Pulse cyclophosphamide treatment for severe refractory cutaneous lupus erythematosus.

Cutaneous lupus erythematosus includes a variety of lupus erythematosus specific skin lesions that, in some cases, can be disfiguring and refractory to conventional therapy. This short report describes our experience in treating six patients with severe, refractory subacute cutaneous lupus erythematosus with monthly cyclophosphamide pulses, followed by azathioprine as maintenance therapy. Significant clinical improvement of the subacute cutaneous lupus erythematosus lesions was achieved in all patients, with four patients in complete remission and two in partial remission. Mean time to clinical response was 4.33 +/- 1.36 months. Minor adverse events and no relapses were noted in a follow-up period of more than 3 years.

Takayasu arteritis: epidemiological, clinical, and immunogenetic features in Greece.

OBJECTIVE: Takayasu arteritis (TA) is an uncommon disease with clinical heterogeneity across different ethnic groups. We aimed to evaluate the epidemiological, clinical, and immuno-genetic features of TA in Greece. METHODS: Demographic, clinical, laboratory, angiographic, and therapeutic data of 42 patients from 4 large referral centers were retrieved. Serology and Human Lymphocyte Antigen (HLA) typing was performed in 22 patients. RESULTS: We studied 37 women and 5 men with a median age of 31 years at disease onset. Median delay in diagnosis was 24 months and median follow-up was 47 months (range 0-178). Constitutional or musculoskeletal symptoms were present in 86%, especially early in the disease course. Vascular findings were universal with reduced or absent pulse being the most common manifestation (98%). Hypertension was frequent (78%). Extensive disease prevailed and stenotic lesions were more common than aneurysms (95% vs. 40%). Erythrocyte sedimentation rate and C-reactive protein showed modest correlation with disease activity. HLA-B52 was expressed by 37% of the patients vs. 2.4% of the controls (p<0.001). Glucocorticoids and cytotoxic agents were used in most patients with remission rates of 83%. A total of 42 surgical procedures were performed with success rates of 87%. CONCLUSION: TA in Greece clinically and epidemiologically resembles the pattern of disease in Japan and the Western hemisphere. There is considerable delay in diagnosis, which may partially reflect failure to recognize a rare disease. New surrogate markers are needed to assess disease activity. Glucocorticoids are the cornerstone of treatment and cytotoxic drugs are frequently used as steroid sparing agents.

High prevalence of metabolic syndrome and cardiovascular risk factors in men with ankylosing spondylitis on anti-TNFalpha treatment: correlation with disease activity.

OBJECTIVE: Ankylosing spondylitis (AS) may be associated with an increased risk for cardiovascular diseases (CVD). We investigated the prevalence of cardiovascular risk factors and metabolic syndrome (MetS) in men with AS and assessed any correlation with AS-related factors. METHODS: This was a cross-sectional study of 63 men with AS, median age 40 (19-69) years, and 126 age-matched controls. Patients were on anti-TNFalpha treatment because of considerable disease activity at some time during the course of the disease. MetS was assessed according to the modified National Cholesterol Education Program Adult Treatment Panel III criteria. The risk for CVD event within the next 10 years was estimated using the Framingham equation. RESULTS: Patients had lower high-density lipoprotein cholesterol (HDL-C) (p<0.001), higher systolic (p=0.001) and diastolic (p<0.01) blood pressure compared with controls. The prevalence of the MetS was higher in patients compared to controls (34.9% vs. 19.0%; p<0.05). AS patients with MetS were older (p<0.01), with higher Framingham risk score (p=0.001), had longer disease duration (p<0.05) and higher BASDAI (5.1 vs. 3.7; p<0.05) than those without MetS, while both BASFI and CRP had an inverse correlation with HDL-C levels. CONCLUSIONS: Men with AS have a higher prevalence of cardiovascular risk factors and MetS compared with controls. The presence of MetS was associated with increased 10 year CVD risk in these patients. The association of AS disease activity with MetS suggests that CVD in AS patients may, at least in part, be attributed to the inflammatory burden of the disease.

Chronic alcohol consumption as a predisposing factor for multiple tendon ruptures in unusual sites in a patient with rheumatoid arthritis.

Simultaneous bilateral patellar tendon ruptures are a rare complication of rheumatoid arthritis (RA). Systemic inflammatory diseases (RA, systemic lupus erythematosus (SLE), chronic renal failure, primary and secondary hyperparathyroidism, diabetes mellitus, obesity, sports activity, older age (>50) and drugs (prolonged use of high doses of steroids, local steroid injections and quinolones) are considered as potent predisposing factors for tendon rupture. We report a case of an alcoholic patient with RA and bilateral spontaneous tendon ruptures of the knees. Circumstantial evidence suggest that in this patient, chronic alcohol consumption, a very frequent cause of toxicity to striated and cardiac muscle, contributed to the injury.

Infliximab therapy in pulmonary fibrosis associated with collagen vascular disease.

