minocycline and Scleroderma--Systemic

The aim of this study was to provide updated information on the prevalence, pathogenesis, diagnostics and therapeutics of calcinosis cutis associated with systemic sclerosis (SSc).. Observational studies show ethnic and geographical differences in the prevalence of calcinosis. In addition to clinical and serological associations, biochemical studies and in-vivo models have attempted to explain theories behind its pathogenesis, including prolonged state of inflammation, mechanical stress, hypoxia and dysregulation in bone and phosphate metabolism. Long-term use of proton pump inhibitors may increase the risk for calcinosis in SSc. Few single-centre observational studies have shown mild benefit with minocycline and topical sodium thiosulfate.. Calcinosis cutis is the deposition of insoluble calcium in the skin and subcutaneous tissues. It affects up to 40% of SSc patients and causes significant morbidity. Long disease duration, features of vascular dysfunction and osteoporosis have been associated with calcinosis. Altered levels of inorganic pyrophosphate and fibroblast growth factor-23 have been implicated in dysregulated phosphate metabolism that may lead to calcinosis in SSc. Plain radiography can help with diagnosis and quantifying the calcinosis burden. Surgical treatment remains the most effective therapy when feasible. At present, no medical therapies have proven efficacy in large randomized controlled trials.

Topics: Calcinosis; Calcium; Diphosphates; Humans; Minocycline; Proton Pump Inhibitors; Scleroderma, Systemic

Minocycline-induced pigmentation (MIP) is an uncommon but well-described adverse effect of oral minocycline treatment. MIP is clinically and histopathologically distinct from post-sclerotherapy pigmentation. We report a case of a patient presenting with blackened skin overlying veins recently treated with endovenous laser and foam sclerotherapy. The patient was a 44-year-old male with systemic sclerosis who commenced minocycline for the treatment of rosacea 5 months prior. Histological examination of the discolored tissue and underlying vein revealed hemosiderin deposition in the dermis and pigmented macrophages within the sub-endothelial layer of the vein wall with a staining pattern consistent with MIP. Venous tissue has not previously been reported in the literature as a target of minocycline pigmentation. Our patient preferred to control his rosacea by continuing to take minocycline. Follow-up ultrasound examinations revealed the treated vessels to be fully occluded with no evidence of recanalization, residual flow or ongoing thrombophlebitis. Despite a good sclerotherapy outcome, the pigmentation did not subside over 2 years. This case demonstrates that oral minocycline may induce significant and potentially long-term pigmentation in predisposed patients undergoing sclerotherapy.

Topics: Adult; Anti-Bacterial Agents; Dermatitis; Humans; Laser Therapy; Male; Minocycline; Phlebitis; Pigmentation; Rosacea; Scleroderma, Systemic; Sclerotherapy

Calcinosis cutis constitutes a heterogeneous group of chronic disorder. It can be associated with disturbance of calcium and/or phosphate metabolism (metastatic, tumor calcinosis, calciphylaxis) but may also develop without any metabolic disorder, in particular during the course of connective tissue diseases. Among these, the most common are dermatomyositis and the limited form of systemic sclerosis. The physiopathology of calcinosis cutis is poorly known. It can cause pain, chronic ulcerations, infections, which are sources of sometimes major disability. Treatment of calcinosis is challenging because no drug has been shown to be reliably effective in stopping the progression or decreasing dystrophic calcifications in controlled trials. Calcium blocker and colchicine are generally prescribed as the first line systemic therapy. In the localized forms of small lesions, surgical excision is often effective and sometimes preceded by local treatments (laser therapy, extracorporeal shock wave lithotripsy, topical sodium thiosulfate, etc.) or systemic treatment (minocycline, warfarine). When calcinosis is disseminated, it may require additional treatments (aluminium hydroxyde, bisphosphonates) possibly associated with surgery in case of large lesions. Time to response may be prolonged from weeks to months. The calcinosis cutis can lead to secondary infection, pain and functional disability that have to be prevented.

