Remission Disease Activity Research Articles

Randomised trial of mycophenolate mofetil versus azathioprine for treatment of chronic active Crohn’s disease

BACKGROUNDCrohn’s disease is a chronic inflammatory disease of the alimentary tract. Azathioprine is an effective agent in the management of chronic active Crohn’s disease leading to long term remission of...

Recognition and management of IgA nephropathy.

IgA (immunoglobulin A) nephropathy is the most common form of primary glomerulonephritis worldwide. It generally has a good prognosis, with 15-year rates of kidney survival from the apparent onset of disease usually well in excess of 70%. Progression, when it occurs, is usually a slow, indolent process, and spontaneous remission of disease activity occurs in 7% of patients. It is possible to predict, from the initial presenting features and laboratory findings, renal biopsy and clinical course during follow-up, which patients are likely to have progressive renal disease. Identification of the factors likely to be associated with progression is of importance in helping to establish which patients will benefit from specific therapeutic intervention. For all patients, attention should be directed toward general health issues in an endeavour to reverse factors that are likely to have an adverse impact on renal function. This should include early detection and tight control of hypertension (present in 50% of all patients with IgA nephropathy during the course of their disease), along with utilisation of antihypertensive agents that have specific renoprotective effects, namely ACE inhibitors or calcium antagonists. Such therapy should also be considered in normotensive patients with heavy proteinuria, as a reduction of proteinuria is often achieved by this means. Other aims should include maintenance of desirable bodyweight, correction of hyperlipidaemia, cessation of smoking, participation in an active exercise programme, avoidance of exposure to nephrotoxins and maintenance of a high fluid intake. A low protein/low phosphate diet together with phosphate binder therapy should be commenced early in the course of renal impairment. Corticosteroid and/or cytotoxic drug therapy should be considered in the small percentage of patients with heavy proteinuria or a rapid decline in renal function. Such therapeutic endeavours are likely to delay the onset of renal failure in patients with progressive IgA nephropathy.

The change of periapical exudate prostaglandin E 2 levels during root canal treatment

We have previously demonstrated that detectable levels of prostaglandin E2 exist in periapical exudates (PE-PGE2) from root canals of periapical periodontitis. Our data from a cross-sectional study also suggested the association of PE-PGE2 concentrations with the active phase of periapical lesions. The objective of this study was to investigate the longitudinal changes of PE-PGE2 levels during root canal treatment. Periapical exudate specimens were quantitatively sampled from root canals of 20 nonvital teeth at consecutive treatment visits to measure PGE2 concentrations. The mean PE-PGE2 levels significantly decreased following the endodontic therapy (158.0 +/- 54.1 pg/microliter in the first samples versus 48.4 +/- 37.9 pg/microliter in the second samples). A significant correlation was also found between the changes in PE-PGE2 levels and the clinical disease expression of periapical periodontitis (p < 0.01). Decreased PGE2 production is considered to reflect the remission of disease activity. These results suggest the central roles of PGE2 in regulatory mechanisms for the expression of periapical disease.

Therapy of Crohn's disease in childhood

The aim of therapy in Crohn's disease in childhood is to induce and to maintain a remission of disease activity so that normal growth and development of the child may occur. Enteral nutrition may now be recommended as the first-line treatment for most children with Crohn's disease. However, the evidence for remission is better for children with Crohn's disease of the small intestine rather than of the large intestine. There is evidence that amino acid feeds (elemental), whole protein (polymeric) and. protein hydrolysate feeds (semi-elemental) may all be successful. Such a therapeutic approach can lead to healing of the mucosa and down-regulation of inflammation. However, in some cases surgery is required, particularly in children with growth failure and delayed puberty. Drug therapy also continues to have a role in therapy especially with severe colonic disease.

Coronary involvement in the Churg-Strauss syndrome.

The Churg-Strauss syndrome (CSS) is a rare systemic disease characterised by vasculitis and peripheral eosinophilia in patients with an atopic constitution. Cardiac involvement is an important cause of morbidity and...

Intestinal epithelial barrier dysfunction in Crohn's disease.

