Methotrexate therapy of oral corticosteroid-dependent asthmatics reduces serum immunoglobulins: correlation with clinical response to therapy

BACKGROUND: Concomitant methotrexate (MTX) therapy of oral corticosteroid (CS)-dependent asthmatics has been shown to spare CS therapy, but the mechanism is unknown. In a previous report, we showed that MTX increases T cell inhibition by CS. In this report we focus on effects of MTX on immunoglobulin concentrations and their possible clinical relevance. OBJECTIVE: To monitor changes in circulating leucocytes and Ig in a group of these patients during MTX therapy, and to relate these changes to clinical 'response' as defined by oral CS reduction. METHODS: Sixteen severe asthmatics dependent on oral prednisolone 15 (7.5-25) mg/day in addition to high dose inhaled CS were treated with MTX 15 mg intramuscularly, weekly for 28 weeks. Prednisolone dosages were maintained constant for 12 weeks then reduced systematically over the next 16 weeks provided that asthma control did not deteriorate. Patients were classified a priori as 'responders' or 'non-responders' to MTX (reduction of initial oral prednisolone requirement by >or=50% or <50%, respectively). Patients were followed-up for a further 12 weeks after MTX withdrawal. Serum Ig and differential blood leucocyte counts were measured at baseline, 12, 28 and 40 weeks. RESULTS: MTX therapy allowed significant, but individually variable, reductions in oral prednisolone dosages (P<0.00001) without alteration of lung function or symptoms. This was associated with significant reductions in mean serum concentrations of Ig of all classes, which reversed following MTX withdrawal. Reductions in IgE and IgG were significantly greater in the MTX 'responders' as compared with 'non-responders', and changes in IgE, IgG and IgM correlated with changes in prednisolone requirements. Differential blood leucocyte counts showed no significant variation. CONCLUSION: MTX therapy reduced oral CS requirements in these severe asthmatics to a degree which correlated with reduced circulating Ig but not lymphopaenia, suggesting a possible cause and effect relationship. These reductions might also contribute to the documented incidence of opportunistic infection in these circumstances.     

Comparison of anti-arthritic properties of leflunomide with methotrexate and FK506: Effect on T cell activation-induced inflammatory cytokine production in vitro and rat adjuvant-induced arthritis

OBJECTIVE AND DESIGN: To examine the effect of leflunomide (LEF) on T cell activation-induced inflammatory cytokine production in human peripheral blood mononuclear cells (PBMC) and rat established adjuvant-induced arthritis (AIA), and compare these effects with methotrexate (MTX) and FK506 (tacrolimus), focusing on improvement of joint function in AIA. METHODS: Human PBMC were cultured with immobilized anti-CD3/CD28 monoclonal antibody to produce tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6. The active metabolite of LEF was used in in vitro study. AIA was induced in female Lewis rats. Paw swelling and grip strength were measured as indicators of arthritis and joint function, respectively. Rats were therapeutically administered LEF (3.2-32 mg/kg) from days 15-24 by oral administration. RESULTS: LEF inhibited anti-CD3/CD28 induced production of TNF-alpha, IL-1beta and IL-6, with IC50 values of 27, 21 and 21 microg/ml, respectively. LEF also suppressed mouse bone marrow cell MTT conversion, with an IC50 value of 15 microg/ml. LEF significantly inhibited paw swelling and loss of grip strength in established AIA at 10 and 32 mg/kg. The inhibition of paw swelling and grip strength loss by LEF was more potent than MTX. However, maximum recovery of grip strength loss by LEF (23.5%) was less potent compared to that with FK506 (57.8%). CONCLUSIONS: LEF inhibited anti-CD3/CD28 induced inflammatory cytokine production in human PBMC at concentrations showing deleterious effects on bone marrow cell proliferation. LEF is superior to MXT in improving arthritis and joint function in established AIA, but is inferior to FK506 in recovering joint function, probably due to its anti-proliferative actions.     

