Efficacy of Subcutaneous Injection of Etanercept for Moderate and Severe Knee Osteoarthritis

Primary aim: evaluate efficacy of subcutaneous injection of etanercept for moderate and severe knee osteoarthritis.

Second aim: investigate the potentiality of serum cytokines (TNF-α, Interleukin 1-α (IL1-α), IL1-β, matrix metalloproteinases1 (MMP1), MMP13) to predict the response of subcutaneous injection of etanercept for moderate and severe knee osteoarthritis.

1. Background:

   Osteoarthritis (osteoarthritis, OA) is a common joint disease. It is characterized by recurrent joint pain, swelling, increasing of disease status, joint deformity and activity disorders.

   The pathogenesis of OA has not been fully understood. It may be associated with a variety of factors, such as: mechanics, biochemistry, genetics, and so on. Its main feature is the imbalance between synthesis and catabolism of articular cartilage cells. The imbalance may refer to cell aging, cell apoptosis, local inflammatory factor in joints as well as stress mechanism and so on.

   OA usually develops in burdened and active joints, such as: the knee, the spine (cervical and lumbar spine), hip and ankle, hand joints, etc. The first session of The National Health and Nutrition Survey (The first National Health and Nutrition Examination Survey, NHANESI) found that 12% of people in The United States have at least one joint in accordance with the clinical diagnosis of OA. Radiographic result shows that rate of American adults knee OA prevalence is 14% and 37%, and women are more common .A large study found that at least one joint in people over 55 years have radiographic hand OA, and female prevalence is 67%, male is 55% .

   The OA in Chinese are more likely happened in elder women than men. Prevalence rate could up to 50% in people over the age of 60, and 80% in 75 years old.

   Osteoarthritis patients suffer huge pain, and it cause huge economic burden to the society, and it becomes a serious impact on social productivity and lead to huge economic burden.

   In the United States, OA cost $ 1,855 billion per year and in 27 million patients, and women spend $ 6212 per year, male $ 4730 per year; OA cost 1% \~ 2.5% of gross domestic product (GDP) in the United States, Britain, France, Canada, Australia and other developed countries. There is no burden of economic data of OA in China .

   Classification criteria of knee osteoarthritis

   According to the affected areas, OA can be divided into knee OA, hip OA, hand OA (distal interphalangeal joints, the first wrist palm joints), foot OA (first plantar toe joints, heel), etc.

   Knee OA is the most common disease in clinical disease. The classification of the knees OA contains clinical criteria, and also clinical and imaging criteria in the modified American College of Rheumatology (ACR) classification criteria in osteoarthritis classification criteria.

   Knee osteoarthritis usually occurs with obvious fricatives, bony enlargement, Baker cyst expansion and joint effusion is generally not associated with skin redness.

   The most common deformity comes out with varus in severe cases, but also it may appear in the early mild disease. That clinically obvious varus may be a predictive factor during the disease progression. That quadriceps become weak is a changeable risk factor for early knees OA disease progression, especially in women . Muscle atrophy occurs in late stage of disease progression. And it brings huge burden of disease to patients.

   Treatment of knee OA

   The aim of the treatment is to relieve pain, prevent and delay the progress of disease, protect the joints function, improve the quality of life. The treatment should be individualized. Full consideration to the patient' illness risk factors should be given, including: joint structure changing, the degree of inflammation and pain, concurrent disease status and other specific situation and condition. Treatment should be given priority to combine non-drug therapy with drug therapy. Operation should be performed when it is necessary .

   Non-drug therapy include psychosocial intervention , decreasing weight, reasonable exercise, physical therapy which includes heat therapy, spa therapy, etc.), etc.

   Drug therapy mainly includes drugs using external, drugs using in whole body and drugs intra-articular injections.

   Topical drugs include: capsaicin, non-steroid anti-inflammatory drugs (NSAIDS) for external use and lidocaine for external use only.

   Systemic medicine include: a: non-opiate drug. Acetaminophen is the first choice of OA treatment, and the main reason is that the less side effects and good curative effect. b: NSAIDS. There are two effect of NSAIDS: anti-pain and anti-inflammatory, which is the most commonly used for the control of OA symptoms. The main adverse reactions are gastrointestinal symptoms, renal or liver damage, effect on platelet function, and it may increase the risk of cardiovascular adverse events. c: opioid analgesics. It can be considered if Pain still difficult to control after non-drug and drug treatment.

   Drugs injection intra-articular, including: intra-articular injection of glucocorticoid and hyaluronic acid derivatives.

   Research of TNF-α application in OA:

   TNF-α and IL1 play an important role in the pathogenesis of osteoarthritis, IL1 - beta often express highly in middle to late course of OA. In the OA flare course, TNF-α and IL1 alpha will increase significantly; TNF-α has been considered to be one of the important factors associated with the degree of OA inflammatory, and the IL1 alpha has a significant relation with the start of OA inflammatory.
2. Aims:

   Primary: evaluate efficacy of subcutaneous injection of etanercept for moderate and severe knee osteoarthritis

   Second: investigate the potentiality of serum cytokines (TNF-α, L1-α, IL1-β, MMP1, MMP13) to predict the response of subcutaneous injection of etanercept for moderate and severe knee osteoarthritis.
3. Patients:

   Recruit Patients of moderate and severe knee osteoarthritis, totally 60 patients (According with classification of "Clinical Image" of 1986 American college of rheumatology criteria in osteoarthritis of the knee )
4. Study Design:

   A 12-week, multi-center, open-labeled, randomized study. Moderately and severe knee osteoarthritis patients, total 60 patients (consider expulsion rate 15%)(According with classification of "Clinical Image" of 1986 American college of rheumatology criteria in osteoarthritis of the knee )

   The 60 patients were randomly assigned into two groups:

   Etanercept treatment group: etanercept of 50 mg/w, subcutaneous injection health education, exercise and diet guidance; treatment: 8 weeks Routine care group: Routine care group, health education, exercise and diet guidance; treatment: 8 weeks

   This study has two stages:
   1. Screening/baseline period: - 4 weeks \~ 0 weeks;

      Patients should have signed informed consent form (ICF) before participating the study.

