MANAGEMENT OF OSTEOARTHRITIS KNEE IN A TERTIARY CARE HOSPITAL. A PROSPECTIVE OBSERVATIONAL PHARMACOECONOMIC
STUDY”
Dissertation submitted to
THE TAMILNADU DR.M.G.R MEDICAL UNIVERSITY In partial fulfillment of the regulations
For the award of the degree of
M.D. PHARMACOLOGY – BRANCH – VI
DHANALAKSHMI SRINIVASAN MEDICAL COLLEGE AND HOSPITAL, PERAMBALUR – 621212
THE TAMILNADU DR.M.G.R MEDICAL UNIVERSITY CHENNAI – 600 032
May – 2020
This is to certify that the dissertation titled ‘EVALUATION OF COST UTILITY ANALYSIS IN THE MANAGEMENT OF OSTEOARTHRITIS KNEE IN A TERTIARY CARE HOSPITAL. A PROSPECTIVE OBSERVATIONAL
PHARMACOECONOMIC STUDY’ is a bonafide research work of Dr. T. DEEPAK KUMAR for the requirements of M.D Pharmacology Branch-VI
Examination of the Tamil Nadu Dr. M.G.R Medical University to be held in MAY - 2020, was carried out by him under our direct supervision and guidance.
Dr.Maragathamani Elangovan MS., Dr. M. Saravana Kumar MD., Dean, Professor and Head
Dhanalakshmi Srinivasan Medical Department of Pharmacology, College and Hospital, Dhanalakshmi Srinivasan Medical
Perambalur-621212 College and Hospital,
Tamilnadu Perambalur-621212
Tamilnadu
DECLARATION
I, Dr. T. Deepak Kumar solemnly declare that, the dissertation title “EVALUATION OF COST UTILITY ANALYSIS IN THE MANAGEMENT OF OSTEOARTHRITIS KNEE IN A TERTIARY CARE HOSPITAL. A PROSPECTIVE OBSERVATIONAL PHARMACOECONOMIC STUDY” was done by me from Department of Pharmacology at Dhanalakshmi Srinivasan Medical College and Hospital, Perambalur, under the supervision and guidance of professor Dr.M.SaravanaKumar.,M.D., This dissertation is submitted to The Tamil Nadu Dr. M.G.R Medical University, towards the fulfillment of requirement for the award of M.D. Degree in Pharmacology (Branch –VI).
Place: Perambalur
Date:
(Dr. T. Deepak Kumar)
GUIDE CERTIFICATE
GUIDE
Dr.M.SaravanaKumar., M.D., Professor,
Department of Pharmacology,
Dhanalakshmi Srinivasan Medical College and Hospital, Perambalur.
Remark of the Guide:
The work done by Dr. T. Deepak Kumar titled
“EVALUATION OF COST UTILITY ANALYSIS IN THE MANAGEMENT OF OSTEOARTHRITIS KNEE IN A TERTIARY CARE HOSPITAL. A PROSPECTIVE OBSERVATIONAL PHARMACOECONOMIC STUDY”is under my supervision and I assure that this candidate has abided by the rules of the Ethical Committee.
Date: GUIDE: Dr.M.SaravanaKumar., M.D., Professor,
Department of Pharmacology, Dhanalakshmi Srinivasan Medical
College and Hospital, Perambalur.
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This is to certify that this dissertation work titled ‘EVALUATION OF COST UTILITY ANALYSIS IN THE MANAGEMENT OF OSTEOARTHRITIS KNEE IN A TERTIARY CARE HOSPITAL. A PROSPECTIVE OBSERVATIONAL PHARMACOECONOMIC STUDY’ of the candidate Dr. T. Deepak Kumar with registration Number 201716551 for the award of M.D in the branch of Pharmacology. I personally verified from the urkund.com website for the purpose of plagiarism Check. I found that the uploaded thesis file contains from introduction to conclusion pages and result shows 6%
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Guide & Supervisor sign with Seal
I am thankful to Dr. Maragathamani Elangovan M.S., The Dean, Dhanalakshmi Srinivasan Medical College and Hospital, Perambalur for permitting me to carry out the study.
I sincerely thank my guide Dr. M. Saravana Kumar M.D., Professor and Head, Department of Pharmacology for his valuable guidance and support to complete my study.
I sincerely express my heartfelt gratitude to Dr. Surendra Kumar Bouddh M.D., former guide and former Professor and Head, Department of Pharmacology who guided me in choosing the topic and for his constant encouragement and guidance during initial stages of the study.
I express my heartiest thanks to Dr. M. Natesh Prabhu M.D., Associate Professor and Dr. S. Bhuvaneshwari M.D., and Dr. V. Leena Ranjini M.D., Assistant Professors, Department of Pharmacology for their support during my study.
I am very thankful to all faculties of the Department of Orthopedics for their constant support throughout the study.
I am very thankful to the Medical Superintendent and Resident medical officer of our institution for their valuable support. My sincere thanks to my co-post graduate friends and tutor for their kind advice and support during the study.
1. COI - Cost of Illness
2. CMA - Cost Minimization Analysis 3. CEA - Cost Effective Analysis 4. CUA - Cost Utility Analysis 5. CBA - Cost Benefit Analysis 6. INR - Indian Rupees
7. QALY - Quality Adjusted Life Years 8. HRQoL - Health Related Quality of life 9. OA - Osteoarthritis
10. NSAIDs - Non-steroidal Anti-Inflammatory Drugs 11. DALY - Disability-Adjusted Life Years
12. MSK - Musculoskeletal conditions 13. TKR - Total Knee Replacement 14. NCDs - Non-communicable Diseases 15. CHD - Coronary Heart Disease
16. ISPOR - International Society for Pharmacoeconomics and Outcomes Research
17. RCT - Randomized Control Trial
18. ECHO - Economic, clinical and Humanistic
19. AHCPR - Agency for Health Care Policy and Research
21. MCO - Managed-care organizations
22. ICER - Incremental cost-effectiveness ratio 23. CCA - Cost Consequence analysis
24. BOI - Burden-of-illness 25. QoL - Quality of Life
26. DALY - Disability-adjusted life years 27. HYE - Healthy-year equivalents 28. VAS - Visual Analog scale 29. RS - Rating Scale
30. SG - Standard Gamble 31. TTO - Time Tradeoff
32. SIP - Sickness Impact Profile
33. SF-36 - 36-Item Short-Form Health Survey 34. EQ-5D - Euroqol
35. ICF - International Classification of Functioning, Disability and Health 36. NHP - Nottingham Health Profile
37. MMP - Matrix Metalloproteinases
38. OARSI - Osteoarthritis Research Society International 39. ACR - American College of Rheumatology
40. AAOS - American Academy of Orthopedic Surgeons 41. APS - American Pain Society
43. ACS - Autologous Conditioned Serum 44. PRP - Platelet Rich Plasma
45. MSC - Mesenchymal Stem Cells
46. SYSADOA - Symptomatic slow-acting drugs for Osteorthritis
47. ESCEO -European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis
S.No PARTICULARS PAGE.NO.
