Safety of ixekizumab in patients with psoriatic arthritis: data from four clinical trials with over 2000 patient-years of exposure.

OBJECTIVES: Ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin 17A (IL-17A), has shown significant efficacy in the treatment of psoriatic arthritis (PsA) and sustained long-term clinical response without unexpected new safety outcome for an IL-17A inhibitor. Here, we report the updated safety profile of ixekizumab up to 3 years in patients with PsA. METHODS: This is an integrated safety analysis from four clinical trials in patients with PsA who received at least one dose of ixekizumab. Treatment-emergent adverse events (TEAEs) and selected adverse events (AEs) exposure-adjusted incidence rates (EAIRs) per 100 patient-years up to 3 years of exposure are reported. RESULTS: A total of 1401 patients with a cumulative ixekizumab exposure of 2247.7 patient-years were included in this analysis. The EAIR of patients with ≥1 TEAE was 50.3 per 100 patient-years and most TEAEs were mild to moderate in severity. Serious AEs were reported by 134 patients (EAIR=6.0). The most reported TEAEs were nasopharyngitis (EAIR=9.0) and upper respiratory tract infection (EAIR=8.3). Infections in general and injection site reactions were the most common TEAEs; the incidence rates of serious cases were low (EAIR ≤1.2). The EAIRs of malignancies (EAIR=0.7), inflammatory bowel disease (EAIR=0.1) including ulcerative colitis and Crohn's disease, depression (EAIR=1.6), and major adverse cerebro-cardiovascular events (EAIR=0.5) were low. As assessed, based on year of exposure, incidence rates were decreasing or constant over time. CONCLUSIONS: In this analysis, the overall safety profile and tolerability of ixekizumab are consistent with the known safety profile in patients with PsA. No new or unexpected safety events were detected. TRIAL REGISTRATION NUMBER: NCT01695239, NCT02349295, NCT02584855, NCT03151551.

Evaluation of the impact of a nurse-led program of systematic screening of comorbidities in patients with axial spondyloarthritis: The results of the COMEDSPA prospective, controlled, one year randomized trial.

OBJECTIVE: To evaluate the impact of a nurse-led program of systematic screening for the management (detection/prevention) of comorbidities. METHODS: Prospective, randomized, controlled, open, 12-month trial (NCT02374749). PARTICIPANTS: consecutive patients with axial Spondyloarthritis (axSpA) (according to the rheumatologist) THE PROGRAM: A nurse collected data on comorbidities during a specific outpatient visit. In the event of non-agreement with recommendations, the patient was informed and a specific recommendation was given to the patient (orally and in a with a detailed written report). Patients were seen after one year in a nurse-led visit. TREATMENT ALLOCATION: random allocation (i.e. either this program or an educational program not presented here and considered here as the control group). MAIN OUTCOME: change after one year of a weighted comorbidity management score (0 to 100 where 0= optimal management). RESULTS: 502 patients were included (252 and 250 in the active and control groups, respectively): age: 47±12 years, male gender: 63%, disease duration: 14±11y. After one year, no differences were observed in a weighted comorbidity management score. However, the number of patients in agreement with recommendations was significantly higher in the active group for vaccinations (flu vaccination: 28.6% vs. 9.9%, p<0.01; pneumococcal vaccination:40.0% vs. 21.1%,p=0.04), for cancer screening (skin cancer screening: 36.3% vs. 17.2%, p=0.04) and for osteoporosis (bone densitometry performed: 22.6% vs. 8.7%, p<0.01; Vitamin D supplementation initiation: 51.9% vs. 9.4%, p<0.01). CONCLUSIONS AND RELEVANCE: This study suggests the short-term benefit of a single-visit nurse-led program for systematic screening of comorbidities for its management in agreement with recommendations, even in this young population of patients with axSpA.

A randomised, double-blind, placebo-controlled study assessing the efficacy of high doses of vitamin D on functional disability in patients with rheumatoid arthritis.

