Azathioprine and prednisone combination therapy in refractory coeliac disease.

INTRODUCTION: Refractory coeliac disease (RCD) is a rare syndrome with a poor prognosis, defined by malabsorption due to gluten-related enteropathy after initial or subsequent failure of a strict gluten-free diet and after exclusion of any disorder mimicking coeliac disease. PATIENTS AND METHODS: Nineteen patients were included and treated. Based on intraepithelial T-lymphocyte(IEL) phenotyping, patients were recorded as having RCD type I with normal IELs, or RCD type II with phenotypically immature IELs defined by a lack of characteristic T-cell markers. Treatment consisted of azathioprine combined with prednisone for 1 year, which was tapered and, if possible, stopped. RESULTS: Clinical improvement was seen in nearly all patients in both groups. Eight of 10 RCD type I patients responded histologically, and complete normalization of villi was seen in four patients. In RCD type II, 6/8 patients developed enteropathy-associated T-cell lymphoma (EATL) and 7/8 patients died. CONCLUSIONS: For the first time we report a promising therapeutic treatment option for RCD type I. In RCD type II, azathioprine and prednisone therapy (APT) is not effective, therefore we suggest that other (chemo)therapeutic agents are considered. Not all RCD type II patients presented with a monoclonal TCRgamma-gene rearrangement and immunohistological changes as is currently reported in the literature. Therefore, immunophenotyping seems mandatory in the work-up of RCD.

Treatment of primary Sjögren's syndrome with D-penicillamine: a pilot study.

BACKGROUND: Up to now no satisfying systemic treatment is available for patients with primary Sjögren's syndrome. METHODS: In a prospective, open study we investigated the effect of D-penicillamine (first three months 250 mg/day, next three months 500 mg/day) on clinical and immunological parameters in 19 patients with primary Sjögren's syndrome and a mean disease duration of 3.8 years. RESULTS: Eight patients had to stop treatment mainly due to severe (reversible) loss of taste. Clinically, a statistically significant increase in basal salivary flow was observed after three months (p<0.05). In addition, improvement was noted in the Schirmer test and stimulated parotid salivary flow after six months, but these differences were not statistically significant. Laboratory values showed a decrease in ESR (p<0.05) and levels of IgA and IgM (both p<0.02) after six months, a decrease in levels of IgA-Rf and IgM-Rf after three months (both p<0.05), and an increase in haemoglobin level (p<0.05). CONCLUSION: From this pilot study we conclude that the treatment of primary Sjögren's syndrome with D-penicillamine has only marginal beneficial effects. Together with its clear side effects this means that D-penicillamine is unsuitable for this indication.

A patient with a spontaneous factor VIII:C autoantibody: successful treatment with cyclosporine.

A 65-year-old man was admitted to the hospital because of extensive spontaneous ecchymoses of the trunk and huge hematomas of the arms and legs. He had no personal or family history of a hemorrhagic diathesis. Coagulation studies revealed a prolonged APTT, no detectable factor VIII:C activity, and a high titer of anti-factor VIII:C antibodies. A diagnosis of acquired hemophilia was made. No underlying disorder could be found. The inhibitor was an IgG antibody. Long-term management of bleeding including immunodepletion by plasma exchange and immunosuppression by corticosteroids and cytotoxic drugs alone and in combination had no effect on the bleeding tendency and coagulation data. The administration of Cs (10 mg/kg/d) in combination with prednisone induced a remission. After a stormy course and a 5-month stay in the hospital the patient could be discharged. A relapse occurred after the Cs and prednisone dosages were reduced. Increasing the Cs dosage induced a remission again.

Immunofluorescence studies of atrophie blanche with antibodies against fibrinogen, fibrin, plasminogen activator inhibitor, factor VIII-related antigen, and collagen type IV.

