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Rheumatoid Arthritisis is an auto-immune disease that affects approximately 400,000 of the United Kingdom population and there are around 20,000 newly diagnosed cases every year1. The prevalence is increasing by age and greatest on aged 65-74 for both genders although RA is three times more common in female than male2. RA is commonly characterised using "The American Rheumatism Association 1987 revised criteria for the classification of RA" (Table 1) designed by committee of the American College of Rheumatology in 19873. However, this classification is meant for research purpose and not useful in clinical practice4. There are several investigations that can be carried out to confirm the diagnosis of RA such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), synovial fluid test, rheumatoid factor (RF), antinuclear antibody (ANA) and radiology4.
RA is chronic and systemic disease that can occur on any synovial joints however it affects mostly the joints on the hands and feet and commonly, both left and right sides are affected symmetrically. Synovial joints are joints that are surrounded with a unique tissue named synovium that maintain the nourishment and smoothness of joints. Thickened joint lining and excessive white blood cells with increased blood vessels were found in inflamed joint. Thus, this causes persistent inflammation, pain, stiffness, swollen joints and finally destruction at the joints (erosion of bone and cartilage) by the inflamed synovial membrane5. The destruction of joints not only causes pain but also disability in