Long-term corticosteroid treatment in giant cell arteritis

Ninety patients with giant cell arteritis were followed up 9-16 years (median 11.3 years) after diagnosis. The mean duration of corticosteroid therapy was 5.8 years (range 0-12.8 years). Together, the patients had received corticosteroids for 492 patient-years. Five years after diagnosis, 43% of the patients were on corticosteroid therapy. After 9 years, 15 of 60 surviving patients (25%) were still being treated with 1.25-10 mg of prednisolone daily (median dose 5 mg). The relapse rate was about 50%, regardless of the time after diagnosis, when an attempt to withdraw the treatment was made. Forty-six per cent of the relapses occurred within one month and 96% within one year of the end of treatment. Most of the flare-ups occurred during the first year of therapy and in 55% of the patients on a prednisolone dosage of 5 mg or less. We did not find any increase in morbidity in our patients compared to the general population. Nor did we see any significant complications which we could attribute to the steroid treatment.     

Changes in serum eotaxin and eosinophil cationic protein levels, and eosinophil count during treatment of childhood asthma.

BACKGROUND AND PURPOSE: Increased serum levels of eotaxin are related to the severity of asthma in adults. There are limited data on the effects of oral corticosteroids and inhaled corticosteroid therapy on serum levels of eotaxin and eosinophil cationic protein (ECP) and peripheral blood eosinophil counts (ECs) in pediatric asthma patients. We investigated prospectively the changes in eotaxin and ECP serum levels and peripheral blood ECs after administering oral corticosteroids and then inhaled corticosteroids plus long-acting beta2 agonist treatment in pediatric patients. METHODS: Serum samples of 20 pediatric patients with mild-to-moderate asthma were collected before treatment, after 5-7 days of oral prednisolone treatment, and after 1-2 months of inhaled fluticasone plus salmeterol treatment. Peak expiratory flow was used as the outcome index. RESULTS: Serum eotaxin levels remained the same after oral prednisolone treatment, but decreased after subsequent inhalation treatment compared with the end of oral steroid treatment (64.7 +/- 22.6 vs 85.7 +/- 36.8 pg/mL, p<0.001). The EC and serum ECP levels declined soon after oral steroid treatment, rebounding to initial levels during inhalation treatment. The decrease in ECP level was positively correlated with the decrease in ECs with oral steroid treatment (r(2) = 0.28, p=0.016). There was no correlation between changes in eotaxin levels and peak expiratory flow. CONCLUSIONS: Our data suggest that the serum eotaxin level, not peripheral blood EC or serum ECP level, declines during inhaled fluticasone plus salmeterol treatment and might serve as a surrogate marker of T helper 2 residual activity in pediatric asthma.     

First-Line Therapy for Chronic Graft-versus-Host Disease that Includes Low-Dose Methotrexate Is Associated with a High Response Rate

We report the results of low-dose methotrexate (MTX) as first-line therapy mostly in combination with other immunosuppressive agents in patients with chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Between November 2001 and March 2008, 86 patients with cGVHD after allo-HSCT received low-dose MTX therapy until a complete or partial response (CR, PR) was achieved, or until treatment failure or intolerable side effects were found. The median time from HSCT to the start of MTX was 154 (range: 80-993) days. The median number of MTX administrations was 4 (range: 2-18). The overall response rate among all enrolled patients was 83% (71 of 86 patients). The response rate for GVHD involving various organs was 90% (45 of 50) in the skin, 75% (39 of 52) in the liver, 42% (5 of 12) in the mouth, 3 of 7 in the eye, and 2 of 2 in the gut. In addition, MTX treatment allowed for a significant reduction in the prednisone dosage (median 90%) from 20 (2.5-100) mg at the start of MTX administration to 5 (0-30) mg 1 month after MTX was last used. Multivariate analysis showed that the only significant factor related to higher CR rate was sole organ involvement (P = .007). Grade 3 toxicities occurred in only 3 patients presenting cytopenias or oral mucositis. From this analysis, MTX appears to be a well-tolerated, effective, and inexpensive agent when used as a first-line treatment in combination with other immunosuppressive agents for cGVHD, especially for skin or sole organ involvement without concomitant thrombocytopenia.     

