An open study of dehydroepiandrosterone in systemic lupus erythematosus

Objective. To determine if dehydroepiandrosterone (DHEA) has clinical benefits in patients with systemic lupus erythematosus (SLE). Methods. Ten female patients with mild to moderate SLE and various disease manifestations were given DHEA (200 mg/day orally) for 3—6 months. The patients were given other medications as clinically indicated, and followed with respect to overall disease activity and specific outcome parameters. Results. After 3—6 months of DHEA treatment, indices for overall SLE activity including the SLEDAI (SLE Disease Activity Index) score and physician's overall assessment were improved, and corticosteroid requirements were decreased. Of 3 patients with significant proteinuria, 2 showed marked and 1 modest reductions in protein excretion. DHEA was well tolerated, the only frequently noted side effect being mild acneiform dermatitis. Conclusion. DHEA shows promise as a new therapeutic agent for the treatment of mild to moderate SLE. Further studies of DHEA in the treatment of SLE are warranted.     

Dehydroepiandrosterone treatment of women with mild‐to‐moderate systemic lupus erythematosus: A multicenter randomized,double‐blind,placebo‐controlled trial

Objective

To evaluate the efficacy and tolerability of dehydroepiandrosterone (DHEA) at a dosage of 200 mg/day in adult women with active systemic lupus erythematosus (SLE).

Methods

In a multicenter randomized, double‐blind, placebo‐controlled trial, 120 adult women with active SLE received oral DHEA (200 mg/day; n = 61) or placebo (n = 59) for 24 weeks. The primary end point was the mean change from baseline in the Systemic Lupus Activity Measure (SLAM) score at 24 weeks of therapy. Secondary end points included time to first flare, change in SLE Disease Activity Index (SLEDAI) score, and physician's and patient's global assessment scores at week 24.

Results

The two groups were well balanced for baseline characteristics. Mean reductions in SLAM scores from baseline were similar and were not statistically significantly different between treatment groups (DHEA −2.6 ± 3.4 versus placebo −2.0 ± 3.8, mean ± SD). The number of patients with flares was decreased by 16% in the DHEA group (18.3% of DHEA‐treated patients versus 33.9% of placebo‐treated patients; P = 0.044, based on time to first flare). The mean change in the patient's global assessment was statistically significant between the two groups (DHEA −5.5 versus placebo 5.4; P = 0.005). The number of patients with serious adverse events, most of which were related to SLE flare, was significantly lower in DHEA‐treated patients compared with placebo‐treated patients (P = 0.010). Expected hormonal effects, including increased testosterone levels and increased incidence of acne, were observed. No life‐threatening reactions or serious safety issues were identified during this study.

Conclusion

The overall results confirm that DHEA treatment was well‐tolerated, significantly reduced the number of SLE flares, and improved patient's global assessment of disease activity.

     

A phase II,randomized, double‐blind,placebo‐controlled,dose‐ranging study of belimumab in patients with active systemic lupus erythematosus

Objective

To assess the safety, tolerability, biologic activity, and efficacy of belimumab in combination with standard of care therapy (SOC) in patients with active systemic lupus erythematosus (SLE).

Methods

Patients with a Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score ≥4 (n = 449) were randomly assigned to belimumab (1, 4, or 10 mg/kg) or placebo in a 52‐week study. Coprimary end points were the percent change in the SELENA–SLEDAI score at week 24 and the time to first SLE flare.

Results

Significant differences between the treatment and placebo groups were not attained for either primary end point, and no dose response was observed. Reductions in SELENA–SLEDAI scores from baseline were 19.5% in the combined belimumab group versus 17.2% in the placebo group. The median time to first SLE flare was 67 days in the combined belimumab group versus 83 days in the placebo group. However, the median time to first SLE flare during weeks 24–52 was significantly longer with belimumab treatment (154 versus 108 days; P = 0.0361). In the subgroup (71.5%) of serologically active patients (antinuclear antibody titer ≥1:80 and/or anti–double‐stranded DNA [anti‐dsDNA] ≥30 IU/ml), belimumab treatment resulted in significantly better responses at week 52 than placebo for SELENA–SLEDAI score (?28.8% versus ?14.2%; P = 0.0435), physician's global assessment (?32.7% versus ?10.7%; P = 0.0011), and Short Form 36 physical component score (+3.0 versus +1.2 points; P = 0.0410). Treatment with belimumab resulted in a 63–71% reduction of naive, activated, and plasmacytoid CD20+ B cells, and a 29.4% reduction in anti‐dsDNA titers (P = 0.0017) by week 52. The rates of adverse events and serious adverse events were similar in the belimumab and placebo groups.

Conclusion

Belimumab was biologically active and well tolerated. The effect of belimumab on the reduction of SLE disease activity or flares was not significant. However, serologically active SLE patients responded significantly better to belimumab therapy plus SOC than to SOC alone.

     

Novel evidence‐based systemic lupus erythematosus responder index

Objective

To describe a new systemic lupus erythematosus (SLE) responder index (SRI) based on a belimumab phase II SLE trial and demonstrate its potential utility in SLE clinical trials.

Methods

Data from a randomized, double‐blind, placebo‐controlled study in 449 patients of 3 doses of belimumab (1, 4, 10 mg/kg) or placebo plus standard of care therapy (SOC) over a 56‐week period were analyzed. The Safety of Estrogens in Lupus Erythematosus: National Assessment (SELENA) version of the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and British Isles Lupus Assessment Group (BILAG) SLE disease activity instruments, the Short Form 36 health survey, and biomarker analyses were used to create a novel SRI. Response to treatment in a subset of 321 serologically active SLE patients (antinuclear antibodies ≥1:80 and/or anti–double‐stranded DNA antibodies ≥30 IU/ml) at baseline was retrospectively evaluated using the SRI.

Results

SRI response is defined as 1) a ≥4‐point reduction in SELENA–SLEDAI score, 2) no new BILAG A or no more than 1 new BILAG B domain score, and 3) no deterioration from baseline in the physician's global assessment by ≥0.3 points. In serologically active patients, the addition of belimumab to SOC resulted in a response in 46% of patients at week 52 compared with 29% of the placebo patients (P = 0.006). SRI responses were independent of baseline autoantibody subtype.

Conclusion

This evidence‐based evaluation of a large randomized, placebo‐controlled trial in SLE resulted in the ability to define a robust responder index based on improvement in disease activity without worsening the overall condition or the development of significant disease activity in new organ systems.     

A phase III,randomized, placebo‐controlled study of belimumab,a monoclonal antibody that inhibits B lymphocyte stimulator,in patients with systemic lupus erythematosus

Objective

To assess the efficacy/safety of the B lymphocyte stimulator inhibitor belimumab plus standard therapy compared with placebo plus standard therapy in active systemic lupus erythematosus (SLE).

Methods

In a phase III, multicenter, randomized, placebo‐controlled trial, 819 antinuclear antibody–positive or anti–double‐stranded DNA–positive SLE patients with scores ≥6 on the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) version of the SLE Disease Activity Index (SLEDAI) were randomized in a 1:1:1 ratio to receive 1 mg/kg belimumab, 10 mg/kg belimumab, or placebo intravenously on days 0, 14, and 28 and then every 28 days for 72 weeks. The primary efficacy end point was the SLE Responder Index (SRI) response rate at week 52 (an SRI response was defined as a ≥4‐point reduction in SELENA–SLEDAI score, no new British Isles Lupus Assessment Group [BILAG] A organ domain score and no more than 1 new BILAG B score, and no worsening in physician's global assessment score versus baseline).

Results

Belimumab at 10 mg/kg plus standard therapy met the primary efficacy end point, generating a significantly greater SRI response at week 52 compared with placebo (43.2% versus 33.5%; P = 0.017). The rate with 1 mg/kg belimumab was 40.6% (P = 0.089). Response rates at week 76 were 32.4%, 39.1%, and 38.5% with placebo, 1 mg/kg belimumab, and 10 mg/kg belimumab, respectively. In post hoc sensitivity analyses evaluating higher SELENA–SLEDAI score thresholds, 10 mg/kg belimumab achieved better discrimination at weeks 52 and 76. Risk of severe flares over 76 weeks (based on the modified SLE Flare Index) was reduced with 1 mg/kg belimumab (34%) (P = 0.023) and 10 mg/kg belimumab (23%) (P = 0.13). Serious and severe adverse events, including infections, laboratory abnormalities, malignancies, and deaths, were comparable across groups.

Conclusion

Belimumab plus standard therapy significantly improved SRI response rate, reduced SLE disease activity and severe flares, and was generally well tolerated in SLE.

