0.016). We conclude that the tumor necrosis factor -308A polymorphism is associated with dermatomyositis, which suggests a pathophysiologic contribution from ultraviolet-induced production of tumor necrosis factor alpha, similar to subacute cutaneous lupus erythematosus. The differences in linkage with HLA-DR3, as well as several divergent clinical features, indicate that there are also fundamental mechanistic differences between dermatomyositis and subacute cutaneous lupus erythematosus.     

Spectrum of antinuclear and anti-cytoplasmic antibodies in dermatomyositis and polymyositis overlap syndromes

Antinuclear antibodies (ANA) of the IgG class were detected in 60% of patients with dermatomyositis. Only in 16% could we demonstrate precipitating antibodies against the nuclear Mi-2 antigen. These antibodies are considered to be serological markers of dermatomyositis. The ANA spectrum in polymyositis-overlap syndrome was considerably more heterogeneous: patients with polymyositis/progressive systemic scleroderma overlap had antibodies against the nucleolar PM-Scl antigen or the nuclear Ku antigen. Cytoplasmic antibodies to Jo-1 were present in polymyositis associated with Sj?gren's syndrome and pulmonary fibrosis. Antibodies against ribosomal ribonucleoprotein were found in polymyositis with systemic lupus erythematosus and antibodies to nuclear ribonucleoprotein in polymyositis associated with mixed connective tissue disease. The investigation demonstrates that the characterization of ANA specificities helps to differentiate between dermatomyositis and distinct forms of polymyositis-overlap syndrome.     

Lupus erythematosus and other autoimmune diseases related to statin therapy: a systematic review

BACKGROUND: Statins have been increasingly associated with drug-induced autoimmune reactions, including lupus erythematosus. OBJECTIVE: To identify and determine the clinical and biological characteristics of statin-induced autoimmune reactions. MATERIAL AND METHODS: The MEDLINE database (1966 to September 2005) was used to identify all reported cases of statin-induced autoimmune diseases. The keywords used were statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, adverse effects, autoimmune disease, lupus erythematosus, dermatomyositis and polymyositis. RESULTS: Twenty-eight cases of statin-induced autoimmune diseases have been published so far. Systemic lupus erythematosus was reported in 10 cases, subacute cutaneous lupus erythematosus in three cases, dermatomyositis and polymyositis in 14 cases and lichen planus pemphigoides in one case. Autoimmune hepatitis was observed in two patients with systemic lupus erythematosus. The mean time of exposure before disease onset was 12.8+/-18 months; range 1 month-6 years. Systemic immunosuppressive therapy was required in the majority of cases. In many patients, antinuclear antibodies were still positive many months after clinical recovery. A lethal outcome has been recorded in two patients despite aggressive immunosuppressive therapy. CONCLUSION: Long-term exposure to statins may be associated with drug-induced lupus erythematosus and other autoimmune disorders. Fatal cases have been reported despite early drug discontinuation and aggressive systemic immunosuppressive therapy.     

Kollagenosen bei Jugendlichen

In this article we provide a brief review of systemic lupus erythematosus, juvenile dermatomyositis, systemic scleroderma, and mixed connective tissue disease in adolescents. As skin manifestations often belong to the presenting symptoms and may have a significant impact on the quality of life, dermatologists play an important role in the management of patients with connective tissue diseases. Early diagnosis and therapy onset are crucial for the patients’ long-term outcome.     

Calcinosis cutis universalis associated with systemic lupus erythematosus: an exuberant case

Calcinosis cutis is an uncommon disease of unclear pathophysiology that is often disabling. It is characterized by the formation of calcium deposits in the skin or subcutaneous tissue. It is classified into four subtypes: dystrophic, metastatic, idiopathic or iatrogenic. It may be seen in a variety of systemic diseases such as hyperparathyroidism and hypervitaminosis D, but is most commonly found in dermatomyositis, scleroderma and overlap syndromes and is a rare complication of systemic lupus erythematosus. The management of secondary complications and the success of therapy are constant challenges in the follow-up of these cases.