On 16 December 2020, FDA approved Benlysta® (belimumab) for both the intravenous (IV) and subcutaneous (SC) administration routes for the treatment of adult patients with active lupus nephritis (LN) ...who are receiving standard therapy. This approval represents the first FDA approved treatment of patients with active LN.
The approved IV dosing regimen (10 mg/kg dose Q2W for three doses, then 10 mg/kg Q4W thereafter) was based on a randomized double-blind placebo controlled clinical trial in adult patients with LN. For the approval of the SC dosing regimen (400 mg dose QW for four doses, then 200 mg QW thereafter), efficacy was supported solely by pharmacokinetics (PK) modeling and simulation which estimated a matched steady state average concentration and higher trough concentrations for the SC administration route, for bridging to the efficacy of IV belimumab in adults with LN. The safety and immunogenicity profile of the SC administration route has been assessed in the SLE studies.
In a population PK analysis, higher proteinuria was associated with greater belimumab clearance and lower belimumab exposure. In an exposure response analysis, the efficacy of belimumab as evaluated by renal response was mainly driven by patients with lower proteinuria at baseline regardless of other baseline characteristics (e.g. baseline renal function, renal biopsy classification), induction therapies, or belimumab exposure levels (within 10 mg/kg dosing regimen), etc. However, post hoc analyses showed that belimumab had activity in LN patients with higher proteinuria at baseline. There is no adequate information to suggest that a higher dose would provide additional benefit for patients with lower exposure (e.g. higher proteinuria).
There is a known drug interaction (DI) between xanthine oxidase (XO) inhibitors and the thiopurine immunosuppressants, azathioprine (AZA) and mercaptopurine (6-MP). Xanthine oxidase inhibition ...increases concentrations of AZA and 6-MP active metabolites, possibly resulting in myelosuppression. When allopurinol is used with AZA or 6-MP, dose reduction of AZA or 6-MP is recommended. Febuxostat is a newer XO inhibitor approved for the treatment of gout.
To determine the clinical impact of the febuxostat-thiopurine DI.
Case series derived from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) and published medical literature.
Nineteen patients who received concomitant febuxostat and either AZA or 6-MP.
Laboratory and clinical data.
Nineteen cases reporting myelosuppressive events were identified in patients receiving febuxostat with AZA or 6-MP. Eighteen cases were treated with the combination of AZA and febuxostat. A median of 1.6 months elapsed from initiation of the drug combination until discovery of the event. Sixteen cases required hospitalization; 15 reported administration of blood products. Thirteen cases reported resolution of the event with discontinuation of both drugs, two reported discontinuation of the thiopurine only, and one reported discontinuation of febuxostat only.
Thiopurine monotherapy may cause myelosuppression. Complications of immunosuppression that may contribute to the real-world morbidity and mortality associated with the febuxostat-thiopurine DI were not examined. Finally, FAERS data are limited by the voluntary nature of reporting.
Current febuxostat labeling contraindicates concomitant administration of febuxostat with either AZA or 6-MP. This case series demonstrates that the DI can result in clinically significant adverse events and is supportive of current febuxostat labeling.
Purpose
To describe the use of tumor necrosis factor‐alpha inhibitors (TNFis) among pregnancies ending in a live birth and with a diagnosis of ankylosing spondylitis (AS), Crohn's disease (CD), ...juvenile idiopathic arthritis (JIA), psoriasis (PsO), psoriatic arthritis (PsA), rheumatoid arthritis (RA), or ulcerative colitis (UC).
Methods
We identified pregnancies among women aged 15 to 54 years between 01/01/2004 and 09/30/2015 from 16 health plans participating in Sentinel. We inferred indication using ICD‐9‐CM codes in the 183‐day period before conception. We assessed proportion of infliximab, etanercept, adalimumab, certolizumab pegol, and golimumab by calendar year, indication, and maternal age, and compared them to proportions in an age‐matched, indication‐matched, and date‐matched non‐pregnant cohort.
Results
Among 19 681 pregnancies with at least one chronic inflammatory condition, 2990 (15.2%) received a TNFi. In both pregnancies and matched non‐pregnant cohort, TNFi use was highest (34.4%; 55.8%) for PsA patients and lowest (6.2%; 13.4%) for PsO patients. Etanercept was most frequently used among AS/JIA/PsA/PsO/RA patients, while infliximab was the preferred TNFi for CD/UC patients. Except for infliximab and certolizumab, TNFi use during pregnancy decreased after the first trimester. Pregnancies among older pregnant women (45‐54 years) were more likely to be treated compared with the matched non‐pregnant cohort.
Conclusion
There was a preference for etanercept among pregnancies with AS/JIA/PsA/PsO/RA, despite the availability of other TNFis. Decline in TNFi use after the first trimester may be related to the desire to reduce TNFis transplacental transfer and to minimize infection risk to the fetus or baby associated with live vaccine immunizations after birth.
