Economic Evaluation of Sequences of Biological Treatments for Patients With Moderate-to-Severe Rheumatoid Arthritis and Inadequate Response or Intolerance to Methotrexate in France.

OBJECTIVES: Biologic disease-modifying antirheumatic drugs (bDMARDs) are prescribed sequentially in the treatment of rheumatoid arthritis (RA). Healthcare decision makers continue to debate their use, mainly because of their high costs. Our aim was to perform an economic evaluation for France of bDMARD sequences for treatment of moderate-to-severe RA after inadequate response or intolerance to conventional DMARDs (eg, methotrexate). METHODS: A discretely integrated condition event simulation was developed to track the course of patients from first bDMARD through switches to further lines in a sequence. The model included 11 events, 91 conditions, and 21 controlling equations. Inputs were obtained from a meta-analysis of clinical trials, a French registry, national drug lists, and databases. Survival, time with minimal activity, quality-adjusted life-years (QALYs), and total costs were output. Structural and probabilistic sensitivity analyses were conducted. RESULTS: Sequences starting with etanercept biosimilars (ETB) cost less, with ETB-abatacept-infliximab the least expensive: the mean lifetime discounted total cost was €116 912 per patient, with a mean of 11.166 QALYs. Most other strategies were dominated or led to small QALY gains (0.0008-0.0329). Only ETB-tocilizumab-abatacept made it onto the efficiency frontier, but at €955 778 per QALY gained. These results were confirmed in several scenarios and uncertainty analyses. CONCLUSION: Given minor differences in QALYs gained between bDMARD sequences with large cost differences, starting with biosimilars was more efficient than starting with branded products. Our model and findings should provide French and other decision makers with useful tools to address the challenges of comparing sequences of treatments for RA.

Rheumatoid arthritis treated with 6-months of first-line biologic or biosimilar therapy: an updated systematic review and network meta-analysis.

OBJECTIVES: The aim of this study was to estimate the effectiveness of first-line biologic disease modifying drugs(boDMARDs), and their approved biosimilars (bsDMARDs), compared with conventional (csDMARD) treatment, in terms of ACR (American College of Rheumatology) and EULAR (European League against Rheumatism) responses. METHODS: Systematic literature search, on eight databases to January 2017, sought ACR and EULAR data from randomized controlled trials (RCTs) of boDMARDs / bsDMARDs (in combination with csDMARDs, or monotherapy). Two adult populations: methotrexate (MTX)-naïve patients with severe active RA; and csDMARD-experienced patients with moderate-to-severe active RA. Network meta-analyses (NMA) were conducted using a Bayesian Markov chain Monte Carlo simulation using a random effects model with a probit link function for ordered categorical. RESULTS: Forty-six RCTs met the eligibility criteria. In the MTX-naïve severe active RA population, no biosimilar trials meeting the inclusion criteria were identified. MTX plus methylprednisolone (MP) was most likely to achieve the best ACR response. There was insufficient evidence that combination boDMARDs was superior to intensive (two or more) csDMARDs. In the csDMARD-experienced, moderate-to-severe RA population, the greatest effects for ACR responses were associated with tocilizumab (TCZ) monotherapy, and combination therapy (plus MTX) with bsDMARD etanercept (ETN) SB4, boDMARD ETN and TCZ. These treatments also had the greatest effects on EULAR responses. No clear differences were found between the boDMARDs and their bsDMARDs. CONCLUSIONS: In MTX-naïve patients, there was insufficient evidence that combination boDMARDs was superior to two or more csDMARDs. In csDMARD-experienced patients, boDMARDs and bsDMARDs were comparable and all combination boDMARDs / bsDMARDs were superior to single csDMARD.

Baseline laboratory test abnormalities are common in early arthritis but rarely contraindicate methotrexate: study of three cohorts (ESPOIR, VErA, and Brittany).