1. Introduction 1
2. Objectives 5
3. Review of Literature 6
4. Materials and Methods 74
5. Results 83
6. Discussion 107
7. Limitation 113
8. Conclusion 114
9 Future therapies 115
10 ANNEXURE-I
a. Certificate of Ethics approval b. Master Chart
c. Case Proforma d. Consent form
e. SF-36 Questionnaire
f. SF-36 Quality of life score sheet- Baseline g. SF-36 Quality of life score sheet- 4 weeks h. SF-36 Quality of life score sheet- 12 weeks
11. ANNEXURE-II
Bibliography
Introduction
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WHY ARE THE MANY POOR?
“Peter Townsend”
INTRODUCTION
Economic evaluations are essential in the field of healthcare and the principal aim is to improve the economic efficiency of the allocated resources which would assist in maximizing benefits from available resources.The term “Pharmacoeconomics” was used on a public forum for the first time in 1986 by Townsend.Pharmacoeconomics and health outcomes researches are playing a vital role in informing clinical development and market access decisions of new innovative medicines. It mainly works on health economics which particularly emphasizes the costs and benefits of drug therapy. [1] It describes the economic association which combines the drug research, its production, distribution, storing, pricing and use by the people.[2]
The objectives of pharmacoeconomic analysis are to:
1. Provide a portrayal and analysis of the costs of drug therapy to health care systems and society.
2. Determine whether the additional benefit of a pharmaceutical product, service or intervention is worth the additional cost of the new intervention.
3. Estimate and compare the total costs and outcomes of pharmaceutical treatments, services, and interventions
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There are five basic types of pharmacoeconomic analysis. In all the types, costs are measured in monetary units. The difference in the pharmacoeconomics is based on handling of the outcomes. The different types of pharmacoeconomic analysis are:
1. Cost of Illness (COI)
2. Cost Minimization Analysis (CMA) 3. Cost Effectiveness Analysis (CEA) 4. Cost Utility Analysis CUA)
5. Cost Benefit Analysis (CBA)
Method Cost Outcome
Cost of Illness Partial analysis in INR
Cost Minimization INR Natural units
(show equivalency)
Cost Effectiveness INR Natural units
Cost Benefit INR INR
Cost Utility INR QALYs
Table 1: Pharmacoeconomic methods, cost and outcome
Cost-effectiveness analysis (CEA) and its sub-form, cost-utility analysis (CUA) assess alternative interventions in terms of their benefits and costs. Cost-utility analysis (CUA) is an economics tool in which the intervention outcome is measured in terms of quantity and quality of life.[3] CUA measures consequences based on years of life that are adjusted by “utility” weights, which range from 1.0 for “perfect health” to 0.0 for “dead”.[4]
A cost-utility analysis thus evaluates alternative interventions in terms of Quality adjusted
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Life Years (QALYs) and costs. The cost per QALY gained for the interventions are calculated.InCUA drugs/interventions with different outcomes can be compared. CUA is the most appropriate method to use when comparing treatment options that are life extending with serious side effects or those which produce reductions in morbidity rather than mortality like medical treatment of arthritis. It is the method employed when Health Related Quality of life (HRQoL) is the health outcome to be examined.
Osteoarthritis (OA) is a complex disease entity that is difficult to diagnose and define. The subcommittee on Osteoarthritis of the American College of Rheumatology
Diagnostic and Therapeutic Criteria Committee defined osteoarthritis (OA) as
"A heterogeneous group of conditions that lead to joint symptoms and signs which are associated with defective integrity of articular cartilage, in addition to related changes in the underlying bone at the joint margins".[5][6] Osteoarthritis (OA) is the most common chronic joint disease of the cartilage. Globally, it is the sixth important cause of “years of living with disability” and estimated to be the fourth important cause of disability by the year 2020.[7] OA can occur at any joint site, more commonly in the knee and hip, but lifetime risk of developing knee OA tends to be higher.
Most cases of osteoarthritis have no known cause and are referred to as primary osteoarthritis. Primary osteoarthritis is mostly related to aging. It can present as localized, generalized or as erosive osteoarthritis. Secondary osteoarthritis is caused by another disease or condition.[8]The disease manifests first as a molecular derangement (abnormal
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joint tissue metabolism) followed by anatomic, and/or physiologic derangements (characterized by cartilage degradation, bone remodeling, osteophyte formation, joint inflammation and loss of normal joint function), that can culminate in illness.[9]
Management of Osteoarthritis Knee includes weight loss and Non-Steroidal Anti- Inflammatory Drugs (NSAIDS) as the first line of treatment. As the disease progresses and the joint becomes increasingly painful, the effectiveness of these treatment options becomes limited.
Globally, of the 291 conditions, hip and knee OA was ranked as the 11th highest contributor to global disability and 38th highest in disability-adjusted life years (DALYs) in 2010.[9] OA was reported to be the 4th fastest increasing condition, behind diabetes (136%), Alzheimers (92%), and other musculoskeletal (MSK) conditions (79%).[10] There is no confirmed management to reverse joint damage from osteoarthritis but often treated with a combination of non-pharmacological measures like physical exercise, weight reduction and pharmacotherapies like Non-Steroidal Anti-inflammatory drugs (NSAIDs), Corticosteroids and sometimes surgical intervention like Total Knee Replacement (TKR).