OBJECTIVE: To study the potential effectiveness of tumor necrosis factor a (TNF-alpha) inhibitor treatment for pulmonary fibrosis associated with a collagen vascular disease, CVD (rheumatoid arthritis, RA and systemic sclerosis, SSc) refractory to conventional treatment. METHODS: Four patients (three men with RA, one woman with SSc) were treated with infliximab. All patients received 3mg/kgr of infliximab at intervals 0, 2 and 6 weeks, and then maintenance infusions every 8 weeks afterwards for at least a 12-month period. Patients had active disease despite treatment with corticosteroids and other immunomodulatory agents. RESULTS: Treatment was well-tolerated from all patients. Pulmonary fibrosis remained stable during treatment in terms of symptoms, pulmonary function tests (PFTs) and High resolution computed tomography (HRCT) appearance. As expected, a clinical response was observed in joint symptoms in patients with RA as evaluated by the DAS28 (Disease Activity Score, the 28 joint version). CONCLUSION: This study suggests that inhibition of TNF-alpha with infliximab may stabilize the progression of pulmonary fibrosis associated with CVD. Prospective, controlled trials are necessary to determine the efficacy of infliximab in pulmonary fibrosis associated CVD.

Metabolic syndrome is common among middle-to-older aged Mediterranean patients with rheumatoid arthritis and correlates with disease activity: a retrospective, cross-sectional, controlled, study.

OBJECTIVES: Patients with rheumatoid arthritis have an increased risk for cardiovascular disease (CVD). The prevalence of metabolic syndrome (MetS)-a major contributor to CVD-in a cohort of patients with rheumatoid arthritis and its relationship with rheumatoid arthritis related factors is investigated here. METHODS: 200 outpatients with rheumatoid arthritis (147 women and 53 men), with a mean (standard deviation (SD)) age of 63 (11) years, and 400 age and sex-matched controls were studied. MetS was assessed according to the adult treatment panel III criteria and rheumatoid arthritis disease activity by the disease activity score of 28 joints (DAS28). A standard clinical evaluation was carried out, and a health and lifestyle questionnaire was completed. RESULTS: The overall prevalence of MetS was 44% in patients with rheumatoid arthritis and 41% in controls (p = 0.5). Patients with rheumatoid arthritis were more likely to have low high-density lipoprotein cholesterol compared with controls (p = 0.02), whereas controls were more likely to have increased waist circumference or raised blood pressure (p = 0.001 and 0.003, respectively). In multivariate logistic regression analysis adjusting for demographics and rheumatoid arthritis treatment modalities, the risk of having moderate-to-high disease activity (DAS28>3.2) was significantly higher in patients with MetS compared with those with no MetS components (OR 9.24, 95% CI 1.49 to 57.2, p = 0.016). CONCLUSION: A high, albeit comparable to the control population, prevalence of MetS was found in middle-to-older aged patients with rheumatoid arthritis. The correlation of rheumatoid arthritis disease activity with MetS suggests that the increased prevalence of coronary heart disease in patients with rheumatoid arthritis may, at least in part, be attributed to the inflammatory burden of the disease.

Low dose of infliximab is inadequate in most patients with spondylarthropathies.

OBJECTIVES: The recommended starting dose for infliximab for ankylosing spondylitis 5mg/kg is higher than that for rheumatoid arthritis. Because of the high expense of the drug lower doses may be considered. We report our experience with lower initial doses. METHODS: Thirty patients with active SpA (16 psoriatic arthritis, 12 ankylosing spondylitis and 2 undifferentiated) received 6 infliximab infusions. Patients had substantial axial disease (mean BASDAI at baseline 5.5). Concomitant therapy (methotrexate or prednisolone) remained stable throughout treatment period. The mean initial dose of infliximab was 3.5 mg/kg/infusion. Clinical efficacy was assessed by BASDAI. The criterion for dose adjustment was a BASDAI improvement of less than 50%. The primary end-points were the proportion of patients requiring a dose adjustment and the percentage of patients achieving 50% improvement in BASDAI after 6 infusions. RESULTS: In this cohort, 2 patients discontinued therapy, 1 for pulmonary infection and 1 for allergic reaction. Twelve patients (40%) showed 50% improvement in BASDAI between baseline and prior to the 7th infusion, while 15 patients (50%) had an improvement > 2 points. To achieve clinical response the frequency and/or the dose of infliximab infusions were increased in 63% of patients. The mean infliximab dose increased from 3.5 mg/kg at the first infusion to 4.3 mg/kg (p < 0.001) at the 7th infusion, resulting in a cumulative dose at the end of the study period comparable to the recommended one. CONCLUSIONS: In the majority of our SpA patients low starting doses of infliximab required subsequent adjustment. In these patients infliximab should be administered at the recommended dose of 5mg/kg/infusion.

Lupus nephritis flares.

