Chloroquines for the treatment of osteoarthritis
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effectiveness and safety of the chloroquine for treating OA. The following hypotheses will be tested:
a) Treatment with chloroquine is effective for OA;
b) Treatment with chloroquine is safe for OA.
Background
Osteoarthritis (OA) is the most common form of arthritis in the United States (Lawrence 1998). It is often painful and impairs quality of life, being caused by a degenerative process primarily affecting articular cartilage. Age is the most powerful risk factor for (OA). It is estimated that 68% of individuals older than 55 years have radiographic signals of OA (Elders 2000). Its high prevalence (Peterson 1996) brings significant costs to society, not only directly coming from the disease itself, but also indirectly including for example absenteeism from work. Costs of musculoskeletal disorders, of which osteoarthritis is the most common have risen over recent decades accounting for up to 1‐ 2,5% of the gross national product for those countries studied so far, including the United States of America (USA), Canada, the United Kingdom, France and Australia (March 1997). Data from the USA show that about 43 million of individuals (1 in 6) have arthritis and most of them are older than 45 years (Elders 2000). It is estimated for the year 2020, 59.4 million individuals affected by arthritis (all arthritis and rheumatism cases) in the USA. The annual cost to society in medical care and lost wages is currently estimated to be $65 billion, and is projected to escalate to $95 billion by the year 2020 (Elders 2000). Prevalence of osteoarthritis varies, depending on the age distribution of the population studied, the method of evaluation, and the diagnostic criteria used. Musculoskeletal disorders are the first cause of disability and the second cause of permanent disablement in Italy. Osteoarthritis is the most frequent rheumatic disease and affects about 4 million Italians (Leardini 2001). Six million new diagnoses of osteoarthritis are reported each year in France, totaling up direct costs (4 billion FF) and indirect costs (at least 600 million FF) represent an enormous burden for the French economy and national health care system (Levy 1993).
Current OA treatment includes non‐pharmacological, pharmacological, and surgical approaches. Non‐pharmacological therapeutic interventions for OA include patient education, temperature modalities (cryotherapy and/or local heat), weight loss, exercises, physiotherapy, occupational therapy, and stress reduction on weight bearing of certain joints like knee and hip (instructing patient to avoid aggravating stress to the affected joint, implementing correction procedures if the patient illustrates poor posture) (Steigelfest 2002). Pharmacological treatments have been divided into three categories (Lequesne 1994 ): (1) analgesics and non steroidal anti‐inflammatory drugs (NSAIDs), (2) symptomatic slow‐acting drugs for osteoarthritis (SYSADOA), and (3) chondroprotective or disease modifying osteoarthritis drugs (DMOAD).The SYSADOA are also known as SADOA (Slow acting drugs for treatment of osteoarthritis) and include: glucosamine sulphate, diacerein, and the non saponifiable oils of avocado and soya.
The antimalarial derived from 4‐aminoquinoline like chloroquine (di‐phosphate or hydroxychloroquine) could be included in this group of SADOA, although this is controversial. As they are effective drugs, with low toxicity and low cost in the treatment of other modalities of arthritis, they have been recruited for the treatment of OA (Hyrosi 1989, Bryant 1995,Robertson 1999, Baptista 1998, Ferraz 1999, Hamdan 2000). However, the official guidelines on the treatment of OA do not recommend the use of the SADOA (American College of Rheumatology Subcommittee on Osteoarthritis Guidelines).
Objectives
To assess the effectiveness and safety of the chloroquine for treating OA. The following hypotheses will be tested:
a) Treatment with chloroquine is effective for OA;
b) Treatment with chloroquine is safe for OA.
Methods
Criteria for considering studies for this review
Types of studies
All eligible randomised controlled trials (RCTs) or controlled clinical trials (CCTs) will be included in this review.
Types of participants
People aging 18 or over, with diagnosis of primary (when it appears without any obvious antecedent insult to the joint) or secondary (when it follows a demonstrable abnormality or injury) osteoarthritis, in both the axial and peripheral skeleton, erosive or non‐erosive (classical) .Studies will not be included it the authors do not present their date separately for different types of conditions (i.e.. osteoarthritis and rheumatoid arthritis).
Types of interventions
Studies comparing the chloroquines prescribed for rheumatology: chloroquine di‐phosphate or hydroxychloroquine, any dose, to another active pharmacological intervention or placebo will be eligible for inclusion.
Types of outcome measures
Primary:
‐ partial or total reduction of pain
‐ improvement on the degree of the studied joint movements
‐ global assessment by the patient
These outcome measures are those agreed to OMERACT III (Bellamy 1997) in which the assessment includes at least one validated measure of pain, physical function or global assessment of the patient.
In addition to these outcomes: validated outcome measures of physical function, such as the WOMAC, HAQ, and LEQUESNE INDEX, physician global assessment and quality of life.