OBJECTIVES: To evaluate the short-term efficacy of vitamin D (cholecalciferol) supplementation on functional disability in RA patients. METHODS: 1) Patients: RA (ACR 1987 revised criteria) in non-remission (DAS28 >2.6) whose treatment was not expected to be changed over a 3-month period following inclusion and presenting with vitD deficits (serum 25OHD <30ng/mL). 2) Study design: prospective randomised placebo-controlled trial (NCT02243800). 3) Study arms: either vitD ampoules (cholecalciferol 100,000IU) or placebo. 4) Outcome measures: primary: improvement in patients' functional disability using the Health Assessment questionnaire (HAQ); secondary: improvement in DAS28ESR, DAS28CRP, ESR, CRP, RAID score, fatigue (EVA and FACIT), and SF36. RESULTS: Overall, 59 patients were included, 83.1% females, aged 59.8±10.9 years on average, with RA for 17.0±9.7 years. Thirty patients received placebo and 29 vitD. At 6 months, HAQ scores tended to be increased in the placebo group (+0.08±0.25), while slightly numerically decreased in the vitD group (-0.03±0.23) (p=0.11). After adjusting for age, gender, season, and initial vitD status, the between-group difference achieved statistically significance (p=0.046). After adjusting for age, gender, season, and initial vitD status, there was no significant difference in the secondary criteria between the 2 groups except for ESR and CRP (p=0.002 and 0.04, respectively). CONCLUSIONS: In this randomised, double-blind, placebo-controlled clinical trial in patients with RA and VitD deficiency, high doses of cholecalciferol resulted in a statistically significant improvement in functional disability at month 6, which, however, was clinically not relevant.

Vitamin D, disease activity and comorbidities in early spondyloarthritis.

OBJECTIVES: To assess the vitamin D status in patients presenting inflammatory back pain suggestive of axial spondyloarthritis and to assess the relationship between vitamin D status and disease activity/severity; comorbidities at baseline and during the first two years of follow-up. METHODS: DESIR is a prospective, multicentre, observational study. Vitamin D deficiency was defined as <50 nmol/L and severe deficiency less than 25 nmol/L. Clinical variables were collected at each six month interval visits during the two-year follow-up. RESULTS: A total of 700 patients were analysed. The mean vitamin D was 54.2±28.7 nmol/L. Severe deficiency were observed in 11.7% versus 5% in the DESIR cohort versus the French population respectively. In the DESIR cohort, after adjusting for season and ethnicity, vitamin D deficiency remained significantly associated with presence of radiological sacroiliitis, higher ASDAS score and elevated BASDAI. Such association was also found between vitamin D deficiency and the mean value of disease activity/severity parameters during the two-year follow-up. Otherwise, vitamin D deficiency was significantly associated with the presence of baseline abdominal obesity (OR=1.65 [1.05-2.61], p=0.03), low HDL (OR=1.71 [1.14-2.55], p=0.01) and presence of metabolic syndrome (OR=2.20 [1.04-4.64], p=0.03) at baseline. CONCLUSIONS: We found a higher percentage of patients with severe vitamin D deficiency in early axial spondyloarthritis. Vitamin D deficiency was associated with higher disease activity and severity and presence of metabolic syndrome. Further longitudinal studies are required to evaluate the interest of vitamin D supplementation on the long-term outcome of the disease.

Evidence of the symptomatic and structural efficacy of methotrexate in daily practice as the first disease-modifying drug in rheumatoid arthritis despite its suboptimal use: results from the ESPOIR early synovitis cohort.

OBJECTIVE: To describe the use of MTX in early arthritis (EA) in daily clinical practice and to evaluate its 6-month symptomatic efficacy and 12-month structural efficacy. METHODS: Patients included in the French observational ESPOIR cohort were assessed. Evaluation of the symptomatic and structural efficacy was performed by generalized linear regression after adjustment on propensity score (PS) in the group of patients receiving at least 3 months of MTX vs the ones receiving any other treatment except LEF, SSZ or TNF inhibitors. RESULTS: Within the first 6 months of follow-up of 777 EA patients, 59% received a DMARD, which was MTX in 68% (N = 313) of patients. The mean dose of MTX was 12.7 ± 3.8 mg/week. Only 53.7% of the patients received folic acid supplementation. MTX was initiated in patients with more active and severe disease. At 6 months, in unadjusted analysis, patients starting MTX had a significantly higher DAS-28 (3.58 vs 3.23; P = 0.001) and a significantly higher HAQ (0.60 vs. 0.48; P = 0.01) compared with controls. After adjustment by PS, there were no significant differences. Adjustment for the PS also revealed a statistically significant decrease in the radiological progression at 12 months in the MTX group [total Sharp-van der Heijde score (SHS), 1.05 ± 0.29 vs 2.02 ± 0.29, P = 0.025]. CONCLUSION: This study confirms the symptomatic and structural efficacy of MTX in EA in daily practice despite the non-optimal use of MTX, including low doses and infrequent concomitant folic acid supplementation.

[Indications and efficacy of biologics in inflammatory arthritis]. / L'apport et les indications des biothérapies dans les rhumatismes inflammatoires.

