Infliximab Therapy in Patients With Refractory Polymyalgia Rheumatica: a Double Blind Placebo Controlled Trial
Infliximab Therapy in Patients With Refractory Polymyalgia Rheumatica: a Double Blind Placebo Controlled Trial
Rheumatic Polymyalgia(PMR) is a relatively common chronic inflammatory disorder of unknown origin which predominantly develops in elderly subjects and presents with severe pain and stiffness in the neck, shoulder and pelvic girdles, along with increased acute phase reactants. Systemic manifestations such as fever, anorexia and weight loss are characteristic signatures of PMR.
Corticosteroids (CS) constitute the standard treatment of PMR. Although in most patients the symptoms of the disease disappear after one or two years of treatment, a proportion of patients remain CS-dependent with the subsequent CS toxicity. Open label studies have suggested that tumour necrosis factor (TNF) antagonists lead to sustained improvement and CS sparing effect in patients with refractory PMR.
The investigators conducted a randomised, double-blind, placebo controlled trial with infliximab in CS-dependent patients with PMR. Patients with CS-dependent PMR (defined as requiring ≥ 5 mg/day after at least 2 years of treatment to maintain remission or ≥ 7.5 mg/day after at least 6 months) were randomly assigned to receive Infliximab (5 mg/kg i.v) at 0, 2, 6, 14 and 22 weeks (n = 12) or placebo (n = 11) together with CS that were reduced according to a predefined schedule. The primary outcome was the proportion of responder patients -defined as individuals with both complete clinical and analytical remission without receiving CS for at least three months- at 24 weeks. Secondary outcomes were cumulative CS doses and adverse events proportion.
The duration of the study will be 1 year, and it will be divided in several phases:
A) Initial phase (double-blind trial): Between week 0 and week 24. Placebo or Infliximab at a dose of 3 mg/kg/day at weeks 0, 2 and 6.
After the screening process, patients who meet the inclusion/exclusion criteria of the protocol will be randomized to receive three infusions of placebo or infliximab as previously described.
After the first infusion (week 0), the prednisone dose will be tapered according to the following schedule: Prednisone (or equivalent) should be decreased at a rate of 1.25 mg per week until complete withdrawal of corticosteroids. In case of relapse, the dose of prednisone will be increased up to the previous dose that controlled the symptoms of PMR, and after 4 weeks of stable dose, prednisone will be again tapered but with a slower schedule: 1.25 mg every 2 weeks until complete withdrawal of corticosteroids. In case of a new relapse, the dose of prednisone will be managed according to the physician criteria.
B) Extension phase (open trial): Between week 24 and week 48. Infliximab at a dose of 3 mg/kg/day at weeks 24, 26 and 30.
At 24 weeks, all the patients included into the trial and still on corticosteroid therapy with or without clinical manifestations of PMR, will receive three infusions of infliximab according to the previous described schedule.
After the first infusion (week 24) the dose of prednisone will be decreased according to the same schedule previously described in the initial phase of the trial.
The schedule therapy proposed in the extension phase is going to be for:
After the first infusion (week 24), it will be reduced prednisone dose following same regimen described in the clinical phase of the study.
Treatment duration.
•Study will be administrate for 24 + 24 weeks. In the end of the study the patient will continue treatment the most efficacy in the investigator opinion.
Objectives:
Primary objective: Proportion of responders (complete remission without corticosteroids) at 24 weeks.
Secondary objectives:
I) CLINICAL ASSESSMENT:
Evaluations will be performed at screening, baseline, every 2 weeks during the first 2 months of treatment and monthly thereafter.
The following data will be recorded at each visit:
All patients will have a PPD test and chest X-rays performed at screening following the current recommendations for anti-TNF therapy (50-52). Those patients with a positive PPD test (induration ≥ 5 mm) or with chest X-ray images showing lesions consistent with latent tuberculosis infection, will have prophylactic treatment with isoniazid, 300 mg daily during 9 months (in case of isoniazid toxicity: rifamycin, 600 mg/day during four months).
In addition, the patients will be instructed to the possible development of infections and other side effects, and new manifestations of GCA, which should be immediately reported to the attending physician.
II) SERUM CYTOKINE STUDY During the study period and after informed consent, patients will be asked to provide a serum sample (around 200 ml) at 7 different time points (week 0 or pre-treatment, and weeks 2, 6, 24, 26, 30 and 48). The blood will be obtained at the same time that the scheduled venipuncture for routine tests.
The analysis will be done using a Cytometric Bead Array (CBA) methodology. The investigators will use the CBA Flex Set system (Becton Dickinson) that includes the following cytokines: IL-1, IL-6, TGF-beta, TNF-alfa, IL-10, IL-12, IL-2, IL-4, IFN-gamma. Following acquisition of sample data using the FACSCalibur flow cytometer (Becton Dickinson), the sample results are generated in graphical and tabular format using the CBA Analysis Software (Becton Dickinson).
Group I:
Infliximab 5 mg/kg. i.v. at week 0, 2, 6, 14 and 22.
Group II:
Infliximab Placebo i.v. weeks 0, 2, 6, 14 and 22.
Extension Phase (weeks 24-48):
Responders at week 24: Treatment discontinuation (GROUP A).
No-responders at week 24:
Inclusion Criteria:
PMR patients that after 2 years of corticosteroid treatment are not able to reduce the dose of prednisone below 5 mg/day or equivalent.
PMR patients that after 6 months of corticosteroid treatment are not able to reduce the dose of prednisone below 7,5 mg/day or equivalent.
PMR patients should fulfill the criteria proposed by Chuang et al (8):
Exclusion Criteria: