Regina Max

Reduced CD4+,CD25− T cell sensitivity to the suppressive function of CD4+,CD25high,CD127−/low regulatory T cells in patients with active systemic lupus erythematosus

OBJECTIVE CD4+,CD25high regulatory T (Treg) cells play a crucial role in the maintenance of self tolerance and prevention of organ-specific autoimmunity. The presence of many in vivo-preactivated CD4+,CD25++ T cells in patients with systemic lupus erythematosus (SLE) poses a difficulty in discriminating CD25++ activated T cells from CD25high Treg cells. To overcome this problem, we analyzed the phenotype and function of CD4+,CD25high,CD127(-/low) natural Treg (nTreg) cells isolated from the peripheral blood of patients with SLE. METHODS CD4+,CD25high,CD127(-/low) nTreg cells and CD4+,CD25- responder T (Tresp) cells from patients with SLE and normal donors were separated by fluorescence-activated cell sorting. Cell proliferation was quantified by 3H-thymidine incorporation, and immunophenotyping of the cells was done using FACScan. RESULTS Comparable percentages of CD4+,CD25high,FoxP3+ T cells were observed in patients with SLE and normal donors. Proliferation of SLE nTreg cells sorted into the subset CD4+,CD25high,CD127(-/low) was significantly decreased compared with that of SLE nTreg cells sorted into the subset CD4+,CD25high (mean +/- SEM 2,223 +/- 351 counts per minute versus 9,104 +/- 1,720 cpm, respectively), while in normal donors, these values were 802 +/- 177 cpm and 2,028 +/- 548 cpm, respectively, confirming that effector cell contamination was reduced. Notably, the suppressive activity of nTreg cells was intact in all groups. However, CD4+,CD25- Tresp cells isolated from patients with active SLE were significantly less sensitive than those from patients with inactive SLE to the suppressive function of autologous or normal donor CD4+,CD25high,CD127(-/low) nTreg cells. Furthermore, a significant inverse correlation was observed between the extent of T cell regulation in suppressor assays and the level of lupus disease activity. CONCLUSION This study is the first to show that, in human SLE, impaired sensitivity of Tresp cells to the suppressive effects of a comparably functional, highly purified nTreg cell population leads to a defective suppression of T cell proliferation in active SLE. Studies aiming to define the mechanisms leading to Tresp cell resistance might help in the development of highly specific, alternative immunotherapeutic tools for the control of systemic autoimmune diseases such as SLE.

Uveitis Subtypes in a German Interdisciplinary Uveitis Center—Analysis of 1916 Patients

Objective Studies on the epidemiology of uveitis are rare and cohorts are small. We analyzed the frequencies of classified forms of uveitis in all patients at our center. Methods We studied 1916 consecutive patients with inflammatory eye disease. Data were analyzed regarding associated systemic disease, infection, ocular syndromes, anatomic localization, age, and sex. Results In 59.1% of patients, a classified form of uveitis was observed: associated systemic diseases in 43.7%, the most frequent ones sarcoidosis (17.4%) and ankylosing spondylitis (16.8%); ocular syndromes in 34.3%, the most frequent HLA-B27-positive anterior uveitis (AU; 35.1%) and Fuchs uveitis syndrome (FUS; 34.3%); and infections in 22.4%, the most frequent herpetic infections (46.1%) and toxoplasmosis (31.5%). We found AU in 45.4% of patients (15.4% HLA-B27-positive AU and 11.3% FUS), intermediate uveitis in 22.9% (unclassified 53.7% and multiple sclerosis 10.3%), and posterior uveitis in 13.5% (24.7% toxoplasmosis). Panuveitis was diagnosed in 6.2% of cases (Behçet’s disease 12.6%; sarcoidosis 10.9%). The remaining 12.0% of cases showed extrauveal manifestations (scleritis, episcleritis, keratitis, optic neuritis, myositis, and orbital inflammation). Conclusion We describe the largest cohort to date of consecutive patients from a specialized uveitis center. The high frequency of classified disease, nearly 60% in our clinic, shows the usefulness of an interdisciplinary approach, oriented on anatomic presentation.

Phase 2 trial of vaccination with tyrosinase peptides and granulocyte-macrophage colony-stimulating factor in patients with metastatic melanoma.