In and around ulcers complicating the chronic venous insufficiency syndrome and atrophie blanche a pericapillary cuff of fibrinoid material has been described. The aim of the present study was to find out whether pericapillary cuffs are present in atrophie blanche ulcerations, whether they consist of fibrinogen and/or fibrin in comparison to normal controls, and whether this cuff is composed of other components. Skin biopsies from ten patients adjacent to atrophie blanche ulcers, and from ten controls were taken. In all patients pericapillary cuffs consisting of fibrin were found. However, no fibrinogen was found in these cuffs. In the controls no cuffs were found. In this fibrin network factor VIII-related antigen and collagen type IV were also present. The finding of plasminogen activator inhibitor-I in the pericapillary cuff in several cases may indicate that breakdown of this fibrin cuff is impaired. The possible diffusion barrier caused by the pericapillary cuff together with the pattern of vascularization may be an important event in ulcer formation and impaired ulcer healing.

Local treatment of venous ulcers with tissue type plasminogen activator containing ointment.

BACKGROUND: The pathogenesis of venous leg ulcers is still not known. One hypothesis states that pericapillary fibrin cuffs might play an important role. These fibrin cuffs might not be broken down because of an inadequate fibrinolytic activity. PATIENTS AND METHODS: To stimulate fibrinolysis, tissue type plasminogen activator (t-PA) containing ointment was applied over 12 weeks on chronic venous leg ulcers of six patients. Three of the six ulcers healed within this period. Biopsy specimens for immunofluorescence studies were taken from the ulcer base and margin before and at the end of treatment and, if the ulcer had healed, from the healed area. RESULTS: Deposition of pericapillary fibrin was seen around the capillaries of all investigated ulcers at the start of the study. Pericapillary fibrin was still present with nearly undiminished intensity at the end of the study even though 3 of the ulcers healed. CONCLUSION: It is most likely that the healing of these ulcers was not improved by the fibrinolytic activity of t-PA, but caused by other wound healing properties of t-PA.

The relationship between the T-helper cell and the T-cell involved in the delayed hypersensitivity.

The common cell type involved in the humoral and cellular responses is the T-cell. Functionally the T-cell, active in the humoral response, is known as Thelper (Th), the T-cell active in the cellular response as Tcellular (Tc). The present experiments are used to study the relationship between Tc and Th. IP immunization, with suboptimal doses of antigen, did not result in antibody formation but induced both a DH (equals Tc) and a Th population. Th and Tc activity changed in a similar way with increasing doses of antigen. Spleen cells taken from mice, which were immunized under conditions which only invoke cellular activity, were able to function even in small numbers as Th in transfer experiments. Educated thymus cells and cells obtained from cortisone or CY treated donor mice had an increased Th and Tc activity when transferred into irradiated recipients. Education in the presence of a high antigen dose reduced both activities below control levels. Cross reactivity between HRBC and SRBC in the hormoral response is known to be at the Th level. It was demonstrated that this cross reactivity also exists at the Tc level. Induction of DH with one antigen acted as pre-immunization, for the humoral response, on the cross reactive antigen too. These results suggest a correlation between the T-cells involved in DH and the Th for antibody formation.

Influence of cyclophosphamide on delayed hypersensitivity and acquired cellular resistance to Listeria monocytogenes in the mouse.

The effect of a single dose of cyclophosphamide (CY) on delayed type hypersensitivity (DH) and acquired cellular resistance (ACR) to Listeria monocytogenes infection in mice was studied. Intraperitoneal or intracutaneous immunization with L forms of L. monocytogenes did not result in protection against lethal challenge. A positive DH could be observed when CY-treated mice were intracutaneously immunized with 10(8) or more L forms. Intraperitoneal injection of viable L. monocytogenes resulted only in a narrow dose range in survival on immunization and partial protection on challenge. Protection was accompanied by DH. Intracutaneous injection of Listeria in Freund's complete adjuvant permitted the use of even 10(9) viable bacteria for immunization. This figure was reduced to 10(5) or less for CY treated mice. In normal mice protection was afforded on immunization with 10(7) bacteria whereas 10(3) bacteria were sufficient to protect CY treated animals. All protected mice showed a positive DH. These results demonstrate that CY treatment reduces the dose of viable bacteria tolerated for immunization 10(4) times. On the other hand after CY treatment the doses of bacteria effective on immunization for ACR and DH could be reduced in the same order of magnitude. Reduction of the CY dose resulted in a peak DH with 4 mg CY, but the protection was less than that obtained after treatment with 6 mg CY. A dissociation between ACR and DH was observed by varying the interval between immunization and challenge. In normal mice DH was preceded by ACR, with peaks at respectively 10 and 5 days after immunization. CY treatment caused a delay in the onset of the ACR, followed by an enhanced and slightly prolonged response. The effect of CY on DH consisted of enhancement and prolongation.