Pretreatment with corticosteroids to alleviate reactions to intravenous contrast material

The x-ray contrast mediums used over the past three decades have been salts of iodinated acids administered in highly hypertonic concentrations. We conducted a multiinstitutional randomized study of the protective effects of pretreatment with corticosteroids against reactions to intravenous contrast material. We gave 6763 patients two doses of oral corticosteroids (methylprednisolone, 32 mg) approximately 12 hours and 2 hours before challenge with contrast material, one dose of oral prednisolone approximately 2 hours before challenge, or placebo in the same dosages. The two-dose corticosteroid regimen, but not the one-dose regimen, significantly reduced the incidence of reactions of all types (P less than 0.05) except a category of reactions dominated by hives, for which the reduction approached significance (P = 0.055). In recent years, several relatively expensive monomeric nonionic iodinated compounds having approximately half the osmolality of the corresponding ionic compounds and a lower reaction rate have become available. With our two-dose corticosteroid regimen, the incidence of reactions necessitating therapy in patients receiving the ionic medium approximated that reported in an unblinded nonrandomized study of patients receiving a newer intravenous nonionic medium without corticosteroid pretreatment. We conclude that the much less expensive ionic medium, if administered with corticosteroid pretreatment, may serve as a reasonable alternative to intravenous nonionic medium, without loss of safety.     

IgG production in ''autoimmune'' chronic active hepatitis. Effect of prednisolone on T and B lymphocyte function.

In vitro IgG production was measured using peripheral blood mononuclear cells from patients with autoimmune chronic active hepatitis (CAH) to determine whether the increased serum IgG levels were related to abnormalities of T or B lymphocyte function. A marked increase in spontaneous and pokeweed mitogen-induced proliferation of IgG producing cells was observed in 30 patients with untreated autoimmune CAH when compared with 25 normal subjects and 21 patients with autoimmune disease in whom a remission had been induced and maintained by prednisolone (P less than 0.01). Co-culture experiments clearly demonstrated that abnormalities of T lymphocyte function in untreated autoimmune CAH were responsible for the heightened IgG production in vitro. Pre-incubation of T lymphocytes from untreated patients with 5 X 10(-8)M prednisolone significantly reduced the number of cells producing IgG (P less than 0.05), suggesting that the modulation of the immune response following corticosteroid therapy is likely to be due to an alteration in T lymphocyte function.     

Immunological mechanisms of corticosteroid therapy in chronic active hepatitis: analysis of peripheral blood suppressor T-cell and interleukin 2 activities

To investigate the immunological mechanisms underlying corticosteroid therapy in chronic active hepatitis (CAH), in vitro effects of prednisolone on suppressor T-cell and interleukin 2 (IL-2) activities were examined in six corticosteroid therapy-effective and six therapy-ineffective patients with CAH prior to the therapy. Whereas low suppressor T-cell activity and decreased response to IL-2 in T cells were found in the corticosteroid therapy-effective group, these reductions recovered to the normal range when the activity or response was tested in the presence of prednisolone (1 and 10 micrograms/ml). Corresponding with these recoveries, suppressor T-cell activity arrived at normal values after corticosteroid therapy for 8 weeks. By contrast, in the corticosteroid-ineffective group, no apparent effects of prednisolone on suppressor T-cell activity and the response to IL-2 were observed. The relationship between the clinical effect of corticosteroid therapy and in vitro improvement in suppressor T-cell activity or in the response to IL-2 by prednisolone suggests that, in CAH, the corticosteroid effect is likely to be due to an immunomodulation in T-cell function.     

Suppressive effect of combination treatment of leflunomide and methotrexate on chemokine expression in patients with rheumatoid arthritis

To study the immunosuppressive and anti-inflammatory effects of combined leflunomide and methotrexate (MTX) therapy on chemokine expression in patients with rheumatoid arthritis (RA), nine patients were enrolled for the combination therapy for 24 weeks. These patients have been on treatment with MTX 15 mg/week for not less than 3 months before entry to the study. A loading dose of l00 mg/day of leflunomide was given for 3 days, followed by 10 mg/day for the rest of the study period. Plasma concentrations of monocyte chemotactic protein-1 (MCP-1), thymus- and activation-regulated chemokine (TARC), and macrophage-derived chemokine (MDC) were assayed before and after combination treatment by ELISA. Gene expression of inflammatory cytokines and chemokines of peripheral blood mononuclear cells was analysed by cDNA expression array. Plasma MCP-1, TARC and MDC concentrations were significantly lower in patients after combination treatment [median (interquartile range) before versus after treatment: MCP-1 of 118.0 (64.0-515.2) versus 3.2 (0.0-22.8) pg/ml, P < 0.01; TARC of 126.1 (27.2-197.4) versus 0.0 (0.0-52.5) pg/ml, P < 0.05; MDC of 503.3 (446.2-600.9) versus 366.8 (337.4-393.4) pg/ml, P < 0.05]. Positive correlations among reductions in plasma chemokines and clinical outcome measures were also found. Expression of chemokine genes including MDC and TARC was suppressed after combination treatment [% suppression of 38.7 (54.3-13.0) and 53.7 (55.9-28.4), respectively]. Combination therapy with leflunomide and MTX exhibits anti-inflammatory activity in the suppression of chemokine expression and subsequent recruitment of inflammatory cells into the inflammatory sites in RA.     

