[How early would we really administer biologics?]. / Wie früh würden wir Biologika wirklich einsetzen?

According to a survey carried out during the annual congress of the German Society for Rheumatology (DGRh) last year, many rheumatologists would like to initiate TNF-alpha inhibitors earlier than suggested in the EULAR recommendations. While most of the survey participants agreed with the initial MTX monotherapy favored therein, more than half would prefer to combine MTX with a biologic instead of a second DMARD after failure of this option. This decision seems to be based mainly on clinical experience. Although international therapy guidelines allow an earlier use of biologic therapy in special cases, particularly in Germany an extensive documentation and justification is needed for this treatment strategy. Future guidelines may allow several parallel drug sequences based on prognostic factors and individual biomarkers.

Combination treatment with infliximab and leflunomide in patients with active rheumatoid arthritis: safety and efficacy in an open-label clinical trial.

OBJECTIVE: To assess the safety and efficacy of combination therapy with infliximab and leflunomide in adults with active rheumatoid arthritis (RA) despite leflunomide therapy. METHODS: Adult patients with active RA who had received leflunomide for at least 16 weeks were eligible for this 30-week, open-label trial. All patients received ongoing oral leflunomide (20 mg/day) and 3 mg/kg infliximab administered IV at weeks 0, 2, 6, 14, and 22. The primary end point was the percentage of patients with adverse events that led to patient withdrawal and were at least possibly related to treatment. Descriptive evaluations of efficacy and other safety assessments were performed. RESULTS: Twelve out of 70 patients (17.1%; upper 90% CI 24.5%) withdrew due to treatment-related adverse events. Adverse events were reported in 69 of 72 patients (95.8%); the most common were nasopharyngitis, diarrhea, and pruritus. Serious adverse events occurred in 16 out of 72 patients (22.2%). Significant improvements were observed in efficacy assessments, including Disease Activity Score 28 (DAS28) and pain. At end point, 19.4% of the patients showed a good improvement in DAS28 score and 46.3% had a moderate improvement. American College of Rheumatology (ACR) 20, 50, and 70 responses were achieved by 47.1%, 21.4%, and 12.9% of the patients, respectively. CONCLUSION: The combination of infliximab and leflunomide neither increased the rate of toxicities nor resulted in unexpected adverse events. Treatment-related withdrawals occurred at an acceptable frequency. Patients experienced clinically significant improvements. Treatment with infliximab plus leflunomide benefits the majority of patients, but monitoring of adverse events is required.

[Revision of the recommendations of the Commission on Pharmacotherapy of the German society for Rheumatology. Therapy with tumour necrosis factor blockers for inflammatory rheumatic illnesses]. / Neufassung der Empfehlungen der Kommission Pharmakotherapie der DGRh. Therapie mit Tumornekrosefaktor-hemmenden Wirkstoffen bei entzündlich-rheumatischen Erkrankungen.

Inflammatory rheumatic illnesses are associated with various types of pain as well as handicaps. The so called basic therapies are not sufficiently effective in many patients or are terminated due to side effects. This is where tumor necrosis factor blockers (TNF) can be used. In many cases, they lead to a substantial improvement of the symptoms, a reduction in disease related laboratory parameters, improvement in quality of life to stopping disease related damage when their effect is rapid. Common and severe side effects are few, although long-term data are still limited. The following contribution lists recommendations for the indications and symptomatology for the use of TNF blockers.

[Rare manifestation of large vessel vasculitis in systemic lupus erythematosus]. / Seltene Manifestation einer Grossgefässvaskulitis bei systemischem Lupus erythematodes.

Case-reports from two female patients with an occlusion of the right external iliac artery and femoral artery are presented due to a large-vessel vasculitis. Both patients suffered from systemic lupus erythematosus This rare manifestation occurred within the first few years of the disease and was important for prognosis and further treatment. Other manifestations of the disease were general symptoms and polyarthritis. In one case the vasculitis was confirmed by histology. A fibrous thickening of the intima and a vasculitis of small vessels within the adventitia were the prominent feature. This observation supports the idea of small vessel vasculitis as the characteristic manifestation in lupus erythematosus.

Increase of intracellular calcium is the essential signal for the expression of CD40 ligand.

CD40 ligand (CD40L) is present on activated but not on resting T cells. In contrast to the activation markers CD25 and CD71, a strong CD40L expression could be induced by calcium ionophore alone but not by phorbol 12-myristate 13-acetate (PMA). Ionomycin induced a very early mRNA and protein surface expression of CD40L within the first 2 h, whereas CD25 and CD71 did not appear earlier than 6 h after stimulation. The mitogens phytohemagglutinin and concanavalin A induced little CD40L, but together with PMA, a markedly increased CD40L expression was observed. In T cells stimulated with immobilized anti-CD3, co-stimulation with anti-CD28 or PMA induced an earlier and higher maximal CD40L expression. CD40L expression of purified T cells was higher and more prolonged compared to that of T cells in unseparated peripheral blood mononuclear cells. We conclude that the expression of CD40L on T cells is profoundly different from other early activation markers with regard to signal requirements, kinetics and the role of accessory cells in the system.