Osteoarthritis reduces the regular physical activity which increases the risk of many adverse health conditions, including the world’s major non-communicable diseases (NCDs) like coronary heart disease (CHD), type 2 diabetes and breast and colon cancers which shortens life expectancy.[11]
Objectives
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OBJECTIVES PRIMARY OBJECTIVES:
1. To Estimate cost utility in the management of Osteoarthritis Knee.
2. To compare the improvement in Quality of Life among different medical management in Osteoarthritis Knee
3. To compare the improvement in Quality adjusted Life Years (QALY) among different medical management in Osteoarthritis Knee
SECONDARY OBJECTIVE:
1. To study the drug utilization pattern in the management of Osteoarthritis Knee.
Review of Literature
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PHARMACOECONOMICS:
Health economics is defined as the field of study that evaluates the behavior of individuals, firms, and markets in health care. It usually emphasizes on the cost (inputs) and consequences (outcomes) of health care interventions, such as the usage of drugs, devices, procedures, services and programs.[12] Pharmacoeconomics is a branch of health economics that targets to quantify the cost and benefit of drugs used therapeutically in economic terms.[13]
Fig.1: Pharmacology today with its various subdivisions[13]
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Innovations in the health sciences have resulted in dramatic changes in the ability to treat disease and improve the quality of life. Expenditures on pharmaceuticals have grown faster than other major components of the health care system since the late 1990s.
Consequently, the debate is on rising health care costs due to the development of new medical technologies in the pharmaceutical industry. Literature review on new medical technologies suggests that though the new technology increases costs, it may increase benefits by an even greater amount.[14]
Evaluating the clinical efficacy of any new health care intervention, as well as medications, is supreme in determining the role of the new intervention. New interventions may provide only a meek advantage over existing treatment, usually at a higher cost. Issues regarding the costs of health care may have more direct relevance to health policymakers and financiers of health care than clinicians. But in the current situation of burgeoning health care costs, the onus should be on all health care professionals to ensure responsible health expenditure.[15]
Pharmacoeconomics has been defined as the description and analysis of the costs of drug therapy to health care systems and society. It identifies, measures and compares the costs and outcomes of pharmaceutical products and services.[1] It examines quantitative relations between the cost and the benefit.[16] Pharmacoeconomic evaluation helps to evaluate and compare the total expenses for the interventions and the outcomes associated with the interventions. It also helps to choose the treatment which involves less cost and provides maximum therapeutic advantage.
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HISTORY OF PHARMACOECONOMICS:
The branch Pharmacoeconomics emerged from 1970. The first book on health economics was published in 1973 and in 1978; McGhan, Rowland, and Bootman from the University of Minnesota introduced the concept of cost-benefit and cost-effectiveness analysis. Utilizing sophisticated pharmacokinetic protocols, Bootman published an early pharmacy research article in 1979 in which cost-benefit analysis was employed to appraise the outcomes of individualizing aminoglycoside dosages to severely burned patients with gram-negative septicemia.[12] In 1983, Ohio State University College of Pharmacy introduced a specialized pharmacy academic program with the aim of providing an overview of the application of cost benefit and cost-effective analysis in healthcare, which highlight on their application to the delivery of pharmaceutical care. The term Pharmacoeconomics was used in public forum in 1986, at a meeting of pharmacist in Toronto, Canada, when Ray Townsend from the Upjohn company, used the term in presentation. In 1992, a journal named “Pharmacoeconomics” was launched.[12]
Currently, pharmacoeconomics research is a prosperous industry with numerous practitioners, an outsized study and an application program.[17] Number of journals and successful professional societies including the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) promote pharmacoeconomics research.
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YEARS DESCRIPTION
1960’s Pharmacoeconomics helps pharmacy evolve from distributive to clinical discipline. Drug decision is based on safety, efficacy
1970’s CBA and CEA introduced into pharmacy.
1979 first pharmacoeconomics research article published.
1980’s Cost containment strategy emerge
Inclusion of economic outcomes into drug decisions.
Misuse of Pharmacoeconomics terminology
Agency for Health Care Policy and Research (AHCPR) created in 1989 to conduct outcomes research
1990’s ECHO (Economic, clinical and Humanistic) Model.
Pharmacoeconomics components commonly included in Phase III Randomized Control Trials (RCTs)
Guidelines for conduct and reporting of pharmacoeconomic studies widespread.
Improved quality/rigor of published pharmacoeconomic studies.
“Applied Pharmacoeconomics” emerges
2000’s Pharmacoeconomics has widespread application by clinicians and administrators. Pharmaceutical manufacturers collaborate to provide specific outcomes data.
Table 2: Global Historical Perspectives of Pharmacoeconomics[18]
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NEED FOR PHARMACOECONOMICS:
Today, India is the world’s third largest economy in terms of its Gross National Income (in PPP terms) and has the potential to grow larger and more equitably, and to emerge to be counted as one of the developed nations of the world. India today, possesses a refined resource of interventions, technologies and knowledge which are required for providing health care to her people.[19]
Health and demographic surveys occupy an inimitable place in developing nations like India because there are lacunae in collecting valid information regarding the measurement and formulation of a policy. National Sample Survey Organization (NSSO) by the Ministry of Statistics and Program Implementation conducts a survey that gives knowledge about the basic quantitative information regarding measurement and formulation of a health care policy.The key indicators of social consumption in India’ was published on June 30th, 2015 which threw light on the information regarding morbidity and health expenditure as analyzed by the NSSO 2014 (NSS 71st round), after a gap of 10 years.[20]
The survey on Social Consumption: Health in the 71st round aimed to generate basic quantitative information on the health sector. The ailments for which such medical care was sought, the extent of use of Government hospitals as well as different (lower) levels of public health care institutions and the expenditure incurred on treatment received from public and private sectors, were investigated by the survey.[21]
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Fig. 2: Average medical expenditure (₹) per hospitalisation case for each broad ailment category in different types of hospitals. [21]
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Fig. 3: Percentage distribution of persons by coverage of health expenditure: rural showing very little proportion of the population (14%) had coverage under health insurance scheme, majority being the share of Government funded insurance. [21]
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Fig. 4: Percentage distribution of persons by coverage of health expenditure: urban showing very little proportion of the population (18.1%) had coverage under health insurance scheme, majority being the share of Government funded insurance. Compared to rural areas coverage is better. Apart from Government funded insurance scheme frequency of other agencies like Employee supplemental health protection and those by insurance companies are seen higher in urban than rural population. [21]
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Fig. 5: Proportion of hospitalisation cases that received part or full reimbursement in major States: rural and urban.