This phase II study was performed to determine the induction of a specific T-cell response, the clinical response rate, and toxicity of vaccination with different HLA class I–binding peptide epitopes derived from the melanocyte differentiation antigen tyrosinase in patients with stage IV melanoma. The study population consisted of 16 patients with metastatic disease and two patients who were macroscopically free of disease at study entry after resection of recurrent skin lesions. Patients received intradermal injections of 200 mg peptide corresponding to their HLA type on day 3, and 75 or 150 &mgr;g granulocyte-macrophage colony-stimulating factor on days 1 to 4. Vaccinations were repeated at weeks 2, 4, 6, 10, and 14. Monitoring of peptide-specific T-cell frequencies in the peripheral blood was performed using an interferon&ggr; ELISPOT assay. Eleven of the 16 patients with metastatic disease went off the protocol within the first 10 weeks because of tumor progression. Of the five patients with metastatic disease who received all six vaccinations, one patient showed a mixed response with regression of some lung metastases; two patients with progressive disease before vaccination had stable disease for 6 and 18+ months; and two patients had progression of their disease. The two patients who had all their metastases resected before vaccination did not have relapses for 6 and 12+ months after vaccination. Induction of tyrosinase-reactive T cells was found in these two patients and in two others with metastatic disease, including the one who achieved a mixed response and one with stable disease. This study shows limited clinical and immunologic activity of HLA class 1-peptide vaccination in combination with granulocyte-macrophage colony-stimulating factor in stage IV melanoma patients.

QuantiFERON TB-Gold—A New Test Strengthening Long-Suspected Tuberculous Involvement in Serpiginous-like Choroiditis

PURPOSE To obtain a diagnosis of tuberculosis in patients with a specific subset of uveitis, serpiginous-like choroiditis. This subset has been suspicious for tuberculous etiology in single case reports and old textbooks. DESIGN Retrospective evaluation of a diagnostic test in a specific uveitis cohort. METHODS QuantiFERON is an approved, antigen-specific test that utilizes synthetic peptides representing Mycobacterium tuberculosis proteins. After incubation, interferon gamma secreted by T lymphocytes in response to these antigens is measured. We used the test in 21 of 26 patients identified from our database with serpiginous-like choroiditis. Rates of QuantiFERON positivity were compared to a group of healthy hospital employees (n = 208), another group of healthy hospital workers after tuberculosis contact (n = 117), and a group of randomly tested patients with other uveitis forms (n = 45). RESULTS Eleven of 21 serpiginous-like choroiditis patients (52%) were tested positive. The rate of QuantiFERON positivity in the healthy control groups was 8.7% and 0.9%, and 13% in the other uveitis subsets. Four of the QuantiFERON-positive serpiginous-like choroiditis patients were treated with standard anti-tuberculostatic therapy; three finished the course and improved. Seven patients are either stable without therapy (n = 4) or on low-dose prednisone (n = 3). CONCLUSIONS QuantiFERON testing revealed a high number of positive patients, which indicates a tuberculous etiology in this uveitis subset. Whether bacterial activity or secondary immunologic processes are causative remains a matter of speculation.

Bone marrow microcirculation analysis in multiple myeloma by contrast-enhanced dynamic magnetic resonance imaging

The aim of our study was to investigate the quantitative microcirculation parameters amplitude A (hypothetical intravascular volume) and exchange rate constant k21 (hypothetical vascular permeability) by contrast‐enhanced dynamic magnetic resonance imaging (dMRI) as markers of angiogenesis in multiple myeloma (MM). Therefore lumbar spine and spina iliaca superior posterior of 16 normal controls and 41 patients with active MM were assessed using a dMRI protocol with a pump controlled bolus infusion of Gadolinium‐DTPA. Pharmacokinetic parameters, amplitude A and exchange rate constant k21 were calculated according to a 2‐compartment model. Color‐coded parameter images were generated from pharmacokinetic data analysis and superimposed onto the conventional MR images. Amplitude A and k21 parameters were significantly increased in patients with MM compared with controls (p = 0.001; median Actr, 0.2 [range, 0.09–0.4]; median AMM, 0.93 [range, 0.2–2.2]; median k21ctr, 0.09 min−1 [range, 0.03–0.9]; median k21MM, 4.58 [range, 0.22–23.8]). Within the group of MM patients the pattern of color‐coded parameter images were found to be either of “diffuse” (n = 13, 31%) or “focal” (n = 28, 69%) type of distribution of microcirculation. Comparison of amplitude A in patients with “focal” vs. “diffuse” pattern of the pharmacokinetic maps revealed a significant increase in the median of amplitude A in the “focal” group. Amplitude A values allowed a classification of patients according to severe osteolytic bone involvement (p = 0.023) with the best cutoff value of 0.7 for amplitude A. Downmodulation of amplitude A was observed in a MM patient treated with standard VAD chemotherapy. Our data demonstrate that dMRI is a novel imaging technique for the detection and monitoring of MM bone lesions. It provides independent evidence for angiogenesis in MM.