Origin and immunoregulation of autoantibodies against intestinal alkaline phosphatase.

In the sera of patients with acute bacterial infections specific autoantibodies (sIAPa) of the immunoglobulin class G (IgG) were found which bind to intestinal alkaline phosphatase (IAP) through the Fab portion. This was demonstrated using immunoaffinity (IA) isolation of sIAPa from patients' sera (particularly bacterial meningitis and ventriculitis) digestion with pepsin, purification of F(ab')2 fragments on protein A and subsequently binding on IAP coupled to CNBr (cyanogen bromide)-activated Sepharose. Immunoblots using specific anti-Fc and anti-Fab antibodies showed that the bulk of F(ab')2 fragments had bound. Additionally, binding of native IAP to the F(ab')2 fragments was observed after separation of F(ab')2 fragments using isoelectric focusing (IEF), blotting onto nitrocellulose and incubation with IAP. Moreover, we have demonstrated the occurrence of natural anti-IAP autoantibodies (nIAPa) which were isolated from sera of healthy individuals using IA chromatography. Investigation of isotype distribution revealed that IgG but not IgM or IgA were predominant even among nIAPa. The nIAPa fraction exhibited lower binding efficiencies on IEF blots than the sIAPa fraction, however, in contrast to sIAPa, cross-reactions with other autoantigens were observed for nIAPa. NIAPa and sIAPa did not show subclass restriction. As revealed by IEF the spectrotypes of sIAPa were found to be patient-specific, poly- to oligoclonal and stable during longer periods.

In vitro and in vivo effect of glucocorticoids on IgE and IgG subclass secretion.

Hydrocortisone (HC) as well as its synthetic derivatives have been shown to strongly enhance interleukin-4 (IL-4)-induced in vitro IgE synthesis. To investigate possible effects on IgG subclasses, peripheral blood mononuclear cells (PBMC) were incubated with different glucocorticosteroids in the absence or presence of IL-4. The glucocorticoids alone led to a strongly enhanced secretion of IgG1, IgG2 and IgG3, but not IgG4. The addition of IL-4 induced marked increases in IgG1 and IgG4, no changes in IgG3, but a consistent decrease in IgG2 synthesis. In order to find out whether these profound in vitro effects of corticosteroids are also reflected by changes in antibody serum levels during steroid treatment, 10 healthy volunteers took 25 mg prednisone for 7 consecutive days. We could not observe any significant changes of IgE or IgG subclass serum levels during or after this period. However, cell cultures performed after the glucocorticoid treatment revealed a marked decrease in the ability to produce IgG4 and a significantly lower potential to produce IgE in response to IL-4 alone or IL-4 and HC. We conclude that, although strongly implicated by the in vitro results, glucocorticosteroid treatment does not result in an increased allergy risk.

Synthetic glucocorticoids potentiate IgE synthesis. Influence of steroid and nonsteroid hormones on human in vitro IgE secretion.

Recently, hydrocortisone (HC) has been shown significantly to enhance interleukin-4 (IL-4)-induced in vitro IgE synthesis. For investigation of possible effects of synthetic corticosteroids but also of effects of other important human hormones, peripheral blood mononuclear cells (PBMC) were incubated with IL-4 and various concentrations of the hormones. IgE secreted in the supernatant was determined after a 14-d culture period. Like HC, all synthetic corticosteroids potentiated IgE secretion. A minor effect was noted for the mineralocorticoid aldosterone. No modulating effect on IL-4-induced IgE formation was observed for adrenocorticotropic hormone (ACTH), somatotropin (STH), thyroid-stimulating hormone (TSH), triiodothyronine, thyroxine, epinephrine, noradrenaline, insulin, and glucagon.

Chronic lymphocytic leukemia cells induce non-T cells to produce IgE in the presence of interleukin-4.

Mononuclear cells from peripheral blood and bone marrow from patients with chronic lymphocytic leukemia (CLL) were cultured with interleukin-4 (IL-4) alone or with IL-4 and hydrocortisone (HC) in order to induce IgE synthesis. From a total of 29 experiments with the cells of 17 different donors an IgE secretion was observed only twice. Even in those two cases the IgE was found to be not monoclonal. The additional stimulation of CLL cells by polyclonal B cell activators induced IgM but not IgE production. When CLL cells were cocultured with monocyte-enriched cell preparations (M phi) in the presence of IL-4 and HC, a substantial IgE secretion could be obtained, which again consisted of both IgE kappa and IgE lambda. Since the irradiation of the M phi but not of the CLL cells abolished the formation of IgE, it is likely that the IgE production resided in the contaminating B cell population of the M phi. When the M phi were replaced by T cell-depleted peripheral blood mononuclear cells (non-T cells), irradiated as well as formaldehyde fixed CLL cells were able to stimulate non-T cells to secrete IgE in the presence of IL-4 or to potentiate IL-4- and HC-induced IgE formation. Furthermore, the coculture of irradiated pure CLL cells and purified B cells induced not only IgE but also IgG and IgM production and B cell proliferation in the presence of lymphokines. Our findings suggest that CLL cells, contrary to current opinion, cannot be induced to produce IgE.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of T cells and the effect of hydrocortisone on interleukin-4-induced IgE synthesis by non-T cells.

The role of T cells for IL-4-induced IgE synthesis by peripheral blood mononuclear cells (PBMC) was investigated. The removal of monocytes from PBMC abolished IL-4-induced IgE synthesis. When PBMC were separated into T and non-T cells, non-T cells alone were not able to secrete significant amounts of IgE in the presence of IL-4. Depending on the separation procedure, the reconstitution of non-T cells with T cells prepared by rosetting did not restore IgE secretion, whereas T cells obtained by the use of anti-CD3 antibodies could co-induce IgE formation. However, when the T cells were first irradiated, large amounts of IgE were produced, which strongly exceeded those found in unseparated PBMC cultures. IL-4-induced IgE synthesis was also obtained in co-cultures of formaldehyde-fixed T cells with non-T cells. Furthermore, not only autologous but also allogeneic T cells, which have been irradiated or fixed, could provide the costimulatory effect on IgE formation by non-T cells in the presence of IL-4. Mitogenically pre-activated T cells, however, were not able to support IgE synthesis. Hydrocortisone (HC) potentiated the IL-4-induced IgE synthesis by PBMC and enabled non-T cells to secrete IgE in the presence of IL-4. Adding both HC and T cells led to a marked synergistic effect on IL-4-induced IgE production. We conclude that monocytes are required for the induction of IgE synthesis in PBMC in addition to T cells and IL-4. Our results support the view that the T cell signal is delivered via cognate and non-cognate T/B cell membrane interaction. Furthermore, active and proliferating T cells rather suppress IgE synthesis. Finally, HC appears to be a potent alternative stimulus, which bypasses the necessity for T cells in IL-4-induced IgE formation.

Interleukin-4-induced IgG subclass and IgE secretion by mononuclear cells from atopic donors.

To investigate the effect of interleukin-4 (IL-4) on the secretion of IgG subclasses and IgE in atopic individuals, peripheral blood mononuclear cells from 10 atopic and 10 normal donors were incubated with IL-4, and the production of IgE, IgG1, IgG2, IgG3, and IgG4 was determined after a 14-day culture period. Like normal peripheral blood mononuclear cells, atopic mononuclear cells were stimulated by IL-4 to secrete IgE and IgG4, but not the other IgG subclasses. This response was in the same quantitative ranges in both donor groups. Addition of interferon gamma to IL-4-containing cultures efficiently antagonized the IL-4-induced IgE and IgG4 secretion. These results do not support the hypothesis that an atopic condition is due to a discordant effect of IL-4 on IgE compared to IgG4 production or to an altered response to the potent antagonist interferon gamma.

Interleukin-4 induces both IgG4 and IgE secretion by peripheral blood B cells.

Peripheral blood mononuclear cells (PBMCs) from healthy nonallergic donors were cultured with recombinant interleukin-4 (rIL-4), and the Ig of different isotypes was quantitated in the culture supernatants by radioimmunoassays. Recombinant IL-4 induced IgG4 and IgE secretion in a dose-dependent manner, whereas it had no consistent effect on the secretion of the other isotypes. In the absence of rIL-4, B cells in the PBMC preparations secreted less than 1 ng IgE/ml and a mean of 5 ng IgG4/ml. In the presence of the optimal dose of 100 U rIL-4/ml, PBMCs from five donors secreted a mean +/- SEM of 37 +/- 8 ng IgE/ml and 66 +/- 25 ng IgG4/ml. In kinetic studies, no IgG4 or IgE secretion was detected during the first 5 days of culture, and approximately 50% of the IgG4 and IgE secreted by day 15 was detected in supernatants on day 7. Cycloheximide, actinomycin-D, and mytomycin-C completely inhibited the rIL-4-induced IgG4 and IgE secretion, indicating that de novo protein, RNA, and DNA synthesis was required. As shown by Percoll buoyant density centrifugation, rIL-4 induced B cells in the high-density fraction to secrete IgG4 and IgE, whereas it inhibited spontaneous IgG4 secretion by low-density B cells. Interferon-gamma inhibited IL-4-induced IgG4 and IgE secretion. The data demonstrate that IL-4 induces small, dense, peripheral blood B cells to secrete not only IgE but also IgG4, which parallells the IL-4-induced IgE and IgG1 secretion by murine B cells.(ABSTRACT TRUNCATED AT 250 WORDS)

IGM-containing immune complexes and antiphospholipid antibodies in patients with Sneddon's syndrome.