Only 6.2% of the hospitalised treatment in urban area and 1.2% of the hospitalised
treatment in urban areas was reimbursed partly or fully. Maximum reimbursement is seen in urban areas of Maharashtra (11.7%) and Minimum reimbursement is seen in rural areas of Telangana (0%). [21]
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Many governments throughout the world are trying to reduce their increasing prescription drug costs by increasing the use of generic drugs, thereby giving importance to cost-effectiveness and cost-benefit analysis studies. In other words, they are implementing the concept of Pharmacoeconomics.[12] The concept of Pharmacoeconomics is still not in use in India to make reimbursement choices by the government. In addition to this the concept of Pharmacoeconomics is not done as academic research also except for few cost-effectiveness studies in different parts of India. Pharmacoeconomics is yet to make an appearance in India where most of the healthcare expenditure is done by patients out of their own pockets, unlike medical insurance policies in most developed countries.[12]
Obtaining maximum benefit at a minimal cost should be taken into consideration while selecting a drug. Not only the poor countries but even rich nations are finding it difficult to control the ever-rising cost of medical care. While trying to prolong the patient’s life, ensuring that his/her quality of life is also enhanced is equally important.[16]
Pharmacoeconomic research should be performed from the stage of clinical trials.
During the post-marketing phase or Phase IV, retrospective and prospective pharmacoeconomic studies can be designed and conducted to gather data in support of use of the drug. Postmarketing pharmacoeconomic studies are extremely important in that they allow evaluation of cost and consequences of drug therapy without the altered interventions that occur in strictly controlled clinical trials.[22] This will ensure the government that the money is spent in the right direction which will subsequently reduce the financial burden on the patients.
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PERSPECTIVES OF PHARMACOECONOMICS:
The value of a pharmaceutical product is highly dependent on the perspective in which it is evaluated. Commonly observed perspectives for evaluation of a Pharmaceutical product are
1. Patient perspective 2. Provider perspective 3. Payer perspective 4. Societal perspective
Though a pharmacoeconomic evaluation can evaluate the value of a product from single or multiple perspectives, interpretation of the perspective is very imperative because the results of a pharmacoeconomic evaluation hinge on the perspective taken. For example, when comparing the value of alteplase (tissue plasminogen activator, or t-PA) with that of streptokinase from a patient or societal perspective, t-PA may be the best-value alternative because a 1% reduction in mortality rates is observed in this large population. But from a small community hospital's perspective, streptokinase may epitomize a better value because it provides similar outcomes for a lesser cost. So, the perspective has to be clear to conduct a full evaluation of the relevant costs and consequences. Again, perspective is critical because the value placed on an alternative will depend comprehensively on the point of view taken.[23]
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1. Patient Perspective:
Patient perspective is of utmost importance because patients are the ultimate consumers of healthcare services. Significances, from a patient's perspective, are the clinical effects, both positive and negative, of a program or treatment alternative.
2. Provider Perspective:
Costs from the provider's perspective are the tangible expenditure in providing a product or service. Providers can be hospitals, managed-care organizations (MCOs), or private-practice physicians. From this perspective, direct costs such as drugs, hospitalization, laboratory tests, supplies, and salaries of healthcare professionals can be identified, measured, and compared.[23] Indirect costs gains less significance to the provider. Provider’s perspective gains importance when designing formulary management or drug-use policy decisions.
3. Payer Perspective:
Here, the costs represent the charges for healthcare products and services allowed or reimbursed by the payer, who are mainly insurance companies, employers, or the government. The prime cost of interest for the payer is of a direct nature. However, indirect costs, such as lost workdays (absenteeism), being at work but not feeling well and therefore having lower productivity (presenteeism), also can contribute to the total cost of healthcare to the payer.[23]
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4. Societal Perspective:
This is the comprehensive of all perspectives. In societal perspective benefit to the society is given utmost importance. All the direct and indirect costs are included when societal perspective is considered. Costs from this perspective include patient morbidity and mortality and the overall costs of giving and receiving medical care.[23]
BASIC CONCEPTS IN PHARMACOECONOMICS:
Fig.6: Basic elements of Pharmacoeconomics.[24]
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The focus of pharamcoeconomic evaluation is frequently on the cost (inputs) and consequences (outcomes) of that use. Outcomes may be clinical, economic, or humanistic based on the type of study selected. This is described as ECHO model.
COSTS:
Costs are calculated to estimate the resources (or inputs) that are used in the production of a good or service.[4] This includes the price of the drug as well as the price for administration of drugs.
Healthcare costs or economic outcomes can be grouped into several
categories: direct medical, direct nonmedical, indirect nonmedical, and intangible costs.
Inclusion of these various cost categories provides a more precise assessment of the total economic impact of a healthcare program or treatment alternatives on a specific
population, organization, or patient.
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1. Direct costs:
Direct medical costs: Medications
Medication monitoring
Medication administration
Patient counseling and consultations
Diagnostic tests
Hospitalizations
Clinic visits
Emergency department visits
Home medical visits
Ambulance services
Nursing services
b) Direct Non-medical costs: Travel costs to receive health care (bus, gas, taxi)
Nonmedical assistance related to condition (e.g., homemaking services)
Hotel stays for patient or family for out-of- town care
Child care services for children of patients
Table 3 : Table showing direct costs used in Pharmacoeconomics research
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2. Indirect costs Lost productivity for patient
Lost productivity for unpaid caregiver (e.g., family member, neighbor, friend)
Lost productivity because of premature mortality 3. Intangible costs Pain and suffering
Fatigue
Anxiety
Table 4 : Table showing indirect and intangible costs used in Pharmacoeconomics research
Apart from the cost mentioned in the table there are two types of costs namely opportunity cost and incremental cost. Opportunity cost is defined as the “benefit forgone when selecting one therapy over the next best alternative”.[25]. Since resources are scarce relative to needs, the use of resources in one way prevents their use in other ways.[26]
According to economic theory, the “true” cost of a resource is its opportunity cost.[4]
Incremental cost refers to the difference in cost between two contending health care interventions. These costs are often difficult to be measured. Marginal cost and incremental cost can be used interchangeably.
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In clinical setting, a convincing choice for the comparison of a new treatment with a standard treatment, difference in these costs is of prime importance for the policy makers. Hence, calculation of the change in costs divided by the change in outcomes should be used as an assessment tool for the analysis. This is termed as incremental cost- effectiveness ratio (ICER) and it can be very different from comparing the average costs of the options or alternatives, especially when the difference in outcomes is small.[4]
OUTCOMES:
Most widely used outcome measure in any research is the direct measurement of health from the patient’s outlook. Quantifying patients’ experience and the magnitude of their functionality in their day to day activitiesis decisive when the principal aim of the treatment is to improve the patient’s feeling.
