Treatment of patients with advanced mycosis fungoides and Sézary syndrome with alemtuzumab

OBJECTIVES: Alemtuzumab (anti-CD52, Campath-1H) has recently been shown to be effective in the treatment of a range of hematological malignancies, including B-cell chronic lymphocytic leukemia and T-cell prolymphocytic leukemia. We undertook a phase II study to evaluate the safety, tolerability and efficacy of alemtuzumab in patients with relapsed or refractory advanced stage cutaneous T-cell lymphoma. PATIENTS AND METHODS: A total of eight patients were enrolled, seven with mycosis fungoides/Sézary syndrome (MF/SS) and one with large-cell transformation of MF. Seven patients had disease refractory to multiple previous therapies. Alemzumab (30 mg) was administered intravenously three times per week for 12 wk or until maximum response. RESULTS: The overall response rate was 38%, with three patients achieving partial remission, two patients with stable disease and three patients with progressive disease (PD) during treatment. The time to progression was short, with all patients developing PD within 4 months of starting alemtuzumab. Response duration in the three PR patients was also brief, with responses lasting less than 3 months in all three cases. Significant hematological and immunosuppressive toxicity was observed, with both grade 3-4 cytopenias and significant infectious complications occurring in a majority of cases. CONCLUSIONS: Our findings suggest that in heavily pretreated, refractory, advanced stage MF/SS, although alemtuzumab has biological activity, it is associated with significant toxicity and only modest clinical utility. As such, combination regimens incorporating alemtuzumab merit further investigation in this difficult to treat patient group.     

The role of malignancies in patients with catastrophic anti-phospholipid (Asherson’s) syndrome

The catastrophic anti-phospholipid syndrome (CAPS) differs from the anti-phospholipid syndrome in its accelerated systemic involvement leading to multi-organic failure. In this study, the occurrence of malignancies in patients with CAPS was evaluated and the clinical findings of CAPS patients with and without malignancies were compared. We investigated the web site-based international registry of patients with CAPS for all cases in which both CAPS and underlying malignancies were present. The clinical characteristics of these cases were subsequently evaluated to establish common characteristics. The CAPS registry included information on a total of 262 cases. Twenty-three (9%) patients suffered from malignancies. In 78% of these patients, the malignancy itself or the treatment modalities instituted for the carcinoma was the precipitating factor of CAPS. Only 39% of CAPS patients with malignancies recovered in comparison to 58% of patients without malignancies (p = 0.07). Treatment modalities, however, did not differ significantly between these patients. Infections were not evident as precipitating factors for any of the malignancy patients. The mean age of patients with malignancies was 9 years older than the average age of other patients with CAPS and the prevalence of SLE was significantly less common than in patients without malignancy. Malignancy may play a pathogenic role in patients with CAPS, whereas infections are more important as triggering factors in patients without malignancies. CAPS patients with malignancies are generally older than CAPS patients without malignancies; they generally have the worst prognosis of the entire CAPS cohort. *The members of the Catastrophic Antiphospholipid Syndrome Registry Project Group are listed in the Appendix.     

The role of exercise in the rehabilitation of patients with systemic lupus erythematosus and patients with primary Sjögren's syndrome

PURPOSE OF REVIEW: The purpose of this review is to present an update on the evidence-based effects of exercise in systemic lupus erythematosus and in primary Sj?gren's syndrome. RECENT FINDINGS: Physical capacity is reduced in both systemic lupus erythematosus and primary Sj?gren's syndrome and fatigue is a dominating and disabling symptom in both conditions. The documentation on the effect of exercise on the rehabilitation of patients with systemic lupus erythematosus and primary Sj?gren's syndrome is sparse; the studies are few and the sample sizes often small. The available studies indicate that patients with systemic lupus erythematosus of mild to moderate disease activity as well as patients with primary Sj?gren's syndrome benefit from exercise of moderate to high intensity. Positive effects can be expected with regard to aerobic capacity, fatigue, physical function and depression. SUMMARY: There is reason to believe that exercise should be included in the rehabilitation of patients with mild to moderate systemic lupus erythematosus and patients with primary Sj?gren's syndrome. Further research is needed and should aim to evaluate the effect of exercise on groups with varying degree of disease severity and to document the long-term impact on the disease.     

A prospective study on the evolution of the T-cell repertoire in patients with Sézary syndrome treated by extracorporeal photopheresis

Sézary syndrome is a leukemic form of epidermotropic cutaneous T-cell lymphoma related to the malignant proliferation of clonal CD4(+) T cells. Extracorporeal photochemotherapy may induce a transient improvement of the clinical signs, but its efficiency is discussed. To investigate the frequency of the T-cell clone in the peripheral blood of patients with Sézary syndrome and to monitor its evolution in patients treated using extracorporeal photopheresis or chemotherapy, we used the immunoscope technique. In one patient, we observed a decrease of the relative frequency of the clone from 15.6% to 0%, paralleling a complete remission of the clinical disease and a disappearance of the circulating Sézary cells. In the other cases, the evolution of the relative frequency paralleled the initial improvement of the clinical status and the absence of long-term efficiency in patients treated with extracorporeal photopheresis or chemotherapy. We observed a quick-acting direct cytotoxicity of the association 8MOP + UVA on the T-cell clone. The immunoscope technique appears to be an efficient tool to appreciate the amount of tumoral cells and to monitor the evolution of the clonal component in the Sézary syndrome.     