OBJECTIVE: To evaluate the prevalence of baseline abnormalities in standard laboratory tests in patients with early arthritis and their impact on selection of disease-modifying antirheumatic drugs according to American College of Rheumatology (ACR) recommendations and/or of nonsteroidal anti-inflammatory drugs. METHODS: In three cohorts of patients with early arthritis (the ESPOIR, VErA, and Brittany cohorts), we evaluated the prevalence of anemia (hemoglobin <1 3 g/dL in men and 12 g/dL in women), leukopenia (<3500 per mm(3)), thrombocytopenia (<150000 per mm(3)), renal dysfunction (mild, creatinine clearance [CrCl]=60-89.9 mL/min; moderate, CrCl=30-59.9 mL/min; or severe, CrCl<30 mL/min), liver cytolysis (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]>N or>2N), and systemic inflammation (erythrocyte sedimentation rate [ESR]>20 and C-reactive protein [CRP]>6). RESULTS: We evaluated 1393 patients (1018 women and 375 men). Anemia was present in 363/1366 (26.5%) patients, leukopenia in 18/1372 (1.3%), and thrombocytopenia in 13/1371 (0.9%). ESR elevation was seen in 50.4% of patients and CRP elevation in 62.7%. The level of AST was above normal in 4% and of ALT in 10% of patients. No patient had severe renal dysfunction, 5.6% had moderate renal dysfunction, and 42.6% had mild renal dysfunction. Among the 1094 patients who had undergone all the tests, only 18 (1.64%, 95% confidence interval, 1-2.64) had a formal contraindication to methotrexate therapy according to ACR recommendations (4 had leukopenia, 12 had high ALT levels, and 2 had high ALT and AST levels). CONCLUSION: Patients with recent-onset arthritis often have anemia, mild or moderate renal dysfunction, and abnormal liver function. However, fewer than 2% have laboratory test abnormalities contraindicating methotrexate therapy.

Contribution of the polymyalgia rheumatica activity score to glucocorticoid dosage adjustment in everyday practice.

OBJECTIVE: To evaluate the usefulness of the polymyalgia rheumatica (PMR) activity score (PMR-AS) in guiding adjustment of glucocorticoid (GC) dosage. METHODS: Rheumatologists prospectively included patients receiving GC therapy for PMR. At each visit, they assessed disease activity using a visual analog scale for physician's global assessment (VASph) and recorded whether a flare was diagnosed and/or the GC dosage was changed. In each patient, the PMR-AS was calculated using the formula of Leeb and Bird: C-reactive protein (mg/dl) + VAS pain score (0 to 10) + VASph (0 to 10) + (morning stiffness in min × 0.1) + elevation of upper limbs (0-3). We evaluated the correlation between PMR-AS and GC dosage changes in the group already treated with GC. RESULTS: We included 89 patients (mean age 74.6 ± 6.2 yrs; disease duration 1.6 ± 2.2 yrs), who had a total of 149 visits. PMR-AS was available for 137 visits. Of those, 124 involved patients already treated with GC, and 13 patients who started GC treatment. The Spearman correlation coefficient between PMR-AS values and GC dosage change was 0.58 (p < 0.001). In the group already treated with GC, when the PMR-AS was higher than 20, GC dosages were never decreased. When the PMR-AS was between 10 and 20, GC dosages were decreased in 4 patients, unchanged in 4, and increased by < 5 mg in 4 patients. When PMR-AS was < 10, GC dosages were generally decreased. CONCLUSION: The PMR-AS is helpful for diagnosing flares of PMR and may also assist in everyday practice to decide how to change the GC dosage.

"Beware man's best friend".