Fig. 7: ECHO model for measurement of outcomes.[27]
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ECONOMIC OUTCOME:
Economic outcomes deals with the methodology for analyzing cost and the benefits of the therapy. In economic outcomes, costs are measured in monetary units. The difference lies in how the outcomes are analysed. The four basic types of pharmacoeconomic analysis are
1. Cost Minimization Analysis (CMA) 2. Cost Effectiveness Analysis (CEA) 3. Cost Utility Analysis (CUA)
4. Cost Benefit Analysis (CBA)
In addition to these types, there are other types of evaluations that are not considered full economic or pharmacoeconomic evaluations. These evaluations include
1. Cost of Illness analysis (COI)
2. Cost Consequence analysis (CCA)
Cost-of-illness (COI) analysis put a figure on the economic burden of disease and illness that is reflected in the society. It is often called burden-of-illness (BOI).[27]They are mainly used to assist in policymaking, resource allocation to line up the resource use for treatment and prevention of a particular disease and can be used as baseline research from which potential benefit of new therapies are determined. They form a foundation stone on which different types of pharmacoeconomic analyses are used to make
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assessments in allocation of healthcare resources. Costs are measured from the societal perspective. Nowadays, cost of disease from the perspective of the patient is gaining more attention.[28] Cost of Illness studies is been done extensively for Diabetes Mellitus.[29] It is also done for other diseases like Atopic Dermatitis.[30]
Cost Consequence Analysis (CCA) compares costs (i.e. the cost of implementing a programme or intervention) with its consequences, such as health outcomes, quality of life, wellbeing, or cost savings.[31] It differs from Cost Benefit Analysis (CBA) and Cost Effective Analysis (CEA) in that multiple outcomes can be studied in Cost Consequence Analysis (CCA). It does not provide a comparison with other treatment options.[23]
COST MINIMIZATION ANALYSIS:
Cost-minimization analysis (CMA) is done to determine the least costly treatment when comparing two or more treatment alternatives. Cost-minimization analysis (CMA) measures and compares input costs and assumes outcomes to be equivalent.[4] In CMA, the types of interventions that could be are limited and the strength lies in the satisfactoriness by the readers or evaluators that outcomes are undeniably equivalent.
Cost-minimization analysis (CMA) is the simplest type of pharmacoeconomic analysis. CMA is frequently portrayed as being the “poor relation”
among health economic methodologies, with its apparent simplicity making it unworthy of being considered alongside more theoretically rigorous health economic methodologies.[27]
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Common example of a CMA is the comparison of generic equivalents of the same drug entity.[32],[33],[34] For a generic treatment to be approved by the U.S. Food and Drug Administration (FDA), the manufacturer must establish that the generic product is bioequivalent to the branded medication. When comparing medications that have the same chemical composition and dose, and the same pharmacological properties, the cost of the medication only needs to be compared for the reason that outcomes should be the same.
Another example of a CMA is by measuring the costs of receiving the same treatment in different settings. It can be used to compare the costs of hospital care with home care. [35],[36],37]
In the field of Dermatology, Cost Minimization Analysis has been done to compare Teledermatology with live consultations which concludes that in order to achieve cost savings, teledermatology should be applied in only those cases with a reasonable probability that a live consultation can be prevented.[38]
Advantage of CMA:
1. It is simple to conduct.
Disadvantages of CMA:
1. It cannot be employed when outcomes of the products are not equivalent.
2. Types of interventions and products that can be compared in a CMA are limited because the outcomes must be equivalent.
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COST EFFECTIVENESS ANALYSIS (CEA):
Cost-effectiveness analysis (CEA) is the most common type of pharmacoeconomic analysis found in the pharmacy literature.[4] This provides a framework for the comparison of two or more decision options by examining the ratio of the differences in costs and the differences in health effectiveness between options. CEA is a tool that has seen increasing use in recent decades as decision makers at all levels of health care provision seek to value alternative interventions.[39] In CEA, cost is measured in monetary terms, and outcomes are measured in terms of obtaining a specific therapeutic outcome. They are expressed in physical units or natural units like cases cured, lives saved, hospitalization prevented.
The Institute for Clinical and Economic Review, a non-profit organization that uses cost-effectiveness analysis as part of a process for assessing the value of drugs and other technologies.[40]
The main aim of CEA is to provide a single measure, the incremental cost- effectiveness ratio (ICER), which relates the amount of benefit derived by making an alternative treatment choice to the differential cost of that option. When two options are being compared, the ICER is calculated by the formula
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ICER = COption2 – COption1
_________________________________________________
EffectivenessOption2 – EffectivenessOption1
COption1 - Cost of Treatment 1
COption2 - Cost of Treatment 2
EffectivenessOption1 - Effectiveness of Treatment 1 EffectivenessOption2 - Effectiveness of Treatment 2 THE COST EFFECTIVENESS PLANE:
The cost-effectiveness plane is drawn with the changes in effectiveness (or incremental effectiveness) between the two options on the x-axis and changes in cost (or the incremental cost) on the y-axis. In this example a new intervention is compared to an existing intervention. The existing intervention acts as the comparator and will be placed at the origin of both the cost and effectiveness axes, which describes the current level of expenditure and benefit with which the new intervention is matched. The new intervention may be more expensive, less expensive, or equivalent in costs compared to the standard intervention. Similarly, the new intervention may be more effective, less effective, or equivalent in clinical effectiveness compared to the existing intervention.
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Fig. 8 : Cost Effectiveness plane[27]
There are four possible options for the results of the analysis of a new intervention compared with an existing intervention.
1. If the new intervention is less expensive and more effective than the existing intervention, the point representing the new program drops into the southeast (SE) quadrant of the cost-effectiveness plane and are called “dominant”. New intervention should be chosen over the existing intervention since they are “cheaper and better” than existing intervention.
2. If the new intervention is more expensive and less effective than the existing intervention, this drops into the northwest (NW) quadrant of the plane. Strategies in this quadrant are considered to be “dominated by the current strategy” and newer intervention is not preferred over established intervention due to poorer outcomes at greater cost.
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3. If the new intervention is both more effective and more costly, this drops in the northeast (NE) quadrant, then a CEA would be beneficial to define the balance between increases in costs and effectiveness and to calculate the cost per unit of effectiveness gained.