     

Dehydroepiandrosterone treatment of women with mild-to-moderate systemic lupus erythematosus: a multicenter randomized,double-blind,placebo-controlled trial

OBJECTIVE: To evaluate the efficacy and tolerability of dehydroepiandrosterone (DHEA) at a dosage of 200 mg/day in adult women with active systemic lupus erythematosus (SLE). METHODS: In a multicenter randomized, double-blind, placebo-controlled trial, 120 adult women with active SLE received oral DHEA (200 mg/day; n = 61) or placebo (n = 59) for 24 weeks. The primary end point was the mean change from baseline in the Systemic Lupus Activity Measure (SLAM) score at 24 weeks of therapy. Secondary end points included time to first flare, change in SLE Disease Activity Index (SLEDAI) score, and physician's and patient's global assessment scores at week 24. RESULTS: The two groups were well balanced for baseline characteristics. Mean reductions in SLAM scores from baseline were similar and were not statistically significantly different between treatment groups (DHEA -2.6 +/- 3.4 versus placebo -2.0 +/- 3.8, mean +/- SD). The number of patients with flares was decreased by 16% in the DHEA group (18.3% of DHEA-treated patients versus 33.9% of placebo-treated patients; P = 0.044, based on time to first flare). The mean change in the patient's global assessment was statistically significant between the two groups (DHEA -5.5 versus placebo 5.4; P = 0.005). The number of patients with serious adverse events, most of which were related to SLE flare, was significantly lower in DHEA-treated patients compared with placebo-treated patients (P = 0.010). Expected hormonal effects, including increased testosterone levels and increased incidence of acne, were observed. No life-threatening reactions or serious safety issues were identified during this study. CONCLUSION: The overall results confirm that DHEA treatment was well-tolerated, significantly reduced the number of SLE flares, and improved patient's global assessment of disease activity.     

Effects of prasterone on corticosteroid requirements of women with systemic lupus erythematosus: a double-blind,randomized, placebo-controlled trial

OBJECTIVE: To evaluate whether treatment with prasterone (dehydroepiandrosterone [DHEA]) would allow the dosage of prednisone (or an equivalent corticosteroid) to be reduced to < or = 7.5 mg/day for 2 months or longer while maintaining stable or reduced disease activity in steroid-dependent women with systemic lupus erythematosus (SLE). METHODS: In a double-blind, randomized trial, 191 female SLE patients receiving prednisone (10-30 mg/day) were treated daily with either placebo, 100 mg of oral prasterone (an adrenal androgen), or 200 mg of oral prasterone for 7-9-months. At monthly intervals, corticosteroid dosages were reduced by algorithm in patients whose SLE Disease Activity Index (SLEDAI) score was stable or improved. Patients for whom a sustained reduction in the dosage of prednisone (< or = 7.5 mg/day) was achieved for at least the last 2 months of the 7-9-month treatment period were classified as responders. RESULTS: Response rates were 41% in the placebo group, 44% in the 100-mg prasterone group, and 55% in the 200-mg group (P = 0.110, 200 mg versus placebo). Among the 137 subjects (45 in the placebo group, 47 in the 100-mg group, and 45 in the 200-mg group) who had active disease at baseline (defined as SLEDAI score >2), 29%, 38%, and 51%, respectively, were responders (P = 0.031 for 200 mg prasterone versus placebo). Acne was the most common adverse event but was generally mild. Clinical and laboratory changes primarily reflected androgenic effects of prasterone. CONCLUSION: Among women with lupus disease activity, reducing the dosage of prednisone to < or = 7.5 mg/day for a sustained period of time while maintaining stabilization or a reduction of disease activity was possible in a significantly greater proportion of patients treated with oral prasterone, 200 mg once daily, compared with patients treated with placebo.     

Effects of prasterone on corticosteroid requirements of women with systemic lupus erythematosus: A double‐blind,randomized, placebo‐controlled trial

Objective

To evaluate whether treatment with prasterone (dehydroepiandrosterone [DHEA]) would allow the dosage of prednisone (or an equivalent corticosteroid) to be reduced to ≤7.5 mg/day for 2 months or longer while maintaining stable or reduced disease activity in steroid‐dependent women with systemic lupus erythematosus (SLE).

Methods

In a double‐blind, randomized trial, 191 female SLE patients receiving prednisone (10–30 mg/day) were treated daily with either placebo, 100 mg of oral prasterone (an adrenal androgen), or 200 mg of oral prasterone for 7–9‐months. At monthly intervals, corticosteroid dosages were reduced by algorithm in patients whose SLE Disease Activity Index (SLEDAI) score was stable or improved. Patients for whom a sustained reduction in the dosage of prednisone (≤7.5 mg/day) was achieved for at least the last 2 months of the 7–9‐month treatment period were classified as responders.