Topics: Calcinosis; Calcium Channel Blockers; Colchicine; Dermatomyositis; Humans; Minocycline; Scleroderma, Systemic; Warfarin

Optimal management for scleroderma (systemic sclerosis) is likely to require treatment of the underlying disease process, which remains incompletely understood, and also of the organ-based complications of this heterogeneous condition. Clinical trials evaluating several potential agents have been completed recently, including D-penicillamine and interferon alpha. Unfortunately none of these studies has suggested significant efficacy. This article focuses on new treatment approaches using existing therapeutic agents, such as prostacyclin, and considers the potential usefulness of new agents (eg, relaxin, halofuginone) or strategies such as intensive immunosuppression with peripheral stem cell rescue. Ultimately, a better understanding of disease pathogenesis may facilitate the development of targeted therapy against key events or mediators, but for the present better evaluation of existing agents and a focus on optimizing protocols for organ-based complications, such as pulmonary vascular disease or hypertensive renal crisis, are important goals.

Topics: Clinical Trials as Topic; Combined Modality Therapy; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Minocycline; Nitric Oxide; Piperidines; Prognosis; Quinazolines; Quinazolinones; Relaxin; Scleroderma, Systemic; Treatment Outcome

To determine if minocycline therapy improved skin thickness in early, diffuse systemic sclerosis (SSc) by > or =30%, a level of improvement unlikely to occur in the natural history of the disease as determined by recent controlled trials.. Subjects with diffuse SSc of < or =5 years' duration were treated with oral minocycline for 1 year. The primary outcome measure was the modified Rodnan skin thickness score (MRSS).. Of 36 subjects initially enrolled, 31 returned for at least 1 followup visit and were included in the analysis (modified intent-to-treat analysis). The group consisted of 23 women and 8 men, with a mean age of 51.7 years (range 26-82 years) and a mean disease duration of 23.5 months (range 6-60 months). The mean MRSS at entry was 22.7 (range 12-43), and at the final visit it was 18.6 (range 2-48). There was no statistically significant difference in the change in skin scores between the minocycline-treated subjects and subjects previously reported in the D-penicillamine (D-Pen) trial. In addition, when adjusted for disease duration, a comparison of MRSS in the minocycline trial subjects (including all subjects active at each time point) and the previously reported D-Pen trial subjects showed no difference and no treatment effect. Fourteen subjects did not complete all 12 months of treatment; 10 of them withdrew due to disease progression. Disease duration was significantly shorter for the noncompleters than for the completers (P < 0.03).. The degree of change in the MRSS was similar to that expected in the natural course of this disease. Based on these data, minocycline is not an effective therapy for SSc.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Minocycline; Penicillamine; Scleroderma, Systemic; Severity of Illness Index; Skin; Treatment Outcome

Vitamin D research is discussed in light of the hypothesis that the lower average levels of vitamin D frequently observed in autoimmune disease are not a sign of deficiency. Instead, it is proposed that the lower levels result from chronic infection with intracellular bacteria that dysregulate vitamin D metabolism by causing vitamin D receptor (VDR) dysfunction within phagocytes. The VDR dysfunction causes a decline in innate immune function that causes susceptibility to additional infections that contribute to disease progression. Evidence has been accumulating that indicates that a number of autoimmune diseases can be reversed by gradually restoring VDR function with the VDR agonist olmesartan and subinhibitory dosages of certain bacteriostatic antibiotics. Diseases showing favorable responses to treatment so far include systemic lupus erythematosis, rheumatoid arthritis, scleroderma, sarcoidosis, Sjogren's syndrome, autoimmune thyroid disease, psoriasis, ankylosing spondylitis, Reiter's syndrome, type I and II diabetes mellitus, and uveitis. Disease reversal using this approach requires limitation of vitamin D in order to avoid contributing to dysfunction of nuclear receptors and subsequent negative consequences for immune and endocrine function. Immunopathological reactions accompanying bacterial cell death require a gradual elimination of pathogens over several years. Practical and theoretical implications are discussed, along with the compatibility of this model with current research.