4. If the new intervention is both less effective and less costly, this drops in the Southwest (SW) quadrant, then a CEA would be beneficial to define the balance between the interventions and to calculate the cost per unit of effectiveness gained.
This graphical display emphasizes one of the most fundamental and important concepts of cost-effectiveness analysis.[27]
Cost Effective analysis can be used to evaluate cost efficacy of drugs used in various diseases like Diabetes Mellitus,[41],[42],[43],[44] Hypertension,[44],[45],[46] Ischemic Heart disease,[47],[48],[49] Infectious disease like Diarrhoea,[50] Pneumonia, [51], [52] HIV, [53]
etc.
Advantages of CEA:
1. Outcomes are measured in Natural units, which the medical practitioners are familiar with and helps to easily explain the concept of cost effectiveness.
2. Provide valuable information to support formulary management, and patient’s treatment decisions
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Disadvantages of CEA:
1. Treatments/alternatives must have outcomes that are measured in the same natural health units
2. Selecting appropriate outcomes for CEAs that incorporate behavioral interventions is more complex.[39]
3. Only one outcome can be measured using CEA. If more than one outcome has to be measured two separate cost-effectiveness analysis must be done.
COST UTILITY ANALYSIS:
Measurement of patient preference or quality of life occupies an important place when comparing the treatment alternatives. Cost-utility analysis (CUA) is used for comparing treatment alternatives that incorporates patient preferences and Quality of Life (Qol). The QoL component is measured using a metric known as a health utility (HRQoL);
hence, the term cost-utility analysis.[27]
In CUA, cost, quality and quantity of patient-years can be compared. Cost is measured in monetary units, and the therapeutic outcome is measured in patient-weighted utilities (Utility units) rather than in physical units. While the term “utility” has a more precise meaning in the field of economics, it is used in a general way in other disciplines to indicate personal or group preferences.[4] “Utility” is also known as “preference weight”
or “preference value”.
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Utility unit commonly used is quality-adjusted life year (QALY) gained.
QALY is a collective measure of health status used in CUA, which combines both morbidity (quality of life) and mortality (quantity of life) data associated with the use of a healthcare intervention. QALY can also be used as a common measurement to compare the benefits of very different healthcare programs. Quality of life is major facet of outcomes research. Quality of life has four principal dimensions:
1. Physical mobility.
2. Freedom from pain and distress.
3. Capacity for self-care.
4. Ability to engage in normal work and social interactions.[54]
For the measurement of Quality of Life (QoL), perfect health is fixed a value of 1.0 utility (μ) per year, and death is fixed a value of 0.0. If a person’s health is reduced by disease or treatment, 1 year of life in this state is valued somewhere between 0 and 1. Some researches point out that there are disease states worse than death, so negative utility weights may be needed to depict these values.[4]
Other utility units that can be used in CUA are 1. Disability-adjusted life years (DALYs) 2. Healthy-year equivalents (HYEs).
But these units are least commonly used.
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For the estimation of utility weights for various conditions or “health conditions” between perfect health and death, two comprehensive approaches exists that elicit these scores:
1. Direct elicitation 2. Indirect elicitation.
Direct elicitation methods Rating scale (RS):
RS consists of a line on a page with scaled markings, like markings in a thermometer with perfect health at the top (100) and death at bottom (0). It differs from Visual Analog Scale (VAS) in that it has markings between the best and worst scores. The subjects are told to mark a “X” somewhere between the two extremes to indicate their preferences.
Fig. 9: Rating scale (RS) with example estimates for various disease states or conditions.[4]
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Standard gamble (SG):
In this method, each subject is presented with two alternatives. Alternative 1 is the intervention with two possible outcomes either the return to normal health or immediate death. Alternative 2 is the definite outcome of a chronic disease state for life based on his life expectancy. A baseline probability is given and the respondent is asked whether he or she would have the intervention or live with the chronic condition.
Fig. 10: Standard gamble (SG). [4]
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Time tradeoff (TTO):
In TTO, subject is given two alternatives. Alternative 1 is a certain disease state for a specific length of time (t), the life expectancy for a person with the disease, and then death. Alternative 2 is being healthy for time x which is less than t. The utility is calculated using the formula x/t.
Fig. 11: Time tradeoff (TTO). [4]
Indirect elicitation methods
Using standardized weightings like Sickness Impact Profile (SIP), 36-Item Short-Form Health Survey (SF-36), Euroqol (EQ-5D), etc.
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CUA is the most suitable method when comparing the treatment alternatives that need long term treatment with serious side effects like cancer chemotherapy[55],[56],[57]
or those interventions which aim at reductions in morbidity rather than mortality like treatment of arthritis,[58],[59] Low Back Ache (LBA),[60] etc.
Advantages of CUA:
1. Different types of health outcomes can be compared.
2. Diseases with multiple outcomes of interest can be compared using one common unit.
3. CUA serves as a practical contrivance for decision-makers faced with making reimbursement decisions.
Disadvantages of CUA:
1. QALY is a difficult concept to understand which is not used frequently by clinicians and policy makers.
2. Lost productivity is not taken into consideration as part of the morbidity aspect of a QALY
3. QALY is a subjective unit, derived from information from the patientsand hence it
is difficult to determine an accurate utility or preference weight value
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COST BENEFIT ANALYSIS:
The first use of CBA in health care dates back to the 1960s. In 1961, Weisbrod assessed the costs and benefits of a vaccination program for children in which the benefits of the program were monetized by using wages to value lost productivity and reduced survival.[4] In CBA, both the inputs (cost) and outcome are measured in monetary units. The most natural approach to evaluate health expenditure is cost-benefit analysis.[61]
Fig.12:Components of cost-benefit analysis (CBA)[4]
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Cost Benefit Analysis is being used in health care providing clinical services[62],[63],[64] and in evaluation of vaccines.[65]
Advantages of CBA:
1. Many different outcomes can be compared because benefits are measured in monetary units.
2. It is a comprehensive analysis.
Disadvantages of CBA:
1. It is difficult to attach monetary value to the outcomes, making the analysis complex to conduct.
OUTCOME:
A standard outline for the depiction of health and health related states is elucidated by “The International Classification of Functioning, Disability and Health (ICF)’. It is a classification of health and health-related domains -- domains that help us to describe changes in body function and structure, what a person with a health condition can do in a standard environment (their level of capacity), as well as what they actually do in their usual environment (their level of performance).[66] The most important use of ICF is in health planning and serves as a deciding tool for policy makers.