Results

Response rates were 41% in the placebo group, 44% in the 100‐mg prasterone group, and 55% in the 200‐mg group (P = 0.110, 200 mg versus placebo). Among the 137 subjects (45 in the placebo group, 47 in the 100‐mg group, and 45 in the 200‐mg group) who had active disease at baseline (defined as SLEDAI score >2), 29%, 38%, and 51%, respectively, were responders (P = 0.031 for 200 mg prasterone versus placebo). Acne was the most common adverse event but was generally mild. Clinical and laboratory changes primarily reflected androgenic effects of prasterone.

Conclusion

Among women with lupus disease activity, reducing the dosage of prednisone to ≤7.5 mg/day for a sustained period of time while maintaining stabilization or a reduction of disease activity was possible in a significantly greater proportion of patients treated with oral prasterone, 200 mg once daily, compared with patients treated with placebo.

     

Sulfasalazine in the treatment of spondylarthropathy

Objective. To assess the efficacy and tolerability of sulfasalazine (SSZ) in the treatment of spondyl-arthropathy. Methods. We conducted a 6-month randomized, placebo-controlled, double-blind, multicenter study of patients with spondylarthropathy whose disease had remained active despite treatment with nonsteroidal antiinflammatory drugs. Patients were treated with SSZ (3 gm/day) or placebo. The primary efficacy variables were the physician's and patient's overall assessments, pain, and morning stiffness. End points were analyzed in the intent-to-treat and completer patient populations; the time course of effect was analyzed in the completer patient population. Results. Of the 351 patients enrolled, 263 (75%) completed the 6-month treatment period. The withdrawal rates were 35 (20%) and 53 (30%) in the placebo and SSZ groups, respectively. In the intent-to-treat analysis of end point efficacy, the between-treatment difference reached statistical significance only for 1 of the 4 primary outcome variables, the patient's overall assessment of disease activity, for which 60% of the patients taking SSZ improved by at least 1 point on a 5-point scale, in contrast to 44% of the patients taking placebo. Laboratory markers of inflammation also showed statistically significant change in favor of SSZ. In subgroup analysis, the most impressive effects were seen in patients with psoriatic arthritis, both for the 4 primary efficacy variables and for secondary efficacy variables such as the number of inflamed joints. Adverse events were more frequent in the SSZ group than the placebo group, but all were transient or reversible after cessation of treatment. Conclusion. The results of this study show that SSZ had greater efficacy than placebo in the treatment of active spondylarthropathy, notably in patients with psoriatic arthritis.     

Association of increased interferon‐inducible gene expression with disease activity and lupus nephritis in patients with systemic lupus erythematosus

Objective

To study 5 type I interferon (IFN)–inducible genes (LY6E, OAS1, OASL, MX1, and ISG15) in patients with systemic lupus erythematosus (SLE) and to correlate expression levels with disease activity and/or clinical manifestations.

Methods

Peripheral blood cells were obtained from 48 SLE patients, 48 normal controls, and 22 rheumatic disease controls, and total RNA was extracted and reverse transcribed into complementary DNA. Gene expression levels were measured by real‐time polymerase chain reaction, standardized to a housekeeping gene, and summed to an IFN score. Disease activity was determined by the Safety of Estrogens in Lupus Erythematosus: National Assessment–Systemic Lupus Erythematosus Disease Activity Index (SELENA‐SLEDAI) composite.

Results

Each gene was highly expressed in SLE patients compared with normal controls (P ≤ 0.0003) or disease controls (P ≤ 0.0008 except for MX1). IFN scores were positively associated with the SELENA‐SLEDAI instrument score (P = 0.001), the SELENA‐SLEDAI flare score (P = 0.03), and the physician's global assessment score (P = 0.005). Compared with patients without nephritis, lupus nephritis patients had higher IFN scores (overall P < 0.0001), especially during active renal disease. IFN scores were weakly associated with neurologic manifestations. Elevated IFN scores were positively associated with the current presence of anti–double‐stranded DNA (anti‐dsDNA) antibodies (P = 0.007) or hypocomplementemia (P = 0.007). LY6E expression levels distinguished active from inactive lupus nephritis (P = 0.02) and were positively associated with proteinuria (P = 0.009).