Pilot study of hepatic intraarterial fotemustine chemotherapy for liver metastases from uveal melanoma: a single-center experience with seven patients

AbstractBackground. Uveal melanoma is characterized by a high frequency of hepatic metastases. For patients with liver metastases, who have a median survival of 5 to 7 months, surgery and systemic conventional chemotherapy have little to offer. Methods. Between February 1995 and July 1999, seven patients with isolated hepatic metastases from uveal melanoma were enrolled into a pilot trial of intraarterial fotemustine therapy. An implantable Port-A-Cath catheter was inserted into the hepatic artery for regional chemotherapy via the gastroduodenal artery. Fotemustine 100 mg/m2 was administered intraarterially over a 4-h period. The induction phase consisted of one administration per week for 4 weeks, followed by a 5-week rest period. Maintenance therapy with administration of fotemustine every 3 weeks continued until progression or toxicity. Results. Ten patients were evaluated for the trial. One patient was not eligible because of impaired liver function, and in two patients implantation of the port system was not possible for anatomic reasons. Seven patients received a median of 16 treatment cycles (range, 4–28) and all were evaluable for response. Two patients achieved a partial response (PR), three had stable disease (SD), and tumor progressed in two patients (PD). The median survival time from diagnosis of liver metastasis was 24 months (range, 4 to 50+ months). Two patients survived for more than 2 years and two patients are still alive. The toxicity was low and the treatment could be administered on an outpatient basis. Conclusion. Intraarterial fotemustine treatment of uveal melanoma metastatic to the liver is well tolerated, and in some patients is associated with prolonged survival.

A three-centre experience with adalimumab for the treatment of non-infectious uveitis

Objective The aim of this study was to assess the efficacy of adalimumab in patients with active non-infectious uveitis in three different centres. Methods In a retrospective study we identified patients from our databases who were treated with adalimumab. The composite outcome measure for efficacy included reduction of macular oedema by optic coherence tomography, visual acuity, anterior chamber cells, reduction of frequency of flares and reduction of prednisone dose during the treatment. At least one of the criteria had to be improved and none worsened to declare treatment as effective. Results 60 patients with an average age of 37.3 years (range 4–71 years) were treated with adalimumab over an average follow-up period of 87.9 weeks (range 12–222 weeks). The indication for treatment was in 41 (68.3%) patients the activity of both uveitis and systemic disease and in 19 (31.7%) patients uveitis activity only. 15 (25%) patients were treated before with etanercept and 10 (16.7%) patients with infliximab. 49 out of 60 (81.7%) patients improved, while the other 11 (18.3%) patients did not meet improvement criteria and were given additional or alternative immunosuppressive treatment. At the last follow-up, 47 (78.3%) patients were still on adalimumab treatment. 13 (21.6%) patients stopped adalimumab treatment, due to inefficacy in eight, another three patients due to side effects (liver enzyme elevation and furunculosis), one patient due to pregnancy and one patient died. Conclusions This large retrospective case series showed that adalimumab is effective in up to 80% of patients with uveitis.

Management of sight-threatening uveitis : New therapeutic options

Over the past 2 decades therapy for the treatment of intraocular inflammation (uveitis) has developed into a highly differentiated approach with an increasing number of drug options. This paper primarily summarises literature from the past 5 years (2000 to May 2004), gives an update on systemic immunosuppressive therapy for non-infectious uveitis and speculates about new developments that could become relevant in the near future for the treatment of uveitis patients. The spectrum of immunosuppressive drugs has been notably expanded by tumor necrosis factor inhibitors, but with some limitations to uveitis. Behçet’s disease is an example of uveitis where a multisystem disorder can affect the eye very severely. This clinical example has been used to investigate the utility of many different types of immunosuppressive therapies and the clinical approach is extensively discussed in this review. An accompanying table summarises the proposed mode of action, standard dosage, common adverse effects, as well as estimated cost of current treatment options.