We report three patients with a Sneddon syndrome in whom predominantly small (500-900 kD) IgM-containing serum immune complexes were detectable. Furthermore, antiphospholipid antibodies and increased von Willebrand factor antigen were found in the sera of two cases. Especially the data demonstrating small circulating immune complex as suggest that Sneddon's syndrome, a rare vasculitis disorder, might immunologically be characterized by circulating IgM-containing immune complexes which, in addition, could play a role in the pathogenesis of this disease entity. The elevated antiphospholipid antibodies as well as the increased von Willebrand factor antigen in the sera of the investigated patients have to be considered as nonspecific vasculitis-associated phenomena.

Improved in vitro diagnosis of allergy to Alternaria tenius and Cladosporium herbarum.

To improve the in vitro diagnosis of mould allergy 22 children suffering from allergic asthma caused by Alternaria tenius and/or Cladosporium herbarum as proven by bronchial provocation test were investigated. Partially purified, standardized mould preparations were used in radioallergosorbent test (RAST) with conventional and new update mould discs, mould-induced histamine release and immunoblotting. Updated RAST discs were found to be superior to the old-type discs for the detection of Alternaria but not Cladosporium sensitivity. In all patients except one, specific IgE-antibodies to the respective mould were demonstrated by immunoblotting. Mould-induced histamine release failed to prove sensitization in only two patients. No differences were found comparing histamine release from whole blood with release from isolated cells. The results demonstrate a high sensitivity of in vitro tests when purified and standardized extracts are used.

Intralymphatic interleukin-2 treatment of a hemophiliac AIDS patient with defective interleukin-2 production.

To improve immune functions in an interleukin-2 (IL-2) deficient hemophiliac AIDS patient suffering from severe Pneumocystis carinii pneumonia, treatment with IL-2 was started in addition to standard antimicrobial therapy. Highly purified IL-2 was administered subcutaneously and then repeatedly intralymphatically in a manner similar to pedal lymphography. No toxicity was observed. The patient temporarily improved clinically as well as with regard to immunological functions. Particularly the in vitro response to phytohemagglutinin (PHA) could partly be restored, and skin tests revealed improved response to recall antigens. These findings indicate that IL-2 can be administered safely and effectively by the intralymphatic route and may--in addition to antibiotics--be of value in AIDS patients with severe opportunistic infections.

Multiple peripheral pulmonary nodules preceding rheumatoid arthritis.

The case of a young woman is reported, presenting multiple peripheral lung nodules, preceding the onset of classical rheumatoid arthritis 3 months later. The nodules observed seemed to be of pleural origin because they all had contact with the pleura which was partly thickened as demonstrated by computer-assisted tomography. The histopathology of material obtained by an open-lung biopsy revealed rheumatoid necrobiotic nodules. Although very rare, rheumatoid arthritis should be considered as a differential diagnosis of pulmonary nodules of unknown origin.

[HLA pattern in patients with lichenoid drug exanthem]. / HLA-Muster von Patienten mit lichenoidem Arzneiexanthem.

27 patients suffering from lichenoid drug eruption have been studied with special reference to histocompatibility standardisation. In comparison with a control group (n = 54), our patients revealed high and statistically significant levels of HLA-A1, HLA-B8, and HLA-DR3 (p less than 0.05). These results are discussed with particular regard to HLA patterns previously obtained in lichen planus.

Different patterns of antigen-induced histamine release during immunotherapy in insect venom and pollen allergy.

Antigen-induced histamine release from whole blood was shown to be a suitable parameter for the diagnosis of hypersensitivity in both patients allergic to bee or wasp venom as well as in patients suffering from seasonal tree pollen allergy. Although both groups were treated successfully by specific immunotherapy, only in patients with insect allergy venom induced histamine release decreased significantly during therapy, whereas, in the patient with pollinosis, pollen induced histamine release did not change significantly during or after treatment. This discrepancy in the antigen-induced histamine release could either be due to different routes of immunization with the allergen and/or is caused by the atopic status which is prevalent in patients with pollinosis but not in insect allergic subjects.