Major advances in our knowledge of the pathogenesis of inflammatory arthritis during the last 20 years, including the identification of precise targets of joint inflammation, led to the development of biologic targeted therapies. TNF inhibitors were the first such agents to be approved in rheumatoid arthritis, followed by ankylosing spondylitis and psoriatic arthritis. Later, rituximab, an anti-CD20 B lymphocyte antibody ; abatacept, which inhibits the T cell co-stimulatory CD28-CD80 pathway ; and tocilizumab, an interleukin-6 receptor inhibitor, were launched in rheumatoid arthritis. These biologics have dramatically changed the management and mid- to long-term outcomes of patients with rheumatoid arthritis and spondyloarthritis. Current therapeutic strategies are based on disease activity and severity. International societies such as EULAR and ASAS have published precise recommendations for routine management of these patients.

Non-drug treatment (excluding surgery) in rheumatoid arthritis: clinical practice guidelines.

OBJECTIVES: Because drugs do not halt joint destruction in rheumatoid arthritis (RA), non-drug treatments are an important adjunct to drug treatment. Establishing rules governing their use is difficult because treatment is multidisciplinary, complex, and difficult to assess. The aims of these guidelines were to (a) establish the indications for physical therapies and for educational, psychological, and other non-drug interventions, (b) address social welfare, occupational, and organizational issues. METHODS: A systematic literature search (MEDLINE, EMBASE, CINAHL, Pascal, Cochrane Library, HTA database) (1985-2006) was completed with information obtained from specialty societies and the grey literature. A review of the studies meeting inclusion criteria, with evidence levels, was used by a multidisciplinary working group (18 experts) to draft guidelines. Consensus was reached when evidence was lacking on key topics. The draft guidelines were scored by 60 peer reviewers, amended when necessary, and then validated by the HAS Board. RESULTS: Of the 1819 articles retrieved, 817 were analysed and 382 cited in the report. Low-power randomized clinical trials constituted the highest level of evidence. Grade B guidelines (intermediate evidence level) concerned aerobic activities, dynamic muscular strengthening, and therapeutic patient education. Grade C (low evidence level) concerned use of rest orthoses or assistive devices, balneotherapy and spa therapy, self-exercise programmes, and conventional physiotherapy. Professional agreement (no scientific evidence) was reached for orthotic insoles and footwear, chiropody care, thermotherapy, acupuncture, psychological support, occupational adjustments, and referral to social workers. CONCLUSION: Aerobic activities, dynamic muscular reinforcement, and therapeutic patient education are valuable in non-drug management of RA.

Methotrexate therapy for rheumatoid arthritis: clinical practice guidelines based on published evidence and expert opinion.

OBJECTIVES: To develop clinical practice guidelines for the use of methotrexate in rheumatoid arthritis (RA), using the evidence-based approach and expert opinion. METHODS: A scientific committee used a Delphi procedure to select five questions, which formed the basis for developing recommendations. Evidence providing answers to the five questions was sought in the Cochrane databases, PubMed, and proceedings of meetings of the French Society for Rheumatology, European League Against Rheumatism, and American College of Rheumatology. Using this evidence, a group of rheumatologists developed and validated the recommendations. For each recommendation, the level of evidence and the extent of agreement among experts were specified. RESULTS: The recommendations were as follows: 1: The starting dosage for methotrexate in patients with RA should not be less than 10 mg/week and should be determined based on disease severity and patient-related factors; 2: When a patient with RA shows an inadequate response to methotrexate, the dosage should be increased at intervals of 6 weeks, up to 20 mg/week, according to tolerance and patient-related factors; 3: When starting methotrexate treatment in a patient with RA, preference should be given to the oral route. A switch to the intramuscular or subcutaneous route should be considered in patients with poor compliance, inadequate effectiveness, or gastrointestinal side effects; 4: At present, there is no evidence indicating that a change in methotrexate dosage is in order when a TNF antagonist is given concomitantly; 5: The investigations that are mandatory before starting methotrexate therapy in a patient with RA consist of a full blood cell count, serum transaminase levels, serum creatinine with computation of creatinine clearance, and a chest radiograph. In addition, serological tests for the hepatitis viruses B and C and a serum albumin assay are recommended. In patients with a history of respiratory disease or current respiratory symptoms, lung function tests with determination of the diffusing capacity for carbon monoxide are recommended; 6: Investigations that are mandatory for monitoring methotrexate therapy in patients with RA consist of full blood cell counts and serum transaminase and creatinine assays. These tests should be obtained at least once a month for the first 3 months then every 4-12 weeks; 7: Folate supplementation can be given routinely to patients treated with methotrexate for RA. In practice, a minimal dosage of 5 mg of folic acid once a week, at a distance from the methotrexate dose, is appropriate; 8: In the event of respiratory symptoms possibly related to methotrexate toxicity, the drug must be stopped and symptom severity evaluated. Should evidence of serious disease be found, the patient should be admitted immediately or advice from a pulmonologist should be obtained immediately. CONCLUSION: Recommendations about methotrexate therapy for RA were developed. These recommendations should help to improve practice uniformity and, ultimately, to improve the management of RA.