Myocardial left ventricular dysfunction in patients with systemic lupus erythematosus: new insights from tissue Doppler and strain imaging.

Objective. Systemic lupus erythematosus (SLE) is associated with high cardiovascular morbidity and mortality. Cardiovascular involvement is frequently underestimated by routine imaging techniques. Our aim was to determine if new echocardiographic imaging modalities like tissue Doppler (TDI), strain rate (SRR), and strain (SRI) imaging detect abnormalities in left ventricular (LV) function in asymptomatic patients with SLE. Methods. Sixty-seven young patients with SLE (mean age 42 ± 10 yrs) without typical symptoms or signs of heart failure or angina, and a matched healthy control group (n = 40), underwent standard transthoracic echocardiography, TDI, SRR, and SRI imaging of the LV as well as assessment of disease characteristics. Results. Despite findings within the normal range on routine standard 2-dimensional echocardiography, SLE was associated with significantly impaired systolic and diastolic myocardial velocities of the LV measured by TDI [mean global TDI: systolic (s): 2.9 ± 0.9 vs 3.9 ± 0.7 cm/s, p < 0.05; early (e): 4.3 ± 1.5 vs 6.3 ± 1.3 cm/s, p < 0.05; late (a): 2.9 ± 0.8 vs 3.4 ± 0.8 cm/s, p < 0.05; values ± SD); SRR (s: −0.8 ± 0.1 vs −1.1 ± 0.1 s−1; e: 1.1 ± 0.2 vs 1.6 ± 0.3 s−1; a: 0.7 ± 0.1 vs 1.0 ± 0.2 s−1; all p < 0.05); and SR (−15.11 ± 2.2% vs −19.7 ± 1.9%; p < 0.05) compared to the control group. Further, elevated disease activity, measured with the ECLAM and the SLEDAI score, resulted in significantly lower values for LV longitudinal function measured by SRR and SR, but not by TDI. Conclusion. SLE is associated with a significant impairment of systolic and diastolic LV longitudinal function in patients without cardiac symptoms. New imaging modalities provide earlier insight into cardiovascular involvement in SLE and seem to be superior to standard echocardiography to detect subclinical myocardial disease.

Interferon versus Methotrexate in Intermediate Uveitis With Macular Edema: Results of a Randomized Controlled Clinical Trial

PURPOSE To compare interferon (IFN) beta with methotrexate (MTX) in the treatment of intermediate uveitis with macular edema. DESIGN Monocentric, prospective, randomized, controlled clinical trial. METHODS SETTING Specialized uveitis center at the University of Heidelberg. PATIENT OR STUDY POPULATION: Patients with either primary intermediate uveitis or uveitis associated with multiple sclerosis. MAIN INCLUSION CRITERIA: Visual acuity of 20/30 or worse (0.2 logarithm of the minimal angle of resolution) and macular edema of more than 250 μm (central 1-mm in optical coherence tomography; Stratus). Randomization into either IFN beta 44 μg subcutaneously 3 times weekly or 20 mg MTX subcutaneously once weekly. MAIN OUTCOME MEASURES At 3 months, the primary outcome parameter of mean change in visual acuity was evaluated and efficacy was determined. Secondary parameters were macular edema by optical coherence tomography, inflammatory activity, and retinal sensitivity by microperimetry (MP-1; Nidek). In case of treatment failure, switching to the other treatment arm was possible. RESULTS Nineteen patients were included. Ten were randomized to MTX, and 9 were randomized to IFN beta. At 3 months, visual acuity improved a mean 0.31 logarithm of the minimal angle of resolution (range, -0.02 to -0.96, 15.6 letters on the Early Treatment Diabetic Retinopathy Study chart) in the IFN beta group versus a mean 0.09 logarithm of the minimal angle of resolution (range, 0.12 to -0.38, 4.7 letters) in the MTX arm (P = .0435, Mann-Whitney U test). Macular thickness decreased by a mean of 206 μm (range, -41 to -416 μm) in the IFN arm, but increased by 47 μm (range, 108 to -28 μm) in the MTX group (P < .0001). CONCLUSIONS Although the sample size is small, results of the trial support superiority of IFN beta over MTX in the treatment of macular edema in the setting of intermediate uveitis.