Despite extensive research, the etiology of Crohn's disease remains unknown. Accumulating evidence suggests the possibility that a primary defect of intestinal barrier function may be present in Crohn's disease. In this review, the possible role of intestinal barrier defect in Crohn's disease is discussed. It has been recognized for some time that Crohn's patients have a defective intestinal epithelial barrier function manifested by an increase in intestinal permeability. Recent studies indicate that a subgroup of healthy first-degree relatives of Crohn's patients (a population at high risk for developing Crohn's disease) also have increased intestinal permeability. Additionally, this subgroup of patients have evidence of increased exposure to foreign antigens, suggesting a possible link between increase in intestinal permeability and increase in antigenic penetration. Furthermore, exacerbation of Crohn's disease is produced by agents that disrupt intestinal epithelial barrier function, while remission of active disease is induced by decreasing intestinal antigenic load. A "leaky gut" hypothesis is advanced which proposes that a preexisting disorder of intestinal permeability is responsible for the intestinal inflammation of Crohn's disease.

Natural history of psoriasis: a study from the Indian subcontinent.

Clinical and epidemiological data from 1220 patients with psoriasis is presented. Psoriatics accounted for 2.3% of the total dermatology outpatients. There was a distinct male preponderance. Mean age of onset was lower in women at 27.6 years, although the severity of the disease was the same in both sexes. Family history was positive in just 2% of patients. Plaque type disease was the most common, seen in over 93% of the patients. Lesional pruritus was a problem in 65%. Remission in summer was experienced by 43%. The scalp was the first site of onset in 25.2%. Nail and joint involvement were seen in 55.7% and 4.4%, respectively. Complete remission of disease activity was experienced by 35% of the patients during some part of the year in the course of their disease.

Management of growth failure in Crohn's disease.

Crohn's disease is one of the chronic inflammatory bowel diseases which at present is still of unknown cause. It has been known for some time that this disorder may lead to significant impairment of linear growth' and delay in the onset of puberty. Indeed Crohn's disease in childhood may present as short stature or delay in pubertal maturation without any gastrointestinal symptoms. There may be irreversible consequences in terms of reduced potential for height unless this diagnosis is made promptly and treatment instituted to induce remission of disease activity, thus permitting restoration of normal growth.2 A full blood count, erythrocyte sedimentation rate, and C reactive protein estimation should be standard screening tests for short stature.' In this paper I shall give an account of my own personal practice in the management of children with Crohn's disease and chronic inflammatory bowel disease in the paediatric inflammatory bowel disease clinic which was first established at St Bartholomew's Hospital in 1978 and transferred to the Royal Free Hospital in 1995.

5.6 T-cell receptor expression in patients with rheumatic diseases

T -cells playa predominant role in the pathogenesis of rheumatic auto-immune disorders. This is best illustrated in experimental models such as adjuvant arthritis, in which the disease can be transferred by inoculation of healthy animals with T-cell lines taken from affected animals (HOLOSHITZ et al. 1983). In human rheumatoid arthritis, the pathogenic role of T -cells is suggested by their presence in close contact with activated macrophages in the inflamed synovial tissue and by the fact that therapies which cause aT-cell immunodepression may lead to remission of disease activity. On condition that the pathogenic T-Iymphocytes and their respective antigenreceptors (T-cell receptors or TCR) are isolated and well characterized, they can be used effectively in the prevention and treatment of T-cell mediated auto-immune disorders. They may indeed serve as specific targets for immuno therapy (passive vaccination with anti-TCR antibodies) or as tools (active vaccination with attenuated T-cell lines or with synthetic idiotypic peptide) (COHEN 1989; VANDENBARK et al. 1989). This has been shown and repeatedly confirmed in different animal models and in different laboratories. Specific anti-TCR therapy has hitherno been unsuccessful in human rheumatic auto-immune diseases, mainly because the pathogenesis of these diseases is still unclear. In fact, we do not know which antigen induces the auto-immune response and which T-Iymphocytes predominate in this pathogenic process. Our study was designed to analyze TCR expression by lymphocytes derived from inflammatory lesions in different rheumatic conditions. Because of their origin (site of inflammation), we assumed them to be involved in the pathogenesis of the disease (guilt by association). Even if the antigen-reactivity of these cells remains unknown, they may be possible candidates for immune targeting.