Successful treatment of chemotherapy-refractory Sézary syndrome with alemtuzumab (Campath-1H)

INTRODUCTION: Sézary syndrome (SS) is a cutaneous T-cell lymphoma characterized by erythroderma, lymphadenopathy and circulating atypical T cells. Median survival after diagnosis is 10 yr, with chemotherapy resistance being a major problem in advanced disease. Alemtuzumab (Campath-1H) is a monoclonal antibody directed against the lymphocytic antigen CD52, expressed on B- and T-cells. Alemtuzumab is approved for relapsing chronic B-cell leukemia and seems to be active also in T-cell lymphomas such as T-cell prolymphocytic lymphoma, SS and mycosis fungiodes. CASE HISTORY: A 32-yr-old male patient presented with advanced stage, extensively pretreated SS with heavily itching erythroderma, peripheral lymphadenopathy, circulating Sézary cells and bone marrow infiltration. The disease had not responded to PUVA/interferon-alpha and progressed on chemotherapy with CHOP, 2-CDA, vinorelbine, etoposide and liposomal doxorubicin. Following treatment with alemtuzumab (30 mg i.v. three times per week for 10 wk), itching resolved rapidly and an almost complete remission was achieved within 3 months after starting this treatment. At 12-month follow up, no disease progression was present. CONCLUSION: In accordance with previous data, this single case underlines the potent activity of alemtuzumab in advanced, chemotherapy-refractory SS.     

Colonic expression of Runx3 protein and TGF-β(1) and their correlation in patients with irritable bowel syndrome

ObjectiveTo investigate the role of Runx3 protein and TGF-β₁ in the pathogenesis of irritable bowel syndrome (IBS), as well as the correlation of these two proteins.MethodsColonic tissue was collected from patients with IBS and normal persons. The colonic expression of Runx3 protein and TGF-β₁ was detected with immunohistochemistry method. Semi-quantitative analysis was used to evaluate the staining degree of these two proteins.ResultsCompared with their counterparts, patients with IBS did not show any changes in the colonic expression of Runx3 protein and TGF-β₁ (P>0.05). Interestingly, there was a significant correlation between Runx3 protein and TGF-β₁ in patients with IBS(P<0.05).ConclusionsThe role of Runx3 protein and TGF-β₁ in the pathogenesis of IBS remains to be further studied.     

Is there a role for laser speckle contrast analysis (LASCA) in predicting the outcome of digital ulcers in patients with systemic sclerosis?

Clinical Rheumatology - Digital ulcers (DUs) represent one major burden for patients with systemic sclerosis (SSc). The objectives of our study were to evaluate blood flow in SSc-DUs with laser...     

Novel role of CD40 in Fas-dependent apoptosis of cultured salivary epithelial cells from patients with Sjögren's syndrome

OBJECTIVE: To determine the role of Fas and CD40 in the molecular mechanism of salivary epithelial cell death in Sjogren's syndrome (SS). METHODS: The expression of Fas and CD40 in SS salivary epithelial cells was analyzed by flow cytometry. Induction of apoptosis with anti-Fas and/or anti-CD40 monoclonal antibodies (mAb) was examined by morphologic analysis, DNA fragmentation, and TUNEL assay. Expression of c-FLIP, Fas-associated phosphatase 1, FADD, Bcl-2, Bcl-x(L), and Bcl-x(S) was determined by Western blot analysis. RESULTS: Expression of Fas and CD40 was significantly higher in SS salivary epithelial cells than in normal cells after interferon-gamma (IFNgamma) stimulation (P < 0.001 for both Fas and CD40). Although neither anti-Fas (CH11) nor anti-CD40 mAb alone could induce typical apoptosis, the two together and preincubation with IFNgamma efficiently induced apoptosis in SS salivary epithelial cells. This apoptosis was almost completely blocked by neutralizing anti-Fas mAb (ZB4), whereas an antagonistic mAb to CD40 (ch5D12) partially inhibited anti-Fas/anti-CD40-induced apoptosis. Also, c-FLIP, an important inhibitory molecule in the Fas death pathway, was strongly expressed in SS salivary epithelial cells, but its expression was down-regulated at the protein level by anti-CD40 mAb. CONCLUSION: CD40 signals promote Fas-dependent death of SS salivary epithelial cells by down-regulating c-FLIP expression. The presence of c-FLIP in these cells may explain their resistance to undergoing apoptosis in response to either anti-Fas or anti-CD40 mAb, despite their surface expression of both proteins. These findings suggest that SS salivary epithelial cell death requires the cooperation of both Fas and CD40.     

