Bortezomib and dexamethasone, an original approach for treating multi-refractory warm autoimmune haemolytic anaemia.

We report the off-label use of bortezomib combined with dexamethasone in eight adults with severe and multi-refractory warm auto-immune haemolytic anaemia (wAIHA). After six cycles of induction therapy, 6 of the 8 patients achieved response (3 complete response, 3 response). Response was obtained after a median of 2 (1-4) cycles. After a median follow-up of 14 (6-36) months, six patients maintained a response (bortezomib/dexamethasone maintenance, n = 4); five patients experienced at least one moderate adverse event, including peripheral neuropathy (n = 2). These results suggest that bortezomib/dexamethasone combination is a promising approach with acceptable toxicity for treating severe refractory wAIHA in adults.

Impaired carbon monoxide diffusing capacity as a marker of limited systemic sclerosis.

BACKGROUND: As impairment of diffusing capacity for carbon monoxide (DLCO) likely reflects underlying pulmonary vasculopathy in limited systemic sclerosis (lSSc), we examined whether DLCO could help to distinguish secondary from idiopathic Raynaud's phenomenon (iRP). METHODS: We compared pulmonary function test (PFT) results in 145 lSSc patients and 24 age- and sex-matched iRP patients. RP duration at time of PFT was similar in the two groups. RESULTS: DLCO values were low (<80% of predicted) in 106 (73%) of the 145 lSSc patients, and in 69 (71%) of the 97 patients with early lSSc. Interstitial lung disease (ILD) was found in 10% of lSSc patients. DLCO was significantly lower in lSSc than in iRP (72±15% versus 89±9%, p<0.0001). When evaluated, alveolar capillary membrane conductance (Dm) was markedly lower in lSSc patients without ILD than in iRP patients (45±12% versus 71±2.5%, p=0.003), although capillary blood volume was not different. DLCO was low in 3 iRP patients (12.5%). The sensitivity and specificity of low DLCO values for early lSSc diagnosis in patients with Raynaud's phenomenon were 71% and 87.5%, respectively. Sensitivity was similar to that of anti-centromere-antibodies (75%) and nailfold capillary abnormalities (81%). A DLCO cutoff of <70% had a sensitivity and specificity of 41% and 100%, respectively. In multivariable analysis, age and low DLCO were the only independent predictors of death; the hazard ratio for DLCO ≤50% was 7.9 (95% CI 2.3-26, p=0.0007). CONCLUSION: Isolated DLCO impairment is significantly more frequent in patients with lSSc than in patients with idiopathic iRP. DLCO measurement could be a useful diagnostic tool for lSSc.

Pulmonary arterial hypertension is a major mortality factor in diffuse systemic sclerosis, independent of interstitial lung disease.

OBJECTIVE: To determine whether pulmonary arterial hypertension (PAH) is a prognostic factor for mortality in diffuse cutaneous systemic sclerosis (dcSSc), independent of interstitial lung disease (ILD). METHODS: ILD was diagnosed by high-resolution computed tomography and PAH (pulmonary arterial systolic pressure [PASP] > or =45 mm Hg) by echocardiography. All patients with ILD underwent testing for total lung capacity (TLC), forced vital capacity (FVC), and diffusing capacity for carbon monoxide. RESULTS: Eighty-six patients with dcSSc (mean age at diagnosis 44.5 years) were followed up for a median of 72.5 months. ILD was found in 52 patients (60%) and PAH in 18 (21%). ILD was associated with PAH in 15 patients. Seventeen patients died (19.8%), 9 of whom had PAH (P = 0.001) and 10 of whom had ILD (P = 0.99). By multivariate analysis, age at SSc diagnosis and PAH were the only independent predictors of death (hazard ratio [HR] 1.057, 95% confidence interval [95% CI] 1.009-1.109, P = 0.020 and HR 4.09, 95% CI 1.47-11.5, P = 0.007, respectively). Mean TLC and mean FVC were similar in ILD patients with and those without PAH (P = 0.71 and P = 0.40, respectively). Among ILD patients, age at SSc diagnosis and PAH were again the sole predictors of death (HR 1.073, 95% CI 1.003-1.149, P = 0.042 and HR 5.07, 95% CI 1.09-23.8, P = 0.038, respectively). Twenty ILD patients received at least 6 monthly pulses of intravenous cyclophosphamide (CYC). In CYC-treated patients with PAH (n = 8), PASP increased significantly during the CYC regimen (mean +/- SD 55 +/- 14.5 mm Hg; P = 0.015 versus baseline), while TLC remained stable during the same period. CONCLUSION: These results indicate that, independent of ILD, PAH is a major prognostic factor for survival in dcSSc.