Conclusion

The 5 IFN‐inducible genes were highly expressed in SLE patients, and increased levels were correlated with disease activity defined by several methods. IFN scores, or LY6E levels, were elevated in lupus nephritis patients, especially during active renal disease, and in patients with anti‐dsDNA antibody positivity and hypocomplementemia. IFN scores, or LY6E levels, may be useful as a biomarker for lupus nephritis therapy.

     

Meaningful improvement criteria sets in a rheumatoid arthritis clinical trial

Objective. To compare 3 sets of criteria for meaningful improvement in a rheumatoid arthritis (RA) clinical trial, and to evaluate the implications of these criteria sets for RA trial design. Methods. Data were obtained from the Minocycline in Rheumatoid Arthritis (MIRA) trial (primary outcome measures: 50% improvement in joint tenderness and 50% improvement in joint swelling, based on joint scores). These MIRA data were evaluated against 1) the Paulus criteria (20% improvement in 4 of 6 measures: joint tenderness scores, joint swelling scores, physician's and patient's global assessments, erythrocyte sedimentation rate [ESR], and morning stiffness); and 2) the American College of Rheumatology (ACR) criteria (20% improvement in joint tenderness and joint swelling counts, and in 3 of 5 other measures: physician's and patient's global assessments, ESR, modified Health Assessment Questionnaire, and patient's pain assessment). The ACR criteria were modified using 3 of 4 remaining measures, since baseline pain assessment data were not available. Results. Percentages of minocycline-treated patients versus placebo-treated patients showing meaningful improvement were as follows: by MIRA criteria, for joint tenderness, 56% versus 41% (P = 0.021), and for joint swelling, 54% versus 39% (P = 0.023); by Paulus criteria, 41% versus 28% (P = 0.040); and by ACR criteria, 44% versus 26% (P = 0.004). Both the modified ACR criteria and the Paulus criteria demonstrated a reduced placebo response rate. Compared with the MIRA criteria, the ACR criteria increased, and the Paulus criteria decreased, absolute between-group differences in improvement; however, both criteria sets increased relative percentages of patients showing improvement in the minocycline group versus the placebo group. Study design considerations indicated that application of the ACR criteria would reduce the required sample size. Conclusion. Different placebo response rates and treatment group differences were found using the 3 RA improvement criteria sets. These findings support the use of the ACR criteria for defining improvement in RA clinical trials.     

Double-blind, randomized, placebo-controlled pilot study of leflunomide in systemic lupus erythematosus

Twelve systemic lupus erythematosus (SLE) patients with mild to moderate disease activity (SLEDAI of > or = 6 and on prednisolone < 0.5 mg/kg/day) were included in a prospective, randomized, double-blind, placebo-controlled pilot study for 24 weeks. Six were randomized to receive oral leflunomide and six received placebo. Primary outcome of this study included the mean change of SLEDAI at 24 weeks. Secondary outcomes included the changes in proteinuria, complement levels, anti ds-DNA binding, and prednisolone dosage. The mean age of the 12 patients was 41+/-9 years, and the mean disease duration was 8.5+/-5.8 years. All were female except one patient. The disease activity of both groups of patients decreased significantly after six months of treatment (14.7+/-6.0 to 3.7+/-2.3 in leflunomide group, P = 0.028, and 9.7+/-3.4 to 5.2+/-4.1 in placebo group, P = 0.027). Reduction in the SLEDAI from baseline to 24 weeks was significantly greater in the leflunomide group than the placebo group (11.0+/-6.1 in the leflunomide group and 4.5+/-2.4 in the placebo group respectively, P = 0.026). Minor adverse events included transient elevation in ALT, hypertension and transient leucopenia. In summary, leflunomide was more effective than placebo in treating SLE patients with mild to moderate disease activity and was safe and well-tolerated.     