Histamine-Releasing Autoantibodies in Chronic Urticaria

Circulating histamine-releasing factors have been identified in the serum and plasma of chronic-urticaria patients by in vivo skin testing and in vitro histamine release from heterologous mixed leukocytes. Quantitative mast cell studies of serum skin test biopsies and electron microscopy indicate that the serum factors release histamine by mast cell degranulation. Peripheral blood basophils and total cellular blood histamine are reduced in chronic-urticaria patients suggesting that the circulating serum factors cause sustained degranulation. Histamine-releasing activity has been identified by skin testing in ultrafiltered serum fractions less than 30 kDa and greater than 100 kDa. In vitro histamine-releasing activity was confined to ultrafiltered serum fractions greater than 100 kDa and was present in IgG purified from some chronic-urticaria sera by protein G affinity chromatography. The dose-response relationship and kinetics of histamine release in vitro were similar to those of anti-human IgE. 'Desensitisation' of basophils by prior incubation with anti-IgE in the absence of calcium and competitive inhibition studies with myeloma IgE serum indicated that histamine-releasing autoantibodies in chronic-urticaria sera and purified IgG have the properties of anti-IgE. Plasma exchange in 4 patients with active chronic urticaria refractory to antihistamine therapy showing in vivo and in vitro histamine-releasing activity was followed by temporary remission of disease activity in 2 of them. It is possible that chronic urticaria is an autoimmune disease.

CYCLOSPORIN-INDUCED REMISSION IN SEVERE COLITIS UNRESPONSIVE TO CORTICOSTEROID THERAPY

Cyclosporln A (CyA) has induced clinical remission in Crohn's disease and one adult with ulc colitis. We have documented remission in disease activity and mucosal inflammation hy sequential biopsies in two adolescents with severe pancolitis unresponsive to IV corticesteroids and TPN. Patient #1 has UC and pt #2 pancolitis (indeterminate type). Patient #1 had persistent bleeding requiring 10 u of blood. After 4 wks of IV Solu-Medrol and TPN, IV CyA 160 mg BID (6 mg/kg/day) was begun. Plasma Cy by HPLC was 200 ng/ml. At one week, stools decreased and gross bleeding subsided. Biopsies on day 7 had reduced PMN infiltration. At day 14, no crypt abscesses were seen; PMN inflammation was minimal at 5-10 cm and normal at 15 cm. Pred was tapered to 20 rag QOD. After 5 mos of oral CyA rx, she is asymptomatic, with mild friability to 10 cm and normal from 10-25 cm. Patient #2 had severe abd pain, hematochezia and wt loss, non responsive to 4 wks of pred and 3 wks of IV Solu-Medrol. IV CyA, 130 mg BID, (6mg/kg/day) was followed by gradual improvement over 2 wks. A decrease in mucosal inflammation was noted at 3 wks and markedly improved at 6 wks. At 3 mos, she is asymptomatic on oral CyA and alt day pred wi th mild rectal edema. Conclusion: CyA reduces inflammation and induces clinical remission which lasts for at least 3-6 mos. A multicenter study of CyA in pediatric patients with severe colitis, unresponsive to corticosteroid therapy, should be established.

Spontaneous reactivation of chronic hepatitis B virus infection

Studies on the natural history of chronic type B hepatitis have shown that loss of hepatitis B e antigen and seroconversion to antibody to hepatitis B e antigen are usually accompanied by remission of disease activity and improvement in serum aminotransferase levels. Twenty-five symptomatic patients with biopsy-documented chronic type B hepatitis were followed for 25 ± 2 mo (mean ± SEM) after disappearance of hepatitis B e antigen, hepatitis B virus-deoxyribonucleic acid, and deoxyribonucleic acid polymerase activity from the serum. Twenty-four patients developed the antibody to hepatitis B e antigen. All 25 patients demonstrated a decrease in serum aminotransferase levels, and most became asymptomatic. However, during subsequent followup, 8 of the 25 patients (32%) exhibited reactivation of chronic type B hepatitis manifested by abrupt elevation of serum aminotransferase levels and reappearance of serum hepatitis B virus-deoxyribonucleic acid, deoxyribonucleic acid polymerase activity, and, in 7 patients, hepatitis B e antigen. All 8 patients developed symptoms: 3 became icteric, 3 developed ascites, and 2 bled from esophageal varices. One of these patients died. Episodes of reactivation invariably occurred within 1 yr of loss of hepatitis B e antigen and lasted for up to 13 mo. These observations suggest that loss of hepatitis B e antigen and seroconversion to the antibody to hepatitis B e antigen do not necessarily imply permanent remission of chronic type B hepatitis, and subsequent spontaneous reactivation may be an important cause of progression of hepatic injury.