Dermatologic manifestations of the antiphospholipid syndrome: two hundred consecutive cases.

OBJECTIVE: To describe dermatologic manifestations of the antiphospholipid syndrome (APS) and to investigate possible correlations between livedo reticularis and other APS manifestations. METHODS: We conducted a single-center study of 200 consecutive patients with primary or systemic lupus erythematosus-related APS. To qualify for the study, patients had to fulfill clinical and laboratory criteria from the most recent international consensus statement on classification of definite APS. Dermatologic manifestations were systematically evaluated by a dermatologist. Only dermatologic lesions that may be related to APS were included in the analyses. Correlations between livedo reticularis and other APS manifestations were determined using Fisher's 2-tailed, chi-square, and nonparametric Mann-Whitney tests. RESULTS: Dermatologic manifestations were noted in 49% of the patients and were the presenting manifestations in 30.5%. Livedo reticularis was the most frequent manifestation, observed in 25.5% of the patients. Livedo reticularis was shown to be significantly associated with cerebral or ocular ischemic arterial events (odds ratio [OR] 10.8, 95% confidence interval [95% CI] 5.2-22.5), seizures (OR 6.5, 95% CI 2.6-16), all arterial events (OR 6, 95% CI 2.9-12.6), heart valve abnormalities detected on echocardiography (OR 7.3, 95% CI 3.6-14.7), and arterial systemic hypertension (>/=160/90 mm Hg) (OR 2.9, 95% CI 1.5-5.7). Conversely, it was observed with decreased frequency in patients with only venous thrombosis (OR 0.2, 95% CI 0.1-0.5). CONCLUSION: The dermatologic manifestations of APS are frequently the presenting feature of the syndrome, and livedo reticularis is significantly associated with the arterial subset of APS.

High ferritin and low glycosylated ferritin may also be a marker of excessive macrophage activation.

OBJECTIVE: A high serum ferritin concentration with a low percentage of glycosylated ferritin (< 20%) have been reported to be a specific marker of active adult Still's disease (ASD). However, high ferritin levels are found during hemophagocytosis syndrome (HS). We investigated the ferritin level and the percentage of glycosylation in a HS series of various causes. METHODS: Diagnosis of HS was confirmed by erythrophagocytosis pictures on a bone marrow cytology or biopsy in all patients. Serum ferritin concentration was determined on a heterogenous immunoassay module. Glycosylated ferritin was separated using concanavalin A (Con-A) sepharose 4B chromatography. The nonglycosylated ferritin unbound to Con-A was recovered in the supernatant and quantified with the same procedure. Percentages of glycosylated ferritin less than 20% are considered to be usual in ASD, between 20 and 40% usual in inflammatory syndrome, and between 50 and 80% normal. RESULTS: In all cases tested during the acute phase of the disease, ferritin blood level was high and the percentage of glycosylated ferritin was low, less than 20%. CONCLUSION: The combination of high ferritin level and low percentage of glycosylation may be a marker of excessive macrophage activation.

Risk of ovarian failure and fertility after intravenous cyclophosphamide. A study in 84 patients.