Dehydroepiandrosterone suppresses interleukin 10 synthesis in women with systemic lupus erythematosus

OBJECTIVE: To study the effects of dehydroepiandrosterone (prasterone, DHEA) 200 mg/day on cytokine profiles in adult women with active systemic lupus erythematosus (SLE). METHODS: In a double blind, randomised, placebo controlled study conducted as part of a larger multicentre study, 30 adult women with active SLE received oral DHEA 200 mg/day or placebo for 24 weeks. Baseline prednisone (<10 mg/day) and other concomitant SLE medications were to remain constant. The levels of cytokines including interleukin (IL) 1, IL2, interferon gamma, IL4, and IL10 were determined by ELISA. The mean change from baseline to 24 weeks of therapy was analysed. RESULTS: The two groups (DHEA n = 15; placebo n = 15) were well balanced for baseline characteristics. Only IL1beta and IL10 could be detected in the serum of lupus patients; however, there was no significant mean (SD) difference in serum IL1beta before and after treatment (9.94 (8.92) v 9.20 (6.49) pg/ml). IL10 demonstrated a greater and significant reduction from baseline (9.21 (9.66) to 1.89 (1.47) pg/ml in the DHEA treatment group). CONCLUSIONS: In a 24 week study of adult Chinese women with mild to moderate SLE, treatment with DHEA 200 mg once daily resulted in significant reduction of serum levels of IL10. This finding may suggest why DHEA could significantly reduce lupus flares.     

Decreases in anti–double‐stranded DNA levels are associated with concurrent flares in patients with systemic lupus erythematosus

Objective

To determine the degree to which changes in anti–double‐stranded DNA (anti‐dsDNA), as determined by Crithidia and enzyme‐linked immunosorbent assays (ELISAs), precede or coincide with changes in systemic lupus erythematosus (SLE) activity, as measured by 5 clinical indices, the physician's global assessment (PGA), modified SLE Disease Activity Index (M‐SLEDAI), modified Lupus Activity Index (M‐LAI), Systemic Lupus Activity Measure (SLAM), and the modified British Isles Lupus Assessment Group (M‐BILAG).

Methods

Disease activity and anti‐dsDNA were measured monthly in 53 SLE patients who were followed up for 1 year. Lupus flare was defined as an increase in PGA of ≥1.0, M‐SLEDAI ≥3, M‐LAI ≥0.1, SLAM ≥3, and M‐BILAG ≥4 within a 1‐month period. Flare rates were calculated for groups, which were defined by “previous” (1 month prior to the flare) or “concurrent” (at the time of the flare) changes in anti‐dsDNA. Logistic regression models were used to determine the significance of the association between recent changes in anti‐dsDNA and flare, controlling for the prednisone dosage.

Results

Flares occurred at 12% of visits, based on the PGA measure of disease activity. Using the other indices, flare rates were 19% (M‐SLEDAI), 25% (M‐LAI), 13% (SLAM), and 12% (M‐BILAG). A concurrent decrease in anti‐dsDNA (ELISA) was associated with significantly higher flare rates based on PGA (18 of 84, 21%; P = 0.0014), M‐SLEDAI (27 of 89, 30%; P = 0.0019), M‐LAI (37 of 89, 42%; P = 0.0001), and M‐BILAG (19 of 89, 21%; P = 0.0264) scores. Flare rates were also significantly higher after a previous increase in anti‐dsDNA (ELISA) based on M‐SLEDAI (26 of 93, 30%; P = 0.0022) and M‐LAI (34 of 93, 37%; P = 0.0117) scores. Flare rates tended to be lowest when there was a concurrent increase in anti‐dsDNA (ELISA). Analysis of specific organ systems showed that a concurrent decrease in anti‐dsDNA (ELISA) was significantly associated with increases in renal disease activity. Similar results were obtained using the Crithidia assay.

Conclusion

A previous increase in anti‐dsDNA levels occurred before SLE flares, as measured by the M‐SLEDAI and M‐LAI only. However, during lupus flares, including the subset of renal flares, anti‐dsDNA levels frequently decreased. We hypothesize that this decrease in anti‐dsDNA represents deposition in tissue at the time of flare.

     

Pilot clinical study of Adacolumn cytapheresis in patients with systemic lupus erythematosus

The aim of this study is to investigate the clinical effects of cytapheresis using the Adacolumn system (selective removal of circulating monocytes and granulocytes by means of an extracorporeal type column) in patients with active systemic lupus erythematosus (SLE). An open uncontrolled multicenter pilot study was conducted in 18 SLE patients who were showing a SLEDAI score of 8 or more under conventional medication. Patients with lupus nephritis (>class 1, WHO classification) were excluded. Extracorporeal cytapheresis with the Adacolumn system was administered once a week for five consecutive weeks. The efficacy of the treatment was evaluated using the SLEDAI for 10 weeks after the first cytapheresis session. The median SLEDAI decreased from 16 at baseline to six at week 11 (10 weeks after the first apheresis) (p<0.001). Significant improvements in musculoskeletal and dermal systems were observed. Arthritis and alopecia were present in 14 and nine patients at baseline and this number decreased to five and one patients, respectively by week 11.Three mild and one moderate adverse events out of the 42 reported events were judged ‘probably related’ to the treatment; no serious adverse events were reported. Selective removal of monocytes and granulocytes from the blood in an extracorporeal circulation system was associated with clinical improvement in this small series of patients with SLE. Since this approach seems not to have the disadvantages of pharmacological immunosuppression, further controlled studies of Adacolumn cytapheresis are warranted in SLE.     