Topics: Animals; Anti-Bacterial Agents; Arthritis, Reactive; Arthritis, Rheumatoid; Autoimmune Diseases; Bacterial Infections; Calcifediol; Calcitriol; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Humans; Imidazoles; Minocycline; Psoriasis; Receptors, Calcitriol; Sarcoidosis; Scleroderma, Systemic; Sjogren's Syndrome; Spondylitis, Ankylosing; Tetrazoles; Thyroid Diseases; Uveitis

To evaluate the effect of minocycline as treatment for cutaneous calcinosis in limited cutaneous systemic sclerosis (lcSSc).. Patients with lcSSc who had cutaneous calcinosis causing pain or ulceration, or both, were prescribed minocycline 50 or 100 mg daily regularly in an open label manner between November 1994 and April 2000. At routine clinical follow up the appearance of the calcinosis deposits was assessed clinically and radiographically, and the patients' assessment of the degree of discomfort, size, and frequency of ulceration was recorded. Demographic data, including disease duration, clinical features, and antinuclear antibody (ANA) titres, were also recorded.. Nine patients have been treated to date. Eight of the nine patients were ANA positive, five of whom were positive for anticentromere antibodies. Eight patients have shown definite improvement and seven patients continue to receive treatment. The frequency of ulceration and inflammation associated with the calcinosis deposits decreased with treatment. The size of the calcinosis deposits also decreased but was less dramatic than expected. Improvement occurred at the earliest after one month of treatment with a mean (SD) of 4.8 (3.8) months. The mean (SD) length of treatment was 3.5 (1.9) years. An unexpected effect was the darkening of the calcinosis deposits to a blue/black colour.. Minocycline may be effective in the control of calcinosis in systemic sclerosis. A low dose only is required and appears to be generally well tolerated. The mechanism of action may be mainly through inhibition of matrix metalloproteinases and anti-inflammatory effects. Calcium binding properties and antibacterial actions may also have a role.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Antibodies, Antinuclear; Calcinosis; Female; Hand; Humans; Middle Aged; Minocycline; Scleroderma, Systemic; Skin Diseases, Metabolic

Minocycline has been used successfully for the treatment of dermal fibrosis in patients suffering from systemic sclerosis. However, little is known of the mechanism of the antifibrotic action of minocycline. We studied the in vitro effects of minocycline by analysing the influence of various amounts of minocycline on cell proliferation and synthesis and degradation of collagen I in cultured human dermal fibroblasts from healthy donors and two patients with systemic sclerosis. Collagen I metabolism of cultured dermal fibroblasts from two- and three-dimensional culture systems was studied by Northern hybridization and real-time RT-PCR. Messenger RNA of collagen I, proline-4-hydroxylase, lysyl-hydroxylase, matrix metalloproteinase I, and protein of MMP-1 (ELISA) and collagen I in culture supernatants were determined. Minocycline did not alter the expression of the investigated mRNAs, irrespective of the dosage, the culture system and the incubation times used. Similarly, the amounts of collagen I and MMP-1 protein were not affected. Consequently, direct antifibrotic effects of minocycline on untreated human dermal fibroblasts in vitro seem unlikely. Therefore, other mechanisms are probably responsible for the clinical effect observed in the treatment of systemic sclerosis.

Topics: Anti-Bacterial Agents; Cells, Cultured; Collagen Type I; Fibroblasts; Gene Expression Regulation; Humans; Matrix Metalloproteinase 1; Minocycline; RNA, Messenger; Scleroderma, Systemic; Skin

Topics: Adolescent; Adult; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Minocycline; Scleroderma, Systemic; Treatment Outcome

Topics: Color; Croton Oil; Epidermis; Hemoglobins; Humans; Melanins; Metabolism; Mining; Minocycline; Oximetry; Oxygen; Oxygen Consumption; Pigmentation; Scleroderma, Systemic; Skin; Ultraviolet Rays