Systemic scleroderma (SSc) is a systemic immune-mediated connective tissue disease characterized by fibroproductive changes in connective tissue and microvascular disorders. The disease affects the skin, musculoskeletal system and internal organs. It is a disease with a significant rate of morbidity and mortality, significantly worsening the quality of life of patients. Early initiation of therapy is necessary to prevent disease progression. This review article discusses the current possibilities of early diagnosis of systemic scleroderma.
- Keywords
- diagnosis, diagnostics, early forms of scleroderma, systemic scleroderma, systemic sclerosis,
- MeSH
- Early Diagnosis MeSH
- Quality of Life MeSH
- Humans MeSH
- Connective Tissue Diseases * MeSH
- Scleroderma, Systemic * diagnosis MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
Systemic sclerosis (SSc) is a generalised connective tissue disease of unknown origin, which clinically shows by skin thickening and sclerosis of different extent (scleroderma) and by typical involvement of visceral organs. At the same time fibrotic and sclerotic changes occur in the blood vesel walls. SSc usually involves females at young and middle age. Myalgias, arthralgias and arthritis are nonspecific, tendon friction rubs in fingers are more typical for this diagnosis. Gastrointestinal involvement starts early in the oropharyngeal part, esophagus and proceeds into the distal parts. Fibrotic changes lead to slow transit dysmotility and pseudoobstruction and/or dilation of the bowels. The main symptoms are dysphagia, pyrosis, malabsorption and constipation. SSc produces two major patterns of abnormality within the lungs a fibrosing alveolitis or a primary pulmonary vascular disease. More frequently an insterstitial process develops which can be followed by pulmonary arterial hypertension. Cardiac involvement can also have different forms. Myocardial fibrosis usually appears at first in the conduction system by arrhythmias and various conduction blocks while pericarditis is mostly asymptomatic. Renal manifestation of SSc is observed in 8-10% patients. The most severe form--scleroderma renal crisis is characterised by the new onset of accelerated hypertension and rapidly progressive oliguric renal failure. No therapies have been proven to modify the course of SSc. Some of the drugs can affect only the skin changes. Majority of the currently applied agents have only a symptomatic effect.
A case of a bullous eruption occurred in a patient being treated with penicillamine for sclerodermatous graft-versus-host disease following bone marrow transplantation. After 7 days of treatment with 150 mg penicillamine, a painful bullous eruption with accompanying purpuric lesions suddenly developed in previous sclerodermatous infiltrations. A diagnosis of epidermolysis bullosa acquisita-like eruption was made, and the patient was treated with drug withdrawal and administration of cyclosporine and methylprednisolone. Epidermolysis bullosa acquisita-like reaction is an extremely rare cutaneous side effect of penicillamine. The surprisingly early onset of this eruption in lesions of sclerodermatous graft-versus-host disease might have been due to severe immune alteration.
- MeSH
- Cyclosporine therapeutic use MeSH
- Epidermolysis Bullosa Acquisita chemically induced MeSH
- Immunosuppressive Agents therapeutic use MeSH
- Middle Aged MeSH
- Humans MeSH
- Methylprednisolone therapeutic use MeSH
- Graft vs Host Disease drug therapy MeSH
- Penicillamine adverse effects MeSH
- Scleroderma, Systemic drug therapy MeSH
- Bone Marrow Transplantation adverse effects MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Publication type
- Journal Article MeSH
- Case Reports MeSH
- Names of Substances
- Cyclosporine MeSH
- Immunosuppressive Agents MeSH
- Methylprednisolone MeSH
- Penicillamine MeSH
Mesenchymal responses are an essential aspect of tissue repair. Failure to terminate this repair process correctly, however, results in fibrosis and organ dysfunction. Therapies that block fibrosis and restore tissue homeostasis are not yet available for clinical use. Here we characterize the nuclear receptor NR4A1 as an endogenous inhibitor of transforming growth factor-β (TGF-β) signaling and as a potential target for anti-fibrotic therapies. NR4A1 recruits a repressor complex comprising SP1, SIN3A, CoREST, LSD1, and HDAC1 to TGF-β target genes, thereby limiting pro-fibrotic TGF-β effects. Even though temporary upregulation of TGF-β in physiologic wound healing induces NR4A1 expression and thereby creates a negative feedback loop, the persistent activation of TGF-β signaling in fibrotic diseases uses AKT- and HDAC-dependent mechanisms to inhibit NR4A1 expression and activation. Small-molecule NR4A1 agonists can overcome this lack of active NR4A1 and inhibit experimentally-induced skin, lung, liver, and kidney fibrosis in mice. Our data demonstrate a regulatory role of NR4A1 in TGF-β signaling and fibrosis, providing the first proof of concept for targeting NR4A1 in fibrotic diseases.