OBJECTIVE: To compare the risk of ovarian failure and the fertility of women treated with intravenous cyclophosphamide (IVCY) according to the underlying inflammatory disease. METHODS: Review of the data of 84 consecutive women: 56 with systemic lupus erythematosus (SLE), 28 with other diseases, mainly Wegener's granulomatosis and systemic vasculitides. RESULTS: The mean age at IVCY initiation was 29 +/- 10 years (range 13-53). The mean dosage was 0.9 +/- 0.14 g per pulse (range 0.5-1), and the mean number of pulses 13 +/- 6.5 (range 3-42). With a mean followup of 5.1 +/- 3.7 years, 23 women developed amenorrhea, with a mean duration of 4 +/- 3.6 months between IVCY initiation and amenorrhea. Amenorrhea was sustained in 19 women (13 with SLE and 6 with other diseases, NS). The mean age at ovarian failure onset was 40 +/- 7.6 years. The risk of ovarian failure correlated with the age at IVCY institution (p < 0.0001), and was independent of underlying inflammatory disease. Eighteen women (13 with SLE and 5 with other diseases) became pregnant during or after CY therapy, with a total of 22 pregnancies. The mean age at IVCY initiation, and the mean number of IVCY (maximum 40 pulses) before pregnancy were similar in women with SLE and those with other diseases. Six pregnancies occurred during IVCY therapy, which ended in induced abortion (n = 3), spontaneous abortion (n = 1), and normal pregnancy after IVCY withdrawal (n = 2) in women who wished to keep their pregnancy despite the risk of teratogenicity. Sixteen pregnancies occurred 2.9 +/- 2.1 years (range 1-9) after IVCY withdrawal. They ended in: 3 induced abortions indicated for severe morphological anomalies (n = 2) and for SLE relapse (n = 1), 3 spontaneous miscarriages, and 10 deliveries of healthy newborns. CONCLUSION: The risk of ovarian failure depends essentially on the age at IVCY initiation. Pregnancy may occur during IVCY therapy, and an efficient contraception is mandatory. After IVCY withdrawal, pregnancy is possible with a favorable outcome in two-thirds of the cases.

Importance of planning ovulation induction therapy in systemic lupus erythematosus and antiphospholipid syndrome: a single center retrospective study of 21 cases and 114 cycles.

OBJECTIVE: To analyze the results and complications of ovulation induction therapy (OIT) in women with systemic lupus erythematosus (SLE) and/or the antiphospholipid syndrome (APS). METHODS: A retrospective study of 21 women followed in a single tertiary-referral French center who underwent 114 OIT cycles with or without in vitro fertilization and embryo transfer (IVFET). RESULTS: Before OIT, SLE was present in 6 women, APS in 3, SLE-related APS in 3, and discoid lupus in 1. Eight women had no identified disease and underwent 36 cycles of OIT. Diagnosis (SLE, n = 3; primary APS, n = 5) was made after OIT complication: spontaneous abortion (n = 5), SLE flare (n = 2), and thrombophlebitis (n = 1). Five women with known disease intentionally concealed their history from their gynecologists and underwent 34 cycles. Forty-four cycles were planned in 11 women, in 3 of them after complications of prior OIT performed without particular therapy and monitoring. Eighteen pregnancies occurred, which ended in 9 live births, 4 fetal deaths, and 5 embryonic losses. The pregnancy rate was higher with gonadotropin and/or gonadotropin-releasing hormone analog (GnRHa) (25% of cycles) than with clomiphene (4% of cycles, P <.0001). When the gynecologists did not know the underlying disease, three-quarters of pregnancies induced by OIT with IVFET ended in embryonic losses or fetal deaths. In contrast, 6 of 7 pregnancies induced by planned OIT with IVFET ended in live births (P <.0001). Phlebothromboses were observed only with gonadotropin treatment. The SLE flare rate was higher with gonadotropin and/or GnRHa (27% of cycle) than with clomiphene (6%, NS). It also was higher (30%) when the gynecologists did not know the underlying disease than in the planned procedures (10%, NS). CONCLUSIONS: The OIT may precipitate SLE or APS. A careful review of the patient's history and appropriate laboratory tests should be undertaken before OIT. Clomiphene complications are rare. When gonadotropins are prescribed, preventive anti-inflammatory therapy should be considered in women with SLE, in addition to heparin and/or anti-aggregant therapy in patients with asymptomatic anti-phospholipid antibodies or prior thrombotic events.