Cell-type specific response of peripheral blood lymphocytes to methotrexate in the treatment of rheumatoid arthritis

The mode of action of methotrexate in the treatment of rheumatoid arthritis is still questionable. Although in vitro results suggest an immunosuppressive effect of methotrexate, several clinical studies have failed to confirm these effects in patients treated with oral low-dose methotrexate. With respect to the highly variable bioavailability of methotrexate, we investigated the effects of an intravenous administration of 15 mg methotrexate per week on peripheral blood lymphocyte subsets in eight patients with rheumatoid arthritis. Methotrexate after 12 weeks significantly (P<0.01) reduced total peripheral blood lymphocytes and led to a pronounced redistribution of lymphocyte subsets with a preferred reductive effect on B-lymphocytes (P<0.005) and T-lymphocytes (P<0.05). Natural killer cells and killer cell-like T cells, on the other hand, were unaffected by the treatment. Our results suggest a cell-type specific effect of intravenously administered low-dose methotrexate on peripheral blood lymphocytes. This effect, in our opinion, may contribute to the mode of action of methotrexate as an immunosuppressive drug in the treatment of rheumatoid arthritis.Abbreviations NSAID nonsteroidal anti-inflammatory drug - DMARD disease-modifying antirheumatic drug - MTX methotrexate - RF rheumatoid factor - CRP C-reactive protein - BSR blood sedimentation rate - NK cells natural killer cells - VAS visual analog scale Correspondence to: T.C. Wascher     

Peripheral airways mucus clearance in stable asthma is improved by oral corticosteroid therapy

Inhaled 99mTc-labelled particles have been used to assess mucus clearance from peripheral, intermediate and inner lung zones of 12 patients with stable asthma. The method of analysis relies on a ventilation image with 81mKr to estimate the distribution of radioaerosol alveolar deposition so that clearance from each zone can be related just to particles deposited in the ciliated conducting airways. In calculating clearance from intermediate and inner lung zones, allowance is made for particles transported into these zones from more distal regions of the lung. Peripheral zone clearance in the asthmatic subjects improved significantly (p less than 0.01) after four weeks of corticosteroid treatment (two weeks on 15 mg prednisolone orally each day, plus two weeks on 30 mg). No significant change occurred in clearance from the inner zone when all patients were considered together. However, the six patients who prior to treatment coughed relatively infrequently did show a significant (p less than 0.05) increase in clearance from the inner zone as well as from the peripheral zone.     

In active chronic rheumatoid arthritis, dipeptidyl peptidase IV density is increased on monocytes and CD4(+) T lymphocytes

The effect of low-dose methotrexate (MTX) treatment on the CD26 density on circulating monocytes and CD4(+) T lymphocytes or levels of soluble CD26 (sCD26) has not yet been described in rheumatoid arthritis (RA). While CD26 in T lymphocytes is involved in the activation and proliferation of T lymphocytes, little is known of the role of CD26 in monocytes as it has only recently been localized to monocytes. We analysed the CD26 density by flow cytometry and levels of sCD26 in plasma before initiation of MTX treatment and 12 weeks later. This was done on 34 RA patients fulfilling the 1987 American College of Rheumatology (ACR) criteria followed for 16 weeks after starting MTX treatment. CD26 density on monocytes was increased in RA patients compared with healthy controls before MTX treatment (P < 0.01). After 12 weeks of MTX treatment, the CD26 density on monocytes decreased significantly in the ACR-50% group (P = 0.03), but not in the ACR-20% and the non-responder group (P = 0.15 and 0.87). The increased CD26 density on CD4(+) T lymphocytes (P < 0.01) was unaffected by the reduction in disease activity in relation to MTX treatment. The percentage of monocytes and CD4(+) T lymphocytes among peripheral blood circulating mononuclear cells did not change during MTX treatment. No effect of MTX treatment was observed on the plasma levels of sCD26. Active chronic RA is characterized by enhanced CD26 density on circulating monocytes and CD4(+) T lymphocytes. MTX treatment decreased CD26 density on monocytes in the ACR-50% responder group and was associated with decreased disease activity. The enhanced CD26 density on CD4(+) T lymphocytes was uninfluenced by MTX treatment.     