The haemopoietic and immunogenic capacities of living hybrid bone marrow cells tested in tumour allograft rejection.

In irradiated mice the capacity to reject allogenic tumours can be reconstituted with syngeneic lymphoid cells if the transferred cells are primed with the allogenicantigen. Living semi-allogeneic cells proved to be 30-100-times more acitve as priming antigen than cell membrane fractions. The tumour-suppressive activity of primed lymphoid cells increased in the following order: bone marrow less than Peyer's patches less than thymus less than spleen less than lymph node cells. Even bone marrowcells showed a considerable suppressing activity after priming with live antigen. It was a great advantage that 2 times 10-6 semi-allogeneic bone marrow cells could be used both for the restoration of the haemopoietic system after irradiation and for stimulation of the transferred parental lymphocytes. Priming with large numbers of semi-allogeneic spleen cells abolished the tumour-suppressive activity of the transferred lymphoid cells. This tolerogenic effect disappeared when the priming cells were pretreated with mitomycin. Tolerance could be induced when the cell donors were treated with cyclophosphamide in combination with the living cells. Cell membranes were not effective.

Hyposensitisation to wasp venom in six hours.

Eleven patients with a history of anaphylaxis, positive reactions to skin tests, and specific IgE antibody to wasp venom underwent hyposensitisation in a six hour procedure. No general reactions occurred. Complement activation and proteinuria could not be shown. The patterns of specific IgE, IgG1, and IgG4 were as described in other procedures--namely, IgE increased sharply and then decreased; IgG1 and IgG4 increased steadily and then decreased--but increase and decrease came earlier. Challenge by a stinging insect at least four weeks after treatment proved complete protection. The skin reactivity two years later showed an unpredictable pattern.

Venous hypertension of the hand caused by hemodialysis shunt: immunofluorescence studies of pericapillary cuffs.

BACKGROUND: Venous hypertension of the hand is an unusual complication of an arteriovenous shunt in patients receiving dialysis. OBJECTIVE: We investigated whether in venous hypertension of the hand pericapillary cuffs are present and whether they consist of fibrin and other components. METHODS: Biopsy specimens were taken from three patients with a side-to-side shunt and venous hypertension of the hand, from three patients with an end-to-side shunt without venous hypertension, and from three control subjects. The specimens were stained with antibodies against fibrinogen, fibrin, plasminogen activator inhibitor-I, factor VIII-related antigen, and collagen type IV. RESULTS: Pericapillary cuffs consisting of fibrin only were observed in patients with venous hypertension of the hand. In this fibrin network, factor VIII-related antigen and collagen type IV were also present. The finding of plasminogen activator inhibitor-I in the pericapillary cuff in the patient with the most severe signs of venous hypertension may indicate that breakdown of this fibrin cuff is impaired. CONCLUSION: Pericapillary cuffs may be of pathogenetic significance in venous hypertension of the hand.

Preliminary report: complement activation in wasp-sting anaphylaxis.

The generation of the anaphylatoxin C3a was measured after a wasp-sting challenge in eight patients with previous anaphylactic reactions to wasp stings. Whereas there was no change in C3a in one patient who showed no reaction and only a slight rise in three patients with mild reactions, C3a rose substantially in the four patients with severe anaphylactic reactions. This complement activation is the first in-vitro variable which correlates with the severity of wasp-sting anaphylactic reactions. A role for complement activation in the pathophysiology of wasp-sting anaphylaxis is therefore suggested.