Experience with monthly, high-dose, intravenous immunoglobulin therapy in patients with different connective tissue diseases

We aimed to investigate the efficacy and safety profile of high-dose intravenous immunoglobulin (HD-IVIG) therapy in patients with severe systemic lupus erythematosus (SLE), inflammatory muscle disease (IMD), Wegeners granulomatosis (WG), and/or concurrent infection who failed to respond to standard therapies. We evaluated the records of eight patients with SLE, eight with IMD, and four with WG who were treated with HD-IVIG (2 g/kg per month for 1–12 months) for active disease in 19 patients and concurrent infection in three (mycobacterial in two with SLE and cytomegaloviral in one with WG). Systemic lupus erythematosus disease activity index (SLEDAI) scores before and after HD-IVIG were statistically analysed. Remission was achieved in 14 cases (70%). The SLEDAI scores significantly decreased in patients with SLE (P=0.02). No serious side effect was observed. High-dose IVIG may be used as an adjunctive treatment in connective tissue diseases that do not respond to standard therapies or as alternative treatment for patients with concurrent severe infections or for whom immunosuppressives are contraindicated.     

Sifalimumab,a Human Anti–Interferon‐α Monoclonal Antibody,in Systemic Lupus Erythematosus: A Phase I Randomized,Controlled, Dose‐Escalation Study

Objective

To evaluate the safety and tolerability of multiple intravenous (IV) doses of sifalimumab in adults with moderate‐to‐severe systemic lupus erythematosus (SLE).

Methods

In this multicenter, double‐blind, placebo‐controlled, sequential dose‐escalation study, patients were randomized 3:1 to receive IV sifalimumab (0.3, 1.0, 3.0, or 10.0 mg/kg) or placebo every 2 weeks to week 26, then followed up for 24 weeks. Safety assessment included recording of treatment‐emergent adverse events (AEs) and serious AEs. Pharmacokinetics, immunogenicity, and pharmacodynamics were evaluated, and disease activity was assessed.

Results

Of 161 patients, 121 received sifalimumab (26 received 0.3 mg/kg; 25, 1.0 mg/kg; 27, 3.0 mg/kg; and 43, 10 mg/kg) and 40 received placebo. Patients were predominantly female (95.7%). At baseline, patients had moderate‐to‐severe disease activity (mean SLE Disease Activity Index score 11.0), and most (75.2%) had a high type I interferon (IFN) gene signature. In the sifalimumab group versus the placebo group, the incidence of ≥1 treatment‐emergent AE was 92.6% versus 95.0%, ≥1 serious AE was 22.3% versus 27.5%, and ≥1 infection was 67.8% versus 62.5%; discontinuations due to AEs occurred in 9.1% versus 7.5%, and death occurred in 3.3% (n = 4) versus 2.5% (n = 1). Serum sifalimumab concentrations increased in a linear and dose‐proportional manner. Inhibition of the type I IFN gene signature was sustained during treatment in patients with a high baseline signature. No statistically significant differences in clinical activity (SLEDAI and British Isles Lupus Assessment Group score) between sifalimumab and placebo were observed. However, when adjusted for excess burst steroids, SLEDAI change from baseline showed a positive trend over time. A trend toward normal complement C3 or C4 level at week 26 was seen in the sifalimumab groups compared with baseline.

Conclusion

The observed safety/tolerability and clinical activity profile of sifalimumab support its continued clinical development for SLE.