Secondary:
‐ death
‐ hospitalization
‐ side effects: retinal toxicity, cutaneous pigmentation, leukopenia, cardiac or renal disorders
‐ drop outs or withdrawals
Search methods for identification of studies
1. Electronic databases: There will not be restrictions in regard to language or date of publication.
A specific search phrase for chloroquines in OA was developed:
#1 osteoarthritis OR osteoarthritic OR osteoarthrosis OR degenerative arthritis OR arthrosis.
#2 chloroquine OR antimalarial* OR antimalarial* OR hydroxychloroquine OR chloroquine phosphate OR plaquinol OR plaquinil OR quensy
#3 #1 AND #2
This search will be associated with a phrase of identification of RCTs or CCTs specific for each database, except for the register of controlled trials of Cochrane Collaboration (CCTR) which is specific for this design of study. The search strategy will be that from Dickersin 1994, modified by the Cochrane Musculoskeletal Group. The following electronic databases will be searched:
‐ CCTR(2002 ‐ issue 3);
‐ LILACS (1982‐2002)
‐ EMBASE (from 1980‐2002)
‐ MEDLINE (1966‐2002)
2. Personal communication: Content experts in the area and authors of relevant studies included in the systematic review will be contacted, to identify additional studies.
3. Contact with pharmaceutical industry: laboratories that trade antimalarials will be contacted.
4. Handsearches: reference lists of abstracts of conferences in rheumatology, Brazilian literature, and previous Cochrane reviews, either systematic or narrative, will also be searched.
Data collection and analysis
Selection of trials:
Two reviewers (PAA and BGOS) will independently review the references found with the search strategy, and apply the inclusion criteria. Differences in the evaluation will be solved by consensus.
Quality assessment:
The methodological quality of the selected trials will be assessed using the criteria described in the Cochrane Handbook (Clarke 2002).
A ‐ Low risk of bias (adequate allocation concealment)
B ‐ Moderate risk of bias (allocation concealment unclear)
C ‐ High risk of bias (inadequate allocation concealment)
For the purpose of the analysis of this review, it will include the trials which meet the criteria A or B.
The Jadad and Schultz scales will also be used to assign an overall quality score to each study (Jadad 1996, Schulz 1995). These scales consider the basis of randomisation, adequate concealment of randomisation, degree of blinding, use of intention to treat analysis and description of dropouts and withdrawals.
Each item receives one point if the answer is positive. In addition, a point can be deducted if either the randomisation or the blinding/masking procedures described were inadequate.
Differences between data extraction and the assessment of the quality will be discussed, decisions documented and, if necessary, the authors of the studies will be contacted to solve the subject. A third reviewer may be consulted to solve the differences.
Data management:
Two reviewers will extract data of the studied population, the intervention and outcomes independently using a predetermined form. Information will be extracted on:
a. General information: published or not, title, authors, contact address, country, resource, publication, publication year, duplication of the publishing, sponsor.
b. Characteristics of the study: design, length, randomised and method, allocation procedure, blinding (patients, administrator care and outcome appraiser), allocation check.
c. Intervention: placebo inclusion, interventions (dose, model of administration and length of treatment), comparisons of the interventions (dose, model of administration and length of treatment).
d. Patients: samples (randomised or convenience), exclusion criterion, total number or number on the comparison group, sex, age, characteristics of basis, diagnostic criteria, length of disease and similarity of the groups of basis (in terms of co‐morbidity)
e. Outcomes: All outcomes reported in papers will be extracted
f. Results: of outcomes of interest and whether intention to treat analysis was performed.
Analysis:
The analyses will compare each chloroquine separately to placebo, active drugs, and others chloroquines; if data is comparable and can be pooled, data analysis will be facilitated using RevMan 4.1 software and meta‐analysis will be performed.
For dichotomous outcomes, results will be expressed as a relative risk (RR) (proportion of events in the treatment group in relation to the proportion of events in the control group), with the 95% confidence intervals. When overall results are statistically significant, the number needed to treat (NNT) or the number needed to cause damage (NND) will also be calculated. The NNT is the number of patients that need to be treated with the objective to prevent an event..Data will be analysed and presented primarily using a random model (Der Simonian 1986), but a fixed effects model will also be calculated to see if it makes any substantive difference.
Continuous outcomes will be analysed according to their difference in mean treatment effects and its standard deviation. If not reported in published paper, means and standard deviation will be sought from the authors.
Heterogeneity in the results of the meta analysis will be assessed both by inspection of graphical presentations (funnel plot) (Egger 1997) and by calculating a chi‐square test defining as significant p < 0.1. Possible reasons for heterogeneity are: different populations, interventions and assessments of outcomes. To explore the differences on the effects of the treatment a sensibility analysis will be conducted looking at different doses of chloroquines.
Three subgroup analysis are planned:
‐ High quality versus low quality studies.
‐ Outpatients versus inpatients.
‐ Erosive versus non erosive OA.