- MeSH
- Liver Cirrhosis, Alcoholic metabolism pathology MeSH
- Adult MeSH
- Fibroblasts metabolism MeSH
- Fibrosis MeSH
- Histone Deacetylase 1 metabolism MeSH
- Sin3 Histone Deacetylase and Corepressor Complex MeSH
- Histone Demethylases metabolism MeSH
- Wound Healing MeSH
- Idiopathic Pulmonary Fibrosis metabolism pathology MeSH
- Nuclear Receptor Subfamily 4, Group A, Member 1 genetics metabolism physiology MeSH
- Liver metabolism pathology MeSH
- Co-Repressor Proteins metabolism MeSH
- Cells, Cultured MeSH
- Skin cytology metabolism pathology MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Mice, Knockout MeSH
- Mice MeSH
- Lung metabolism pathology MeSH
- Repressor Proteins metabolism MeSH
- Aged MeSH
- Signal Transduction MeSH
- Case-Control Studies MeSH
- Scleroderma, Systemic metabolism pathology MeSH
- Transforming Growth Factor beta metabolism MeSH
- Sp1 Transcription Factor metabolism MeSH
- Animals MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Mice MeSH
- Aged MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Histone Deacetylase 1 MeSH
- Sin3 Histone Deacetylase and Corepressor Complex MeSH
- Histone Demethylases MeSH
- Nuclear Receptor Subfamily 4, Group A, Member 1 MeSH
- Co-Repressor Proteins MeSH
- Repressor Proteins MeSH
- SIN3A transcription factor MeSH Browser
- Transforming Growth Factor beta MeSH
- Sp1 Transcription Factor MeSH
Methotrexate is an anti-cancer drug used to treat several malignancies including pediatric acute lymphoblastic leukemia and choriocarcinoma. Despite recent advances in cancer chemotherapy, it remains a mainstay of therapy since its discovery in the early second half of the previous century. Moreover, low-dose methotrexate is a gold standard antirheumatic drug in the treatment of rheumatoid arthritis, psoriasis, systemic scleroderma and other autoimmune disorders. Side effects of methotrexate treatment are well known and described; however, their occurrence may often be unpredictable due to lack of specific biomarkers of toxicity. Methotrexate plasma levels are routinely monitored by therapeutic drug monitoring, nevertheless, occurrence and concentrations of its metabolites are not measured. During methotrexate treatment 7- hydroxymethotrexate and 2,4- diamino- N10- mehylpteroic acid appear in plasma. The latter can further be hydroxylated and glucuronidated resulting in five possible extracellular methotrexate metabolites. In addition, methotrexate is intracellularly converted to its active polyglutamylated forms. Therapeutic efficacy is dependent on formation of methotrexate polyglutamates as it keeps intracellular pool of the drug and enhances its affinity towards various target enzymes. In this study, we describe pharmacokinetic and pharmacodynamic characteristics of methotrexate metabolites. We also review methotrexate blood brain barrier transport to cerebrospinal fluid regarding its use in the prevention of leukemic central nervous system involvement and management of methotrexate toxicity with the use of carboxypeptidase- G2. Finally, we discuss laboratory methods for monitoring methotrexate metabolites and benefits of simultaneous determination of methotrexate and metabolites as possible biomarkers of therapeutic efficacy and clinical toxicity.
- MeSH
- Drug Resistance, Neoplasm MeSH
- Tetrahydrofolate Dehydrogenase metabolism MeSH
- Humans MeSH
- Methotrexate analogs & derivatives metabolism pharmacokinetics therapeutic use MeSH
- Biomarkers, Tumor analysis MeSH
- Antimetabolites, Antineoplastic pharmacokinetics therapeutic use MeSH
- Check Tag
- Humans MeSH
- Publication type
- English Abstract MeSH
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
- Names of Substances
- 7-hydroxymethotrexate MeSH Browser
- Tetrahydrofolate Dehydrogenase MeSH
- Methotrexate MeSH
- Biomarkers, Tumor MeSH
- Antimetabolites, Antineoplastic MeSH
