tacrolimus and Scleroderma--Systemic

We retrospectively compared the therapeutic effects of combination therapy with prednisolone (PSL) and oral tacrolimus (TAC) or azathioprine (AZA) on progressive interstitial pneumonia with systemic sclerosis (SSc-PIP).. The effects of PSL (0.2-0.5 mg/kg/day) and TAC (3 mg/day) or AZA (1-2 mg/kg/day) therapies (n = 18) were evaluated for short (12 months) and long (36 months or more) periods.. In the short period, IP improved in 6 and 5 patients and was stable in 12 and 13 patients in the TAC and AZA groups, respectively. In the long period, 11 patients were followed up in the TAC group and 12 in the AZA group. IP improved in 4 and 2 patients and was stable in seven and nine in the TAC and AZA groups, respectively. The rates of evolution of total fibrosis score, and those corrected by disease duration for the long period, in the TAC group were significantly lower than those in the AZA group (p = .017 and .025, respectively).. The inhibitory effect of PSL and TAC combination therapy on the progression of fibrosis in SSc-PIP may be superior to that of PSL and AZA in the long period.

Topics: Azathioprine; Drug Therapy, Combination; Fibrosis; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Prednisolone; Retrospective Studies; Scleroderma, Systemic; Tacrolimus; Treatment Outcome

A 62-year-old Japanese man with swollen fingers and walking difficulty due to myalgia and muscle weakness in proximal limb muscles was admitted to our hospital. Serum creatine kinase was remarkably increased (7,380 U/l) and rapidly progressing interstitial pneumonia developed. Muscle biopsy showed necrotic and regenerating fibers without mononuclear infiltration and fibrosis. Anti-Th/To antibodies were detected in the serum, and anti-Th/To antibody-positive systemic sclerosis was diagnosed. Anti-Th/To antibody-positive sclerosis-associated myopathy has not yet been reported in the literature. The present case suggests that anti-Th/To antibody-positive systemic sclerosis can be accompanied by immune-mediated necrotizing myopathy and be effectively treated with immunotherapy comprising corticosteroids, tacrolimus and immunoglobulin.

Topics: Adrenal Cortex Hormones; Autoantibodies; Autoantigens; Humans; Immunoglobulins; Immunotherapy; Lung Diseases, Interstitial; Male; Middle Aged; Muscle, Skeletal; Muscular Diseases; Necrosis; Scleroderma, Systemic; Skin; Tacrolimus

We retrospectively investigated efficacy and safety of combination therapy with prednisolone (PSL) and tacrolimus (TAC) for progressive interstitial pneumonitis with systemic sclerosis (SSc-PIP).. We studied 11 patients with SSc-PIP who received combination therapy with PSL (0.5 mg/kg/d) and TAC (3 mg/d).. Baseline Hugh-Jones grades were I, II, III, and IV in 2, 6, 2, and 1 patients, respectively. Krebs von den Lungen-6 (KL-6) values were elevated to 914 (range 300-2614) U/mL. % Diffusing capacity of carbon monoxide (%DLco) remarkably decreased to 47.4 (range 9.7-64.4) %. All patients were alive at 1 year after therapy. In response to treatment, interstitial pneumonia (IP) improved in three patients, stable in seven patients, and deteriorated in one patient. Total ground-glass opacity (GGO) score improved (p = .005). No significant changes occurred in values of KL-6, % forced vital capacity (%FVC), and %DLco. Presently, all seven patients who could be followed up were alive. IP improved in three patients and stable in four patients. Total GGO score improved (p = .016). KL-6, %FVC, and %DLco did not change. Mild cytomegalovirus or herpes zoster infection occurred in two patients. Grade I renal injuries were observed in three and one patient at 1 year and present, respectively.. Combination therapy with PSL and TAC appeared to be well tolerated and effective in suppressing the disease activity of SSc-PIP.