     

Evaluating systemic lupus erythematosus disease activity using molecular markers of hemostasis

Objective. To determine the usefulness of measuring sensitive markers of the coagulation–fibrinolysis system (i.e., thrombin–antithrombin III complex [TAT], D dimer fragments [DD], and plasmin–α₂-plasmin inhibitor complex [PIC]) for evaluating disease activity in patients with systemic lupus erythematosus (SLE). Methods. We studied 57 SLE patients. Plasma concentrations of DD were measured by latex agglutination using monoclonal antibodies; TAT and PIC were determined by sandwich enzyme-linked immunosorbent assay. Disease activity was determined by using the SLE Disease Activity Index (SLEDAI). Results. Levels of TAT, DD, and PIC were higher in SLE patients than in healthy controls (P < 0.05). Levels of TAT and DD showed good correlations with SLEDAI scores (for TAT r = 0.66, P < 0.001; for DD r = 0.50, P < 0.001). Elevated levels of TAT, DD, and PIC were decreased following treatment. Conclusion. These results strongly suggest that measurement of molecular markers of hemostasis is useful for evaluating disease activity in patients with SLE.     

Antinuclear antibodies measured by enzyme immunoassay in patients with systemic lupus erythematosus: relation to disease activity

To evaluate the correlation between measurements of antinuclear antibodies serum levels by enzyme immunoassay (ANA-EIA), and the degree of systemic lupus erythematosus disease activity. To retest the performance of the test compared to measurement of antinuclear antibodies by immunofluorescence (ANA-IIF). Eighty-five sera from 71 patients with SLE were tested. Demographic, clinical, laboratory, and SLEDAI status were collected. The sera were tested for ANA-EIA and by ANA-IIF at 1:40 and 1:160 dilutions. Serum levels of ANA-EIA were compared to the overall SLEDAI score and to each of its components. A SLEDAI score of ≥6 was considered clinically significant. The sera of fifty-one healthy volunteers served as controls. Serum levels of ANA-EIA were significantly higher in patients with a SLEDAI score of ≥6 compared to the group of patients with a SLEDAI score of <6 (P = 0.004). High serum levels of ANA-EIA correlated significantly with elevated anti DS-DNA antibodies (P < 0.001), low C₃ or C₄ levels (P < 0.001), pyuria (P < 0.011), arthritis (P = 0.019), and new rash (P = 0.019). Levels of ANA-EIA were significantly higher in patients tested positive by IIF compared to those who tested negative. Higher serum levels of ANA-EIA correlated with clinically significant disease activity in patients with SLE. Higher serum levels of ANA-EIA also correlated with some single items of the SLEDAI. The results also reiterated the validity of ANA-EIA testing in patients with SLE. Further longitudinal studies are needed in order to test the hypothesis that serum ANA-EIA levels might reflect fluctuations in disease activity.     

Mycophenolic acid area under the curve correlates with disease activity in lupus patients treated with mycophenolate mofetil

Objective

Mycophenolic acid (MPA) is the active metabolite of mycophenolate mofetil (MMF), which is widely used to treat systemic lupus erythematosus (SLE). In transplantation, MPA area under the plasma concentration–time curve from 0 to 12 hours (MPA AUC_0–12) is correlated with clinical outcome. We undertook the present study to assess possible relationships between SLE activity and MPA AUC_0–12.

Methods

Using a Bayesian estimator, MPA AUC_0–12 was determined in 71 consecutive SLE patients (61 women and 10 men; mean ± SD age 34 ± 10 years) receiving a stable MMF dose. On the same day, SLE activity was assessed using the SLE Disease Activity Index (SLEDAI; active disease defined as a SLEDAI score ≥6) and the British Isles Lupus Assessment Group (BILAG) index (active disease defined as BILAG A or B).

Results

Two groups were studied: patients with active SLE (mean ± SD SLEDAI score 11.6 ± 4.4; n = 26) and patients with inactive SLE (mean ± SD SLEDAI score 1.9 ± 1.6; n = 45). MPA AUC_0–12 correlated weakly with the dose of MMF (r = 0.33, P = 0.005). Mean ± SD MPA AUC_0–12 in the group with active SLE was significantly lower than that in the group with inactive SLE (26.8 ± 13.6 μg.hour/ml versus 46.5 ± 16.3 μg.hour/ml; P < 0.0001). MPA AUC_0–12 was negatively correlated with the SLEDAI (r = –0.64, P < 0.0001). In multivariate analysis, MPA AUC_0–12 was the sole parameter associated with SLE activity (odds ratio 0.89 [95% confidence interval 0.83–0.96], P = 0.002). The MPA AUC_0–12 threshold value of 35 μg.hour/ml was associated with the lowest risk of active SLE.

Conclusion

Our data show that SLE activity is strongly correlated with MPA AUC_0–12. An individualized dosing regimen of MMF, with a target AUC_0–12 of 35 μg.hour/ml, should be considered for SLE patients.