STUDY DESIGN: Case report. OBJECTIVE: To illustrate the usefulness of broad-range bacterial polymerase-chain-reaction (PCR) testing in osteoarticular infections by Capnocytophaga canimorsus. SUMMARY OF BACKGROUND DATA: C. canimorsus is a gram-negative bacillus that was first identified in 1976. It is a normal inhabitant of the oral mucosa of dogs (26%) and cats (15%). The main clinical patterns are septicemia, which may cause fatal septic shock (in 30% of cases) but arthritis and discitis are possible. C. canimorsus is susceptible to many antimicrobials including ß-lactam antibiotics. METHODS: About a case report of 54-year-old man transferred to our institution for discitis, we discuss about PCR for C. canimorsus discitis diagnosis. RESULTS: At admission, the only abnormal physical finding was global pain and stiffness of the lumbar spine. Radiographs of the lumbar spine and pelvis showed lumbar spondylosis, degenerative disc disease, and previously known degenerative facet joint disease. Magnetic resonance imaging indicated L3-L4 discitis with damage to both vertebrae and adjacent discs. Findings were negative from blood and urine cultures, serological tests for the HIV and brucellosis, and sputum tests for Mycobacterium tuberculosis. A percutaneous biopsy of the L3-L4 disc was performed but the bacteriological studies recovered no organisms. A second needle biopsy was performed for broad-range 16S rDNA PCR testing, which identified C. canimorsus. CONCLUSION: Broad-range PCR provided the microbiological diagnosis of culture-negative discitis in our patient. Broad-range PCR should be considered in patients with culture-negative osteoarticular infections.

Performance of the polymyalgia rheumatica activity score for diagnosing disease flares.

OBJECTIVE: To evaluate the effectiveness of the polymyalgia rheumatica activity score (PMR-AS) in diagnosing disease flares. METHODS: Rheumatologists prospectively included 89 patients with PMR (mean +/- SD age 74.6 +/- 6.2 years, mean +/- SD disease duration 1.6 +/- 2.2 years). At each visit, the rheumatologist assessed disease activity using a visual analog scale (VAS) and recorded whether a disease flare was diagnosed and/or the glucocorticoid dose changed. Overall, 137 visits including 49 pairs (allowing intraindividual comparisons) were available; a disease flare was diagnosed at 32 visits. We evaluated statistical associations linking flare diagnosis to the PMR-AS, each of its components (VAS, VAS for pain, C-reactive protein, morning stiffness, and elevation of upper limbs), and changes in these parameters between 2 visits. RESULTS: Associations with disease flare diagnosis were strongest for PMR-AS scores > or =9.35 (agreement 92%, 95% confidence interval [95% CI] 85.8-95.7%, kappa = 0.78; sensitivity 96.6%, 95% CI 80.4-99.8; specificity 90.7%, 95% CI 83.2-95.2) and for DeltaPMR-AS scores > or =6.6 (agreement 98%, 95% CI 88.0-99.9%, kappa = 0.95; sensitivity 100%, 95% CI 74.7-100; specificity 97.1%, 95% CI 82.9-99.8). Other parameters showed weaker diagnostic performance. CONCLUSION: This study supplies new evidence that the PMR-AS is useful for monitoring PMR activity in everyday practice and for managing glucocorticoid tapering. PMR activity changes seem even more relevant than absolute values.

Does the BAFF dysregulation play a major role in the pathogenesis of systemic lupus erythematosus?

Given the prominent role currently assigned to B lymphocytes in systemic lupus erythematosus, it is not surprising that the B cell activity factor belonging to the tumor necrosis factor family (BAFF) is involved in its pathogenesis. This cytokine is produced in excess, and inserted into its receptors on the surface of circulating B cells. Up-regulation of BAFF is most likely to lead to breach of tolerance by aberrant survival of B cells directed to the self. Trials aimed at blocking BAFF have thus been set out. Yet the results are awaited.

Outcome of early monoarthritis: a followup study.