Differential precipitation of the Clq subcomponent of the first complement component (C1) by polyethylene glycol from normal human serum and sera of patients with collagen diseases.

Sera were, under strictly standardized conditions, centrifuged in the presence of 0-5% PEG and the Clq concentration in the precipitates was measured by radial immunodiffusion. The presence of circulating immune complexes and rheumatoid factor(s) resulted in a shift of Clq precipitation to lower PEG concentrations. Clq precipitation at 1.5% PEG was shown to be specific for sera containing immune complexes. Under similar conditions addition of aggregated IgG to normal human serum gave rise to Clq precipitation directly proportional to the amount of aggregated IgG. Precipitation of endogenous Clq at 1.5% PEG and assay by radial immunodiffusion may therefore be useful for the detection and quantitation of immune complexes in human serum.

Isolation of swine-like influenza A(H1N1) viruses from man in Switzerland and The Netherlands.

Swine influenza A (H1N1) viruses were isolated from two people in Switzerland and one in the Netherlands in early 1986. In haemagglutination-inhibition and neuraminidase-inhibition assays, the three viruses were closely related to one another and to the A/New Jersey/8/76 strain. The Swiss patients showed only mild symptoms, whereas the Dutch patient suffered from severe pneumonia. Two of the patients had been in close contact with diseased pigs. No such contact could be established for the third patient. None of the three individuals was known to suffer from immunodeficiency. No man-to-man transmission of the virus has been detected.

Immune reactions in patients with superficial bladder cancer after intradermal and intravesical treatment with bacillus Calmette-Guérin.

The immune reactivity of patients with strongly recurrent superficial bladder cancer was followed after combined intravesical and intradermal bacillus Calmette-Guérin (BCG) immunotherapy. All patients in this study were previously treated without success with intravesical chemotherapy. The BCG treatment regimen consisted of weekly administrations with BCG (RIVM) for six consecutive weeks, both intravesically and intradermally. In this study, sera and peripheral blood leukocytes (PBL) of patients were tested serially. Besides BCG-antigen-specific reactions, e.g. skin reactivity to purified protein derivatives of Mycobacterium tuberculosis (PPD), antibody formation and antigen stimulation of PBL in vitro, non-antigen-specific immune reactivities were also measured, e.g. mitogen response and spontaneous cytotoxic activity of PBL. In addition the antibody response to bladder carcinoma antigens and the cytotoxic activity of PBL for the bladder carcinoma cell line T24 and the natural-killer-sensitive K562 cell line were investigated. The results obtained from the various assays were evaluated for their prognostic value in relation to the length of the tumor-free interval after the BCG treatment. Because sera and PBL were only obtained during the first 6 months after the BCG treatment, the immune reactivity was compared to the clinical results at that same time. At 6 months after therapy 12 out of 40 BCG-treated patients were tumor-free whereas 28 out of 40 showed a recurrence. Skin reactivity to tuberculin PPD was measured in 40 patients during a period of 3-6 months after therapy. Of patients who showed a recurrence of the tumor within 6 months, 48% of them showed a transient response or developed no response at all to PPD. In the group of patients with a longer tumor-free period (n = 10), only one patient lost the response to tuberculin PPD. Although PBL of a limited number of patients were tested, it was observed that the cytotoxicity to the bladder carcinoma cell line T24, and the natural-killer-sensitive K562 cell line increased in a number of the patients (7 out of 14, and 9 out of 14 respectively). Reactivity of PBL to mitogens and subset distribution (ratio T-helper: T-suppressor/cytotoxic) were not influenced by the BCG treatment. Antibody response to mycobacterial antigen was detected in 9 out of 23 patients investigated. Of these 9 patients, 8 belonged to the group with a recurrence of the tumor within 6 months (n = 17). There was no correlation between the skin reactivity and the antibody response to tuberculin PPD.(ABSTRACT TRUNCATED AT 400 WORDS)