      Obtain the history before treatment, medical records, disease history and demographic information of patients. And also perform pregnancy test (optional), HIV testing (optional), hepatitis B virus (HBV) detection (optional), hepatitis C virus (HCV) detection (optional), electrocardiogram examination, chest radiograph, tuberculin test (PPD) test, vital signs, physical examination, blood routine, urine routine and blood biochemical examination, imaging examination (anteroposterior/lateral of X-ray in knee joint, horizontal position/lateral projection/side lateral projection of ultrasound in knee, supine position in knee joint of MRI (sagittal and coronary are commonly used), measure the erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) and store serum in - 80 ℃ to detect serum protein markers level during baseline period, at the same time keep the plasma to - 80 ℃.(refer to "9.3 lab operation"). Collect disease assessment result in baseline, and record the pain Visual Analog Pain Scale (VAS) score, MOS 12-item Short Form Health Survey (SF12) score, the knee injury and osteoarthritis score (KOOS) score, 30 s - Chair Stand Test (CST) score, 40 m Fast-paced Walk Test (FPWT) score, ultrasonic relative index score and MRI relative index score.
   2. Follow-up: 2, 4, 8, 12 weeks supervision.

   At 2nd week, vital signs will be recorded, pain VAS score, SF12 score, KOOS score, condition of drug combination and adverse events will be recorded as basic disease assessment.

   At 4th week, vital signs will be recorded, and blood routine, urine routine, blood biochemical, the ESR and CRP will be examined and recorded, collect basic evaluation results such as: pain VAS score, SF12 score, KOOS score, and condition of drug combination and adverse events will be recorded as basic disease assessment.

   At 8th week, 12th week, vital signs, blood routine, urine routine and blood biochemical will be examined and recorded and imaging examination will be performed (horizontal position/lateral projection/side lateral projection of ultrasound in knee、 supine position of MR in knee joint (MRI will be performed only at 8th week, sagittal and coronary will be used as usual)). Measure the ESR and CRP and store serum in - 80 ℃ to detect serum protein markers level during baseline to 8th week and 12th week, at the same time, store plasma to - 80 ℃.(refer to "9.3 lab operation"). Collect disease assessment result, and record the pain VAS score, SF12 score, KOOS score, 30 s - CST (Chair Stand Test) score, 40 m FPWT (Fast-paced Walk Test) score, ultrasonic relative index score and MRI relative index score. And condition of drug combination and adverse events will be recorded.
5. Laboratory tests

   Main laboratory examination:

   Detect the level of TNF-α, L1-α, IL1-β, MMP1, MMP13 levels in patients peripheral blood at baseline period and 4th week, 8th week by using enzyme-linked immunosorbent assay.
6. The curative effect evaluation/check points:

   The primary checkpoint: at 8th week and 12th week, changes of pain VAS score, KOOS score relative to the baseline.

   The Secondary checkpoints: at 8 weeks and 12 weeks changes of SF12 score, 30s-CST score, 40 m FPWT score, ultrasound score, MRI score, level of TNF alpha, IL1 alpha, IL1 - beta, MMP1, MMP13 in serum relative to the baseline.
7. Statistical methods:

Based on the curative effect data of patients, analysis by using R software or Statistical Analysis System (SAS) statistical software:

Calculate the measurement data using t-test and rank test; Rate is calculated using chi-square test.

Perform single factor and multiple factors regression analysis on indicators of baseline prognostic factors of patients (protein markers) and curative effect.

Eligibility Criteria:
Inclusion Criteria

1. Willing and able to give full consent;
2. According with classification of "Clinical Image" of 1986 American college of rheumatology criteria in osteoarthritis of the knee ;
3. Grade II-IV of Kellgren-Lawrence (KL) grading system, revealing synovial inflammation or synovial fluid by combining ultrasound and MRI
4. Knee pain for at least 1 Month and average pain of last week rated as moderate and severe, Pain VAS Score\>4;
5. Fertile women agreed to adopt effective contraceptive measures during the test.

Exclusion criteria

1. Allergic to pharmaceutical ingredients;
2. Received Tumor Necrosis Factor inhibitor (TNFI) or other biologics preparation within 3 months;
3. Received physical therapy or articular injection, taking antidepressants or antispasmodic, opioids within 3 months ;
4. Patients with history of knee surgery or upcoming surgery within 10 years;
5. Patients accompanied by other complications or joint disease (such as septic arthritis, osteonecrosis,haemochromatosis, ochronosis, etc.);
6. Patients with active or a history of recurrent infections;
7. Patients existing active tuberculosis (TB) or has a history of active TB;
8. Patients with positive on hepatitis b surface antigen or hepatitis c antibody;
9. Patients with a history of severe lung disease, tumor;
10. Patients with severely abnormal function on liver and kidney (liver enzyme \> = 2 times normal, creatinine \> = normal);
11. Patients with pregnancy, ready for pregnancy or lactation;
12. Patients with other conditions which not suitable for use of Etanercept.