Hypogammaglobulinemia in steroid-dependent asthmatics correlates with the daily dose of oral prednisolone

BACKGROUND: Steroid-induced adverse effects including suppression of humoral immunity should be considered in steroid-dependent severe asthma. Only a few studies have determined the exact steroid dose that could potentially suppress humoral immunity in asthmatics. METHODS: Randomly selected 100 adult asthmatics treated with inhaled beclomethasone dipropionate (BDP) were classified into three groups based on the dose of steroid to determine the serum IgG, IgA and IgM levels by radioimmunoassay. Relationships between serum immunoglobulin levels and the daily dose and duration of oral prednisolone (PSL) therapy were examined. RESULTS: None of the patients on inhaled corticosteroid alone had hypogammaglobulinemia. Patients on oral PSL at a dose >12.5 mg/day for at least 1 year had low serum IgG. There was no significant correlation between the duration of oral PSL therapy and serum IgG. CONCLUSIONS: Oral PSL can potentially suppress humoral immunity in severe asthma. In asthmatics, hypogammaglobulinemia could develop in those on a daily dose of PSL >12.5 mg, but is independent of the duration of such treatment. No suppression of humoral immunity was noted on inhaled corticosteroid therapy alone, either at low or high dose.     

Effects of allergen inhalation and oral glucocorticoid on serum soluble CTLA-4 in allergic asthmatics

BACKGROUND: The serum soluble cytotoxic T lymphocyte associated antigen-4 (sCTLA-4) concentration is significantly elevated in patients with asthma, and sCTLA-4 concentration correlate with the severity of asthma. The aim of the present study was to investigate effects of allergen inhalation and oral glucocorticoid on concentration of serum sCTLA-4 in patients with allergic asthma. METHODS: Allergen inhalation challenge was conducted in allergic asthmatics with isolated early asthma response and those with dual asthma response. In a randomized, double-blind, placebo-controlled, parallel group fashion, prednisolone or placebo was give orally once a day for 2 weeks. Venous blood samples were collected before and after allergen inhalation or prednisolone administration for obtaining sera. The serum sCTLA-4 concentrations were determined using enzyme-linked immunosorbent assay. RESULTS: The serum sCTLA-4 concentrations in the dual responder group increased from 29.0 (14.5-43.7) microg/l [median (25-75 percentiles)] before allergen inhalation to 44.0 (24.3-61.3) microg/l 24 h after allergen inhalation. In the isolated early responders, there were no significant increase in serum sCTLA-4 concentrations after allergen inhalation compared with baseline levels. There was a significant decrease in serum sCTLA-4 concentrations after 2 weeks of glucocorticoid therapy [22.0 (15.5-31.0) microg/l] compared with baseline values [37.0 (19.5-53.0) microg/l], whereas there was no significant difference in the placebo group. CONCLUSION: This study has demonstrated that serum sCTLA-4 concentrations increased after allergen inhalation in sensitized asthmatic subjects, and that serum sCTLA-4 concentrations were downregulated by prednisolone therapy.     

Liver biopsies from psoriatics related to methotrexate therapy. 2. Findings before and after methotexate therapy in 88 patients. A blind study.

Eightyeight patients with severe, recalcitrant psoriasis had liver biopsies performed before and after Methotrexate (MTX) therapy. MTX was given for an average of 26 months as a single, weekly, oral dose of 25 mg maximum. The mean cumulative dose was 1733 mg (range 175-4590 mg). A statistically significant increase in the number of pathological post-MTX liver biopsies was found (p less than 0.0001). Of the 88 patients 6 developed cirrhosis and another 5 developed fibrosis, in all 12.5 per cent, during MTX therapy (95 per cent confidence limits for cirrhosis: 3-14 per cent). There was no statistically significant correlation between the number of pathological post-MTX liver biopsy findings in the 88 patients and the following variables one by one: cumulative dose of MTX, duration of MTX therapy and admitted alcoholic intake during MTX therapy. Cirrhosis and fibrosis did not develop statistically more frequently from pathological than normal pre-MTX liver histology (p = 0.062). The liver damage appeared to be due to a multifactorial interaction of straining factors on the liver during MTX therapy. A multifactorial index comprising: cumulative dose of MTX, admitted alcoholic intake during MTX therapy, age, obesity and, if available, pre-MTX liver histology gave an estimate of the probability of developing cirrhosis or fibrosis during treatment of psoriasis with weekly, oral doses of MTX. For use of MTX therapy in psoriasis the following precautions are suggested: MTX therapy should be used only in disabling cases; a pre-MTX liver biopsy and repeat liver biopsies at regular intervals of 1/2-1 year should be performed, alcohol should be prohibited and frequent inquiries should be made about the patient's alcoholic intake; and strong reliance should not be placed on the SGOT as an indicator of abnormal liver histology.     

Low-dose methotrexate therapy for intravenous immunoglobulin-resistant Kawasaki disease

Purpose

The aim of this study was to evaluate the efficacy of low-dose oral methotrexate (MTX) as a treatment for patients with Kawasaki disease (KD) which was resistant to intravenous immunoglobulin (IVIG).

Patients and Methods

The patients who had persistent or recrudescent fever after treatment with IVIG were subsequently treated with low-dose oral MTX [10 mg/body surface area (BSA)] once weekly.

Results

Seventeen patients developed persistent or recrudescent fever after treatment of KD with IVIG and were consequently given MTX. The proportion of children with coronary artery lesions (CALs) was 76%. The median value of maximum body temperatures decreased significantly within 24 hours of MTX therapy (38.6℃ vs. 37.0℃, p < 0.001). The median CRP (C-reactive protein) level was found to be significantly lower 1 week after administering the first dose of MTX (8.9 mg/dL vs. 1.2 mg/dL, p < 0.001). The median duration of fever before MTX treatment was shorter in CALs (-) group than in CALs (+) group (7 days vs. 10 days, p = 0.023). No adverse effects of MTX were observed.

Conclusion

MTX treatment for IVIG-resistant KD resulted in quick resolution of fever and rapid improvement of inflammation markers without causing any adverse effects. MTX therapy should further be assessed in a multicenter, placebo-blinded trial to evaluate whether it also improves coronary artery outcome.     

Therapeutic strategy for autoimmune pancreatitis

Autoimmune pancreatitis (AIP) is a particular type of pancreatitis that is thought to have an autoimmune etiology. Before therapy for AIP is begun, accurate diagnosis of AIP is necessary. It is important to distinguish AIP from pancreatic cancer. Since there is currently no diagnostic serological marker for AIP, AIP should be diagnosed on the basis of a combination of abnormalities unique to AIP. The Japanese "Diagnostic Criteria for Autoimmune Pancreatitis 2006" require the characteristic imaging findings of AIP and that at least one of the laboratory criteria or histopathological criteria have to be present. Unlike in patients with usual chronic pancreatitis, corticosteroid therapy is frequently effective in resolving the morphological findings and the symptoms of AIP patients. Therefore, administration of oral steroid therapy has become standard therapy for AIP. Indications for steroid therapy for AIP are thought to include obstructive jaundice due to stenosis of the bile duct, associated extrapancreatic sclerosing lesions, and diabetes mellitus coincidental with AIP. Oral prednisolone is usually started at 30 mg/day and tapered by 5 mg every 1-2 weeks. Serological and imaging tests are followed periodically after commencement of steroid therapy. Patients in whom complete radiological improvement is documented can stop their medication. To prevent relapses, continued maintenance therapy with prednisolone 2.5-5 mg/day is sometimes required. Patients who relapse should be re-treated with high-dose steroid therapy. A poor response to steroid therapy should raise the possibility of pancreatic cancer and the need for further examination, including laparotomy.     

A preliminary study of long-term treatment with interferon gamma-1b and low-dose prednisolone in patients with idiopathic pulmonary fibrosis.