OBJECTIVE: To evaluate clinical, laboratory, and radiological features and outcomes in patients with monoarthritis (MA), identified in a cohort of patients with early arthritis. METHODS: A cohort of 270 patients with undiagnosed arthritis of less than 1 year's duration was divided into 3 groups: single episode of MA (MA, n = 27), MA with a history of patient-reported arthritis (MA + past, n = 23), and oligo- or polyarthritis (OA/PA, n = 220). At 6-month intervals, all patients underwent a standardized examination, radiographs, and standard laboratory tests including rheumatoid factors (RF), antiperinuclear factor (APF), antikeratin antibody (AKA), anticyclic citrullinated peptide antibody (anti-CCP), antinuclear antibodies, and HLA-AB-DR typing. After a median followup of 30 months, the diagnosis was evaluated by a hospital-based rheumatologist. RESULTS: Age and sex did not differ across the 3 groups. Knee involvement was more common in the MA group than in the MA + past group (p < 0.03), whereas hand and metatarsophalangeal involvement was less common (p < 0.03 and p < 0.0001, respectively). RF and anti-CCP were less often positive in the MA group than in the MA + past group (p < 0.02 and p < 0.001, respectively) and the OA/PA group (p < 0.02 and p < 0.03). No patient in the MA group received a diagnosis of rheumatoid arthritis (RA). RA was less common and disease modifying antirheumatic drugs were prescribed less often in the MA group than in the other 2 groups (p < 0.0001 for both comparisons). CONCLUSION: The MA group was clearly different from the other groups, with a favorable outcome and no risk of progression to RA.

Usefulness of the disease activity scores for polymyalgia rheumatica for predicting glucocorticoid dose changes: a study of 243 scenarios.

OBJECTIVE: To evaluate associations linking glucocorticoid dose changes in patients with polymyalgia rheumatica (PMR) to the PMR activity score (PMR-AS) and its components. METHODS: Nine clinical vignettes of PMR were written by a panel of experts and submitted to 35 rheumatologists, who were asked to assess disease activity using a visual analog scale (VASph) and to determine whether there was a relapse of PMR requiring an increase in the glucocorticoid dose. In 7 vignettes, >80% of the rheumatologists agreed on the diagnosis of relapse justifying the glucocorticoid dose decision. A total of 243 vignette-physician combinations were obtained. Using these vignettes, we evaluated statistical associations linking a decision to increase the glucocorticoid dose to the value of PMR-AS, of its components (VASph, visual analog scale for pain [VASp], C-reactive protein level [CRP], morning stiffness [MST], and elevation of upper limbs [EUL]), or to the difference in these variables between the last 2 visits (dPMR-AS, dVASph, dVASp, dCRP, dMST, and dEUL). RESULTS: The strongest associations with a decision to increase the glucocorticoid dose occurred with dPMR-AS >4.2, dMST >10 minutes, dVASph >1.55, and dCRP >4 mg/dl (99.3% sensitivity, 100% specificity for all 4 variables); MST >or=10 minutes (100% sensitivity, 99.3% specificity); PMR-AS >or=7 (98.1% sensitivity, 94.3% specificity); VASph >or=2.25 (94.2% sensitivity, 83.6% specificity); and CRP level >or=14.5 mg/liter (66.3% sensitivity, 99.3% specificity). CONCLUSION: Despite inter-individual variations in VASph, PMR-AS was a good indicator of disease activity. However, MST, dMST, dVASph, dPMR-AS, and dCRP performed better than PMR-AS. These variables may be useful in tailoring the glucocorticoid dose to the individual needs of each patient.

Group B streptococcal arthritis.

Recent data suggest that group B streptococcal arthritis is being increasingly diagnosed. We retrospectively reviewed the records of patients admitted to our Teaching Hospital Rheumatology Department for septic arthritis between May 2000 and May 2004 and we reviewed the relevant literature to determine the characteristics of group B streptococcal arthritis. We compared age, hospital stay duration, and number of joints involved in the patients with group B streptococcal arthritis and in those with septic arthritis due to other organisms. Of 48 consecutive patients with septic arthritis, five (10.4%) had arthritis due to group B streptococci. Mean age of these five patients was 51.6+/-18.3 years and mean hospital stay duration was 13.2+/-9.23 days. Arthritis distribution was oligoarticular in three patients, polyarticular in one patient, and monoarticular in one patient. The mean number of involved joints was significantly (P=0.005) higher in the patients with group B streptococcal arthritis than in the other patients (2.6+/-1.5 vs 1.1+/-0.4 joints). Age and hospital stay duration were not significantly different. The frequently oligoarticular or polyarticular distribution of group B streptococcal arthritis, together with the sometimes limited symptoms, may lead to diagnostic wanderings or delays.