Reduced T-lymphocyte subsets in systemic lupus erythematosus: Effects of immune complexes and lymphocytotoxic antibodies

Patients with active systemic lupus erythematosus (SLE) show significant reductions of T cells with receptors for the Fc portion of IgG, Tγ cells, which have been found to suppress in vitro B-cell responses to pokeweed mitogen. T cells with receptors for the Fc portion of IgM, Tμ cells, which show both helper and suppressor functions, are also reduced in SLE. Levels of both Tγ and Tμ cells in patients with inactive disease are intermediate between those of patients with active SLE and normal individuals. In a majority of individual patients, levels of Tγ cells were found to fluctuate with disease activity. SLE patients with reduced levels of Tγ cells showed high levels of circulating immune complexes, although a uniform inverse correlation was not detected. The pathophysiologic mechanisms in the observed decrease of T-cell subsets in SLE patients were studied by determination of the effect of aggregated IgG (an in vitro model of immune complexes) and lymphocytotoxic antibodies on T-cell subsets from normal individuals. Addition of aggregated IgG led to irreversible reduction of Tγ cells with no effect on Tμ cells. By contrast, both types of T-cell subsets were reversibly decreased by SLE sera with lymphocytotoxic antibody activity. Thus the observed decrease in T-cell subsets appears to be secondary to both immune complexes and lymphocytotoxic antibodies in SLE patients, and is reversible with remission of disease activity. Analysis of T-cell subpopulations in SLE appears to reflect other laboratory parameters associated with disease activity in these patients.

HEGENER'S GRANULOMATOSIS (WG) IN CHILDHOOD WITH PROLONGED SURVIVAL FOLLOWING CYTOTOXIC THERAPY

Wegener's granulomatosis is a systemic disease of unknown etiology involving mainly the kidney and respiratory tract in a necrotizing and granulomatous vasculitis, though other organ systems may be affected. Only 6 cases have been reported in children under age 16 years and each had a rapidly fatal outcome despite supportive therapy and corticosteroids. Although several studies have reported a good response in adults to cytotoxic therapy, this form of therapy has not been tried in children with WG. We have treated 2 girls, aged 10 and 13 years, with a combination of prednisone and cyclophosphamide therapy for generalized WG with renal, ocular, nasopharyngeal, sinus and cutaneous involvement. One patient also had middle ear pulmonary and laryngeal granulomata. Multiple biopsies of involved tissues confirmed the diagnoses. Cyclophosphamide was capable of inducing remission in disease activity initially and during subsequent relapses. Proteinuria decreased in one patient from 5.2 to 0.8 gm/24 h and her serum creatinine concentration fell from 2.1 to 1.3 mg/dl. Pulmonary granuloma regressed in the second patient. Hemorrhagic cystitis was the only complication of therapy, but did not recur with readministration. These patients have survived 2½ and 5 years respectively. Both are in good health and attending school at present. These are the first children of which we are aware to receive this form of therapy for WG.

Rheumatoid arthritis treated with chlorambucil: a five-year follow-up.

The results of a five-year study of chlorambucil in patients suffering from rheumatoid arthritis are presented. The effect of treatment was to allow a reduction in corticosteroid dosage and a sustained remission of disease activity in patients. Three patients of the series of 22 developed neoplastic disease, and the signficance of this is discussed.

Selection of patients with rheumatoid arthritis to be treated with penicillamine, and their management.

SummaryThirty-one patients with rheumatoid arthritis were treated with penicillamine and followed for up to 18 months. Patients selected for treatment were those with persistently intractable disease who had failed to respond to or were unsuitable for more conventional forms of therapy.In 21 patients the initial daily dose of 250 mg. penicillamine was increased every 2 weeks by 250 mg. until the daily total was 1.5 g. Because penicillamine can cause potentially hazardous side-effects (such as thrombocytopenia, proteinuria, neutropenia, and rashes), which often appear for the first time after months of treatment, monthly checks of general health, blood and urine are essential. Only 4 of the patients studied escaped side-effects and in 10, side-effects enforced withdrawal of the drug. In the remaining 10 patients, a different dose schedule was used in an attempt to decrease side-effects and still retain remission of disease activity. Increments of 250 mg. were made every 4 weeks until the daily dose was 750 mg., thereafter no further increments were made for at least 3 months. Further increments were made at 3-monthly intervals thereafter if the daily dose of 750 mg. proved inadequate. Although the longest follow-up in this group did not exceed 9 months no patient had to discontinue treatment though 2 developed thrombocytopenia.Experience with this group of 31 patients confirms that penicillamine induces a remission of clinical and laboratory indices in patients with rheumatoid arthritis. It is also evident that there is no pre-determined dose of penicillamine which will suit all patients. The dose for each individual must be sought by careful monitoring over a period of months.