BACKGROUND AND METHODS: Patients with idiopathic pulmonary fibrosis have progressive scarring of the lung and usually die within four to five years after symptoms develop. Treatment with oral glucocorticoids is often ineffective. We conducted an open, randomized trial of treatment with a combination of interferon gamma-1b, which has antifibrotic properties, and an oral glucocorticoid. We studied 18 patients with idiopathic pulmonary fibrosis who had not had responses to glucocorticoids or other immunosuppressive agents. Nine patients were treated for 12 months with oral prednisolone alone (7.5 mg daily, which could be increased to 25 to 50 mg daily), and nine with a combination of 200 microg of interferon gamma-1b (given three times per week subcutaneously) and 7.5 mg of prednisolone (given once a day). RESULTS: All the patients completed the study. Lung function deteriorated in all nine patients in the group given prednisolone alone: total lung capacity decreased from a mean (+/-SD) of 66+/-8 percent of the predicted value at base line to 62+/-6 percent at 12 months. In contrast, in the group receiving interferon gamma-1b plus prednisolone, total lung capacity increased (from 70+/-6 percent of the predicted value at base line to 79+/-12 percent at 12 months, P<0.001 for the difference between the groups). In the group that received interferon gamma-1b plus prednisolone, the partial pressure of arterial oxygen at rest increased from 65+/-9 mm Hg at base line to 76+/-8 mm Hg at 12 months, whereas in the group that received prednisolone alone it decreased from 65+/-6 to 62+/-4 mm Hg (P<0.001 for the difference in the change from baseline values between the two groups); on maximal exertion, the value increased from 55+/-6 to 65+/-8 mm Hg in the group that received combined treatment and decreased from 55+/-6 mm Hg to 52+/-5 mm Hg in the group given prednisolone alone (P<0.001). The side effects of interferon gamma-1b, such as fever, chills, and muscle pain, subsided within the first 9 to 12 weeks. CONCLUSIONS: In a preliminary study, 12 months of treatment with interferon gamma-1b plus prednisolone was associated with substantial improvements in the condition of patients with idiopathic pulmonary fibrosis who had had no response to glucocorticoids.     

A randomized, comparative trial of treatment of kerion celsi with griseofulvin plus oral prednisolone vs. griseofulvin alone.

Glucocorticoids are often recommended along with oral antifungals in the treatment of kerion celsi. In this randomized study, the efficacy of combination therapy with oral griseofulvin and oral prednisolone (n =17) was compared to oral griseofulvin alone (n=13) in the treatment of kerion celsi. Both groups were treated with oral griseofulvin for 8 weeks whereas oral prednisolone was given in tapering doses for 3-4 weeks to the first group only. The final evaluation at week 12 showed a cure rate of 100% in both groups without any significant difference in terms of clinical or mycological cure (P>0.05). No adverse events were noted in either group. In our opinion the combination of oral prednisolone with griseofulvin does not result in additional objective or subjective improvement compared to griseofulvin alone in cases with kerion celsi.     

Induction of apoptosis and modulation of activation and effector function in T cells by immunosuppressive drugs

Immunosuppressive drugs (ISD) are used for the prevention and treatment of graft rejection, graft-versus-host-disease (GVHD) and autoimmune disorders. The precise mechanisms by which ISD interfere with T cell activation and effector function or delete antigen-specific T cells are defined only partially. We analysed commonly used ISD such as dexamethasone (DEX), mycophenolic acid (MPA), FK506, cyclosporin A (CsA), rapamycin (RAP), methotrexate (MTX) and cyclophosphamide (CP) for apoptosis-induction and modulation of activation and effector function in human peripheral T cells, cytotoxic T cell lines (CTL) and Jurkat T cells. Of all drugs tested only CP and MTX prevented antigen-specific proliferation of T cells and decreased cytotoxicity of alloantigen specific CTL lines by direct induction of apoptosis. MTX and CP also slightly increased activation-induced cell death (AICD) and CD95-sensitivity. In contrast, all other drugs tested did not induce T cell apoptosis, increase CD95-sensitivity or AICD. CsA and FK506 even prevented AICD by down-modulation of CD95L. DEX, MPA, CsA, FK506 and RAP inhibited activation of naive T cells, but were not able to block proliferation of activated T cells nor decrease cytotoxic capacity of CTL lines. These results show that ISD can be classified according to their action on apoptosis-induction and inhibition of proliferation and would favour a rational combination therapy to delete existing reactive T cells and prevent further T cell activation.