Sézary syndrome patients demonstrate a defect in dendritic cell populations: effects of CD40 ligand and treatment with GM-CSF on dendritic cell numbers and the production of cytokines

Sézary syndrome (SzS) is an advanced form of cutaneous T-cell lymphoma associated with involvement of the peripheral blood by malignant T cells. The disease is defined by impaired cell-mediated immunity and the production of interferon-gamma (IFN-gamma) and interleukin-2 (IL-2), possibly as a result of deficient IL-12 production. To understand the mechanism of this impairment, we examined the composition and function of dendritic cells and monocytes in the blood of SzS patients with different levels of peripheral blood tumor burden. Consistent with our previous observations, numbers of monocytes in SzS patients were comparable to numbers observed in healthy donors. In contrast, decreased IL-12 production correlated with a decrease in the numbers of CD11c(+) dendritic cells, which was particularly profound among patients with medium (20%-50% circulating malignant T cells) and high (more than 50% circulating malignant T cells) tumor burden. Furthermore, CD123(+) dendritic cells, major producers of IFN-alpha, were significantly diminished in SzS patients, regardless of the level of tumor burden. Granulocyte macrophage-colony-stimulating factor-treated patients experienced an increase in the number of dendritic cells but not in IFN-alpha or IL-12 production. However, in vitro stimulation of peripheral blood mononuclear cells from SzS patients with rCD40L and IFN-gamma significantly increased the production of IL-12. Thus, our results demonstrate a profound defect in circulating dendritic cells in SzS patients that may contribute to the pathogenesis of the cytokine disorders and to the depressed cellular immunity. Importantly, the ability of rCD40L to potently induce IL-12 production from monocytes and residual dendritic cells of SzS patients could potentially serve as an immune-restorative therapeutic agent.     

Receptor of advanced glycation end product (RAGE) expression in the minor salivary glands of patients with Sjögren's syndrome: a preliminary study

OBJECTIVE: Receptor for advanced glycation end product (RAGE) is a cell-surface receptor with ligands capable of inducing proinflammatory responses in autoimmunity. We investigated the immunohistochemical expression and immunoblotting of RAGE in labial salivary glands from Sj?gren's syndrome (SS) patients. MATERIAL AND METHODS: Ten minor salivary glands from SS and 15 from normal salivary tissue adjacent to mucocele were stained immunohistochemically using an antibody to RAGE. Immunoblotting was performed on four SS biopsies and four controls from normal gland. RESULTS: Immunohistochemistry showed all sections positive for RAGE. The SS sections did not statistically differ from controls. In immunoblotting, SS samples expressed approximately 100% more RAGE than controls [probability (p)<0.03, Student's t-test]. CONCLUSIONS: RAGE is present in the labial salivary glands of both normal and SS patients, with preliminary data suggesting over-expression in SS tissues. The role of RAGE in the pathogenesis of SS has yet to be determined.     

Will the use of low-molecular-weight heparin (enoxaparin) in patients with acute coronary syndrome save costs in Canada?

BACKGROUND: One-year follow-up data from the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events (ESSENCE) trial show that use of low-molecular-weight heparin (enoxaparin) compared with unfractionated heparin in patients hospitalized with unstable angina or non-Q-wave myocardial infarction is associated with a 10% reduction in the cumulative 1-year risk of death, myocardial infarction, or recurrent angina. Given the higher acquisition cost of enoxaparin relative to unfractionated heparin, we assessed whether the reduced use of revascularization procedures and related care makes enoxaparin a cost-saving therapy in Canada. METHODS AND RESULTS: We analyzed cumulative 1-year resource use data on the 1259 ESSENCE patients enrolled in Canadian centers (40% of the total ESSENCE sample). Patient-specific data on use of drugs, diagnostic cardiac catheterization, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, and hospital days were available from the initial hospital stay and cumulative to 1 year. Hospital resources were costed with the use of data from a teaching hospital in southern Ontario that is a participant in the Ontario Case Costing Project. During the initial hospital stay, use of enoxaparin was associated with reduced use of diagnostic catheterization and revascularization procedures, with the largest effect being reduced use of percutaneous transluminal coronary angioplasty (15.0% vs 10.6%; P =.03). At 1 year, the reduced risk and costs of revascularization more than offset increased drug costs for enoxaparin, producing a cost-saving per patient of $1485 (95% confidence interval $-93 to $3167; P =.06). Sensitivity analysis with lower hospital per diem costs from a community hospital in Ontario still predicts cost savings of $1075 per patient over a period of 1 year. CONCLUSIONS: The acquisition and administration cost of enoxaparin is higher than for unfractionated heparin ($101 vs $39), but in patients with acute coronary syndrome, the reduced need for hospitalization and revascularization over a period of 1 year more than offsets this initial difference in cost. Evidence from this Canadian substudy of ESSENCE supports the view that enoxaparin is less costly and more effective than unfractionated heparin in this indication.