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Fig.13: International Classification of Functioning, Disability and Health[66]
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MEASUREMENT OF HEALTH OUTCOME:
Within the ICF system, health outcomes may be categorized based on the effect upon body functions, body structure, limitations in activities, and limitations in participation.
Based on effect upon body functions: Health outcomes that measure body functions include those which are used to put a figure on physiological functions of body like ejection fraction, glucose level, depression, etc.
Based on effect upon body structure: Outcomes that measure body structures are mainly the measures of anatomical parts and their components like computed tomography to measure tumor size, etc.
Based on effect upon limitation of activities and participation: Activity is defined as the performance of an action, whereas participation, more broadly, is defined as involvement in meaningful activities and fulfillment of roles that are socially or culturally expected of that person.[27] Impairments are due to complications with either body functions or structures. Having an impairment of a body structure or function may ultimately lead to limitations in activities, including activities of daily living that might also lead to restrictions in participation.
Comprehensive assessment of an individual’s health includes measures of body systems and function, as well as limitations in activities and participation.
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Health-Related Quality of Life (HRQoL):
There exist a diffence that distinguish between the terms quality of life (QoL) and health-related quality of life (HRQoL). QoL, is a broad concept with many aspects that quantiy people’s complete perception of their life. QoL comprises of both health-related as well as non–health-related aspects of their lives like economical, political and cultural aspects. HRQoL is the part of a person’s overall QoL that “represents the functional effect of an illness and its consequent therapy upon a patient, as perceived by the patient.” [4] The term QoL is often seen used interchangeably with HRQoL in various health related research and articles. Both the terms may be used to indicate the narrower definition relating to a person’s health.
Health-related quality of life (HRQoL) measures the broad concept of health which is defined as a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity. [67] It looks into the extent of difficulty with activities of daily living and how these difficulties have an impact on social relationships with family, and friends. It also measures the degree of contentment derived from doing them. HRQoL instruments questions related not only to the measure of body function (e.g., pain, depression, anxiety) and but also to the limitations with activities and participation.
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Some of the health profiles used in measuring Health-Related Quality of Life are
Sickness Impact Profile (SIP)
Nottingham Health Profile (NHP)
36-Item Short-Form Health Survey (SF-36)
12-Item Short-Form Health Survey (SF-12)
Euroqol (EQ-5D)
These measure overall wellbeing, including physical, functional, and emotional components of health pertinent to all health states which includes even healthy individuals.
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Sickness Impact Profile (SIP):
The Sickness Impact Profile 68 (SIP-68) is a self-report/interview-style generic health status measure which assesses physical, mental and social aspects of health-related function.[68]
Fig. 14: Assessment Overview of Sickness Impact Profile 68
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Nottingham Health Profile (NHP):
The Nottingham Health Profile is intended for primary health care, to provide a brief indication of a patient's perceived emotional, social and physical health problems.[69]
Fig.15: Questionnaire in Nottingham Health Profile
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36-Item Short-Form Health Survey (SF-36):
SF-36 is a set of generic, coherent, and easily administered quality-of-life
measures. These measures rely upon patient self-reporting and are now widely utilized by managed care organizations and by Medicare for routine monitoring and assessment of care outcomes in adult patients.[70]
Fig.16: 36-Item Short-Form Health Survey (SF-36)
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12-Item Short-Form Health Survey (SF-12):
The 12-Item Short Form Health Survey (SF-12) was developed for the Medical Outcomes Study (MOS), a multi-year study of patients with chronic conditions. The resulting short- form survey instrument provides a solution to the problem faced by many investigators who must restrict survey length.[71]
Fig.17: 12-Item Short Form Health Survey (SF-12)
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Euroqol (EQ-5D):
The EuroQol Group is a network of international multidisciplinary researchers devoted to the measurement of health status. EQ-5D is a standardised measure of health status developed by the EuroQol Group in order to provide a simple, generic measure of health for clinical and economic appraisal.[72]
Fig.18: Sample EQ-5D questionnaire
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OSTEOARTHRITIS
Osteoarthritis (OA), also known as ‘osteoarthrosis or ‘degenerative joint disease,’
is the most common type of arthritis and is the one of the important cause of chronic disability between fourth and fifth decade of life. The name “osteoarthritis” arose from observation of the striking overgrowth of marginal and subchondral bone by the pathologists and radiologists.[73]
In the 2015 World Health Organization (WHO) publication “World Report on Ageing and Health” report defines Healthy Ageing as the process of developing and maintaining the functional ability that enables well-being in older age. [74] It is clear that the pain and loss of mobility associated with Osteoarthritis (OA) becomes more apparent as people age and hence, people with OA are denied the right to healthy ageing. [4]
Osteoarthritis (OA) is a chronic degenerative disorder of multifactorial etiology characterized by loss of articular cartilage, hypertrophy of bone at the margins, subchondral sclerosis and range of biochemical and morphological alterations of the synovial membrane and joint capsule.[8] Pain is the most prominent and disabling symptom of OA.[75] Pain results in reduction of activities and also has negative effects on mood, sleep, and overall quality of life. Osteoarthritis (OA) is the most common form of arthritis and a leading cause of disability worldwide, largely due to pain, the primary symptom of the disease.[76] It is known that OA is more common in women than in men, and the prevalence of OA increases steeply with age.Among OA, OA of the hip and knee are the most common types, often resulting in joint replacement surgeries. With the increase in aging and obesity
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throughout the world, it is estimated that the burden of OA will become a major problem for health systems globally.The economic costs of OA are high, including those related to treatment, for thoe individuals and their families who must adapt their lives and homes to the disease, and those due to lost work productivity.[77]
Knee osteoarthritis (OA) is a disease caused by biomechanical stresses affecting the articular cartilage and subchondral bone of the knee.[78] Detrimental mechanical loading across the knee joint is speculated to be one of the main factors in the pathophysiology of knee OA.[75]
EPIDEMIOLOGY OF OSTEOARTHRITIS:
Fig.19: Total data count for knee osteoarthritis DisMod-MR analysis, Global Burden of Disease 2010 study[10]
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Knee OA is a very common condition with prevalence rising with age. The global prevalence of radiographically confirmed symptomatic knee OA in 2010 was estimated to be 3.8%.[10]
Fig.20: Age-standardised prevalence of knee OA by region and sex, GBD 2010 study.[10]
Prevalence was noted to be higher in females than males. Prevalence in 2010 was highest in the Asia Pacific high-income region, followed by Oceania and North Africa/Middle East. Prevalence was lowest in South and Southeast Asia. [10]
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Epidemiological profile of this disease in India is not clear but it is estimated that osteoarthritis (OA) is the second most common rheumatological problem and is most frequent joint disease with prevalence of 22% to 39% in India.[8],[79] The reported prevalence of OA from a study in rural India is 5.78%.[73]
ETIOLOGY AND RISK FACTORS:
OA is a heterogeneous disease and it is caused due to a variable combination of numerous risk factors affecting different individuals and different joint sites. OA arises as a result of a mixture of both systemic predisposition and local biomechanical risk factors.
Fig.21: Systemic predisposition and local biomechanical risk factors in OA.[80]
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Major risk factors of OA include
Systemic predisposition o Genetics
o Age o Gender
o Diet and obesity
Local biomechanical factors
o Abnormal joint shape and size o Previous injury
o Neuromuscular problems o Obesity
o Loading/occupational factors
Bone mineral density
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GENETIC PREDISPOSITION
Genetic factors account for 60% of hand and hip OA and 40% of knee OA.[81] But there exist no ‘OA gene’ to confer for the predisposition rather it is due to the presence of genes important for skeletal development, suggesting that bone size and shape are
important determinants of the likelihood of getting OA.[80] The genes could also play a role in the disease onset and could provide targets for future pharmacological treatments (e.g., genes encoded for vitamin D receptor, insulin-like growth factor 1, type 2 collagen, growth differentiation factor 5).[81]
AGE
Strong association of OA with increasing age is not because age-related changes in joints. As age progresses, cartilage gets thinner which in turn weakens the muscles and the stability of major joints such as the knee may be affected. Muscle weakness precedes the development of knee OA. [80]Sarcopenia may be an independent risk factor of knee OA and also participate in its progression. [81]
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GENDER:
Fig.22: Incidence of symptomatic osteoarthritis (OA) of the hand, knee and hip in men.
[80]
Fig.23: Incidence of symptomatic osteoarthritis (OA) of the hand, knee and hip in women. [80]
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DIET AND OBESITY:
Obesity is a strong risk factor, particularly for knee OA. [80] Increased preponderance of OA in obesity is due to the changes in obesity-related biochemical factors such as leptin levels. There is also correlation between vitamin deficiencies (vitamins C, D and K) and development of OA.
LOCAL BIOMECHANICAL FACTORS:
ABNORMAL JOINT SHAPE AND SIZE:
Joint shape is an important risk factor, particularly for hip OA. Hip dysplasia is a risk factor for development of hip OA in later life.
PREVIOUS INJURY:
Injuries that disturb the shape or stability of a joint predispose to OA. This is more seen in uncommon joints such as the wrist or ankle. At the knee joint, meniscal and ligament injuries, particularly ACL rupture, are the important predisposing factors for OA.
NEUROMUSCULAR PROBLEMS
Severe neurological problems can lead to the important variant of OA called
‘Charcot’s joints’. [80] Joint laxity is an important risk factor for OA. In contrast, spasticity lead to very tight joints supplemented by abnormal joint load which leads to joint damage and secondary osteoarthritis. OA of the hip is particularly common in persons suffering from spastic cerebral palsy. [80]
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JOINT LOADING, OCCUPATION AND OBESITY:
Certain specific occupations involving repetitive ‘overuse’ of joints can predispose to OA, resulting in special forms of the condition such as ‘picca-thumpers thumb’[80] (OA seen at the base of the thumb in population who were shifting printing blocks around with their thumbs). Obesity is particularly an important risk factor for knee OA, which indicates that a portion of the risk is likely due to loading factors apart from systemic influence.
BONE MINERAL DENSITY:
The association between bone mineral density (BMD) and osteoarthritis (OA) had been a topic of debate in the literature. High bone mineral density is a risk factor for OA, and low bone mineral density is protective.[80] Animal models have suggested that drugs reducing bone turnover (antiresorptives) may retard OA progression.[82]
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PATHOGENESIS OF OSTEOARTHRITIS KNEE:
Numerous factors contribute to both degradative and nociceptive pathways associated with the progression of OA.
Fig.24: Pathophysiological status of each component in synovial joint and its relation to joint degeneration and related pain perception.[83]
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ROLE OF INLAMMATION:
Inflammatory stimuli initiate a cycle of events, which includes the release of cytokines by chondrocytes, leading to complex biochemical and mechanical interaction with other biological mediators which in turn leads to OA and causes pain. Biological mediators include proinflammatory members from the interleukin family (IL-1, IL-6, and IL-17), tumor necrosis factor-α (TNF-α), and prostaglandin E2 (PGE2).[83] These mediators stimulate the production of cartilage-degrading proteases to induce Extracellular matrix (ECM) degradation, and also contributes to OA-associated pain pathways.
Fig.25: Inflammatory mediators and Osteoarthritis.[83]
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Fig.26: Mediators in Osteoarthritis Knee.[83]
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Fig.27: Complex cellular interplay in synovial joint.[83]
In osteoarthritic state, abnormally activated chondrocytes produce ECM- degrading proteases (MMPs, aggrecanases), pro-inflammatory cytokines (eg. IL-1), and catabolic growth factors (eg. FGF-2). These proteins are secreted into synovial fluid.
Fragments obtained from ECM degradation are also present in the synovial fluid which acts as catabolic inducers. In OA, a subpopulation of chondrocytes undergoes hypertrophic changes due to the expression of type X collagen. In Chondrocytes upregulation of
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apoptosis occurs, which results in diminished local cellularity. Pathological remodeling of subchondral bone occurs in response to cartilage loss which gives rise to sclerosis and osteophyte formation. Synoviocytes (fibroblasts and macrophages) also actively synthesize proteases and cytokines which can negatively effect on the articular cartilage and synovium.[83]
SIGNS AND SYMPTOMS OF OSTEOARTHRITIS KNEE:
Symptoms o Pain
o Joint stiffness o Fatigue
o Sleep disturbance o Depression
o Reduced functional ability and activities
Signs
o Tenderness of the joint o Bony swelling
o Reduced range of movement with pain at the end of the range o Crepitus on movement of the joint
o Weakness and wasting of muscles acting on the joint o Signs of inflammation
o Deformity and instability in severe cases