Objective. To compare the relative safety and efficacy of naproxen and acetaminophen in the treatment of osteoarthritis (OA) of the knee. The major outcome measures were radiographic progression and ...withdrawal from the trial due to lack of efficacy.
Methods. One hundred seventy‐eight patients with OA of the knee were enrolled in a 2‐year prospective, controlled, double‐blind multicenter trial and were randomly assigned to receive acetaminophen (ACT) or naproxen (NPX) treatment.
Results. After 6 weeks of treatment, modest improvement in pain on motion and in physician's global assessment was seen in both the ACT and the NPX groups, and the NPX group also had modest improvement in pain at rest and in 50‐foot walk time. Sixty‐two patients completed the 2‐year study. Among these patients, radiographic progression was similar in the 2 treatment groups. Withdrawal from the trial due to lack of drug efficacy was slightly more frequent among patients in the ACT group (22% versus 16%), but withdrawal due to adverse drug effects was slightly more common in the NPX group (23% versus 18%).
Conclusion. The efficacy of ACT treatment and NPX treatment was similar, although it was slightly better for NPX. The toxicity rate was slightly lower with ACT. However, the high rate of withdrawal in both treatment groups suggests that neither is satisfactory for the treatment of OA.
To review the diagnoses after 5 years in patients who were identified within 12 months of the onset of well established and undifferentiated connective tissue diseases (CTD); to examine death rates ...and disease remissions in these patients.
This inception cohort of 410 patients was identified in 10 academic rheumatology practices. They had less than one year of signs and/or symptoms of CTD. Diagnoses of specific well established CTD were made using accepted diagnostic and classification criteria. The diagnoses after 5 years were determined.
Patients with well established CTD tended to remain with the original diagnosis. The progression of unexplained polyarthritis to rheumatoid arthritis occurred infrequently. Ten percent of patients with isolated Raynaud's phenomenon progressed to systemic sclerosis (SSc). The 5 year survival was over 90% in all diagnostic categories, with the exception of SSc, in which it was 64%.
Patients with a well established CTD usually continued with the same diagnosis. Patients with undifferentiated CTD tended to remain undifferentiated or to remit.
To assess radiographically determined disease progression in patients in the Minocycline in Rheumatoid Arthritis (MIRA) Trial.
A double blind, randomized, multicenter, 48 week trial of oral ...minocycline (200 mg/day) or placebo in 6 clinical centers in the United States. Patients include 219 adults with active RA previously receiving limited treatment with disease modifying drugs. Posteroanterior films of the hands from baseline and final visits, blinded for sequence, were read for erosions and joint space narrowing by trained observers. Outcomes included rate of disease progression (change/month) and percentage of patients with progression from baseline, newly involved joints, and newly erosive disease.
Using intent-to-treat analyses, progression rates for erosions (0.11 +/- 0.42 minocycline, 0.17 +/- 0.41 placebo; p = 0.47) and joint space narrowing (0.16 +/- 0.55 minocycline and 0.23 +/- 0.71 placebo; p = 0.14) were similar. (Power 43% to detect a 50% difference.) Newly erosive joints occurred more frequently in the placebo group (44 vs 32%; p = 0.08), not a statistically significant difference.
Radiographic measurement of disease progression using 4 measures failed to show a significant difference between minocycline and placebo treatment, although for all methods there was a trend toward treatment benefit, consistent with reported clinical results. A one year trial duration, high measurement variability, and slow rate of radiographic progression in this cohort may explain the low power to detect a treatment effect. The measurement that denoted "newly involved" joints was most sensitive in detecting change. In future trials longer term assessment (minimum 2 years) of radiographic changes and further comparison of measures of disease progression are warranted.
Objective. To examine the effect of alleles encoding the “shared”/“rheumatoid” epitope on rheumatoid arthritis (RA) disease severity in patients who participated in the minocycline in RA (MIRA) ...trial.
Methods. Of 205 patients with a week‐48 visit, blood was available for typing of HLA‐DRB1 and HLA‐DQB1 in 174 (85%) and successfully completed in 169 (82%). Baseline erosions were used to assess disease severity and new erosions at the last visit served as a proxy for progression.
Results. At baseline, there was no association between the presence of erosive disease or rheumatoid factor status and the dose of rheumatoid epitope (homozygous, heterozygous, none) or the specific alleles identified. At the final visit, a gradient was observed for the 3 allelic subgroups (and their gene doses) in the occurrence of new erosions among the Caucasian placebotreated, but not the minocycline‐treated, patients. A treatment group/HLA‐DR4 epitope interaction was demonstrated in multivariate analyses. Approximately two‐thirds of African‐American patients did not have the rheumatoid epitope.
Conclusion. HLA‐DRB1 oligotyping may be useful in predicting the progression of disease in some Caucasian patients. Our study corroborates the infrequency of the epitope among African‐American patients with RA.
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.
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