Topics: Administration, Oral; Adult; Aged; Disease Progression; Drug Therapy, Combination; Female; Humans; Japan; Lung Diseases, Interstitial; Male; Middle Aged; Prednisolone; Respiratory Function Tests; Retrospective Studies; Scleroderma, Systemic; Severity of Illness Index; Tacrolimus; Vital Capacity

Topics: Biopsy; Brain; Drug Combinations; Female; Humans; Kidney Diseases; Middle Aged; Posterior Leukoencephalopathy Syndrome; Scleroderma, Systemic; Steroids; Tacrolimus; Therapeutics

To investigate the effects of FK-506 on the expression of the human alpha2(I) collagen gene and transforming growth factor beta (TGFbeta) signaling in normal and scleroderma fibroblasts.. The expression levels of type I procollagen protein and alpha2(I) collagen messenger RNA (mRNA) were analyzed by immunoblotting and Northern blotting, respectively. The promoter activities of alpha2(I) collagen gene and 3TP-Lux were determined by transient transfection assay. Interaction between TGFbeta receptor type I and FK-506 binding protein 12 (FKBP12) was evaluated by immunoprecipitation.. FK-506 did not affect the basal expression of type I procollagen protein or alpha2(I) collagen mRNA, but it significantly reduced the TGFbeta1-induced expression of type I procollagen protein and alpha2(I) collagen mRNA in normal fibroblasts. The effect of FK-506 was regulated posttranscriptionally, but not transcriptionally. In scleroderma fibroblasts, FK-506 significantly reduced the expression of type I procollagen protein and alpha2(I) collagen mRNA through posttranscriptional regulation, but not transcriptional regulation. FK-506 increased the basal activity of the 3TP-Lux promoter, but it did not affect the TGFbeta1-induced promoter activity in normal fibroblasts. In contrast, FK-506 did not affect the basal or the TGFbeta1-induced 3TP-Lux promoter activity in scleroderma fibroblasts. Furthermore, FKBP12, which protects TGFbeta receptor type I from ligand-independent activation by TGFbeta receptor type II, constitutively dissociated from TGFbeta receptor type I in scleroderma fibroblasts.. FK-506 inhibits alpha2(I) collagen gene expression by reducing the stability of mRNA without exhibiting its activation effect on TGFbeta signaling in scleroderma fibroblasts.

Topics: Cells, Cultured; Collagen Type I; Fibroblasts; Gene Expression; Humans; Immunosuppressive Agents; Procollagen; Scleroderma, Systemic; Signal Transduction; Tacrolimus; Transforming Growth Factor beta

Cyclosporin and tacrolimus are immunomodulatory drugs which act predominantly on T cells. Improvements in certain manifestations, particularly skin tightness, have been observed in a number of patients with scleroderma treated with these drugs. However, to date there have been no reports of their use in a routine clinical setting.. Patients attending clinical immunology clinics who had progressive systemic sclerosis and related syndromes and who had received cyclosporin and/or tacrolimus were identified. Details of their treatment, including drug dosage, duration of and response to treatment, side-effects and reasons for withdrawal, were recorded.. Sixteen patients had been given cyclosporin and 13 of these had been treated for skin tightness. Half noticed significant softening of their skin whilst on treatment, and resolution was observed in all four of the patients treated for digital vasculitis. Side-effects were common and dose-limiting, and contributed to withdrawal in 12 out of 13 patients. Eight patients had been treated with tacrolimus; two of these had stopped the drug because of progression of their disease, one developed diarrhoea, prompting withdrawal, one stopped tacrolimus following improvement, and four remained on the drug. Side-effects had occurred in three patients.. Improvements in skin occur in approximately half of all cases of scleroderma treated with either cyclosporin or tacrolimus, suggesting a beneficial effect. Side-effects, especially hypertension, are common with cyclosporin and often necessitate withdrawal. Adverse effects are also observed with tacrolimus, but in the small cohort so far treated only one patient had stopped the drug for this reason.

Topics: Adult; Child; Cyclosporine; Elasticity; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Scleroderma, Systemic; Skin; Tacrolimus