The clinical course of lupus nephritis varies remarkably among SLE patients, even between those with the same histological type. Current immunosuppressive agents induce remission in the majority of the patients with proliferative lupus nephritis, but a substantial proportion of them - ranging in different studies from 27% to 66% - will flare. Flares represent a significant problem because of the potential for cumulative damage that may lead to deterioration of renal function as well as toxicity due to the additional immunosuppression. Maintenance therapy with azathioprine, mycophenolate mofetil or quarterly pulses of cyclophosphamide is usually recommended. Renal flares can be characterized as nephritic or nephrotic and can be mild or severe. The majority of the patients that flare restore renal function, if diagnosed early and treated promptly. However, current immunosuppressive agents have limitations concerning efficacy and toxicity profiles. Unresolved management issues include the value of repeat renal biopsy and issues related to optimal strategy/regimen to prevent flares. Renal flares are an important feature of the natural history of lupus nephritis and provide an opportunity for additional preventive strategies, as well as measures of efficacy in future therapeutic trials.

Infliximab treatment for rheumatoid arthritis, with dose titration based on the Disease Activity Score: dose adjustments are common but not always sufficient to assure sustained benefit.

BACKGROUND: Randomised controlled trials have shown that treatment with anti-tumour necrosis factor (anti-TNF) agents is effective in refractory rheumatoid arthritis (RA). OBJECTIVE: To determine the effectiveness of anti-TNF in a general unselected group of patients with refractory RA. METHODS: 68 patients with active RA despite treatment with disease modifying antirheumatic drugs were studied during 12 infliximab infusions. Infliximab (3 mg/kg/infusion) was given every 8 or 6 weeks. Clinical efficacy was assessed by the Disease Activity Score (DAS) index (44 joints). Dose adjustments were based on residual disease activity (DAS score >2.4). The primary end points were the percentage of patients achieving good or moderate response by the EULAR response criteria and the proportion of patients requiring dose adjustment. RESULTS: 20 (29%) patients discontinued treatment owing to side effects, early inefficacy, or other considerations. Among the patients who continued treatment, 27 (56%) and 32 (67%) were responders on the 6th and 12th infliximab infusion, respectively. In the same patients, disease activity gradually improved without modifications in the initial dosing in 10 (21%), whereas in 38 (79%) the dose of infliximab and/or methotrexate was increased. Intensification of treatment led to a significant decrease in the mean DAS score in this group (from 5.27 just before dose modification to 4.54 before the 12th infusion, p<0.002). The EULAR response category improved in only 10/38 (26%), however. CONCLUSIONS: In this initial observational study of patients with RA treated with recommended doses of infliximab, adjustments in treatment were common but not always sufficient to maintain adequate disease control. Longitudinal controlled trials are needed to define the optimal dose escalation in patients with suboptimal response.

Non-Hodgkin's lymphoma in patients with systemic lupus erythematosus.

Two cases of non-Hodgkin's lymphoma (NHL) associated with systemic lupus erythematosus (SLE) are described. Patient-1 was a 65-year-old woman in whom SLE and diffuse large B-cell lymphoma were concurrently diagnosed. The patient presented with low-grade fever, butterfly rash, arthritis and generalized lymphadenopathy without splenomegaly or bone marrow involvement. Complete remission of NHL and SLE was achieved with cyclophosphamide, adriamycin, vincristine and prednisone. Patient-2 was a 56-year-old woman in whom SLE had been diagnosed 14 years earlier. The patient presented with low-grade fever, bulky splenomegaly without lymphadenopathy, IgMA paraproteinemia, and expansion of a monoclonal CD19+/CD22+ lambda-type B-cell population in both bone marrow and peripheral blood. Diagnosis of a lympho-plasmacytoid lymphoma was established histologically after splenectomy. A partial remission of the neoplasm was achieved with cyclophosphamide, vincristine and prednisone. We suggest that the development of NHLs in patients with SLE may not be coincidental and we recommend the search for NHL in cases of SLE with prominent lymphadenopathy, massive splenomegaly or expansion of a monoclonal CD19+/CD22+ B-cell population.

Perspective on future therapy of vasculitis.

This article summarizes recent advances in the management of various vasculitic syndromes and discusses potential new therapies based on a better understanding of their pathogenesis and natural history. Current efforts for optimization of testing for antineutrophil cytoplasmic antibodies and improvement of diagnostic criteria will certainly have a significant impact on future therapy. Biologic agents such as interferon-alpha are already in use in various vasculitides, whereas others, such as inhibitors of tumor necrosis factor-alpha, are in phase I clinical trials. Agents that selectively inhibit distinct steps in the pathogenesis of vasculitis are in preclinical or early clinical stages of development. Newer (mycophenolate mofetil, leflunamide) or older (methotrexate, azathioprine) immunosuppresive agents are finding new roles in the management of vasculitides. For patients with severe vasculitis, short-term use of cytotoxic agents, such as cyclophosphamide, alone or in combination with biologic agents, may expedite remission, which could then be better maintained with other, less toxic (and less expensive) immunosuppressive agents, such as methotrexate, azathioprine, mycophenolate mofetil, and leflunamide. For patients with mild or moderately severe vasculitis, these latter agents alone may be adequate. New therapeutic studies in vasculitis should better address the impact of therapy on health-related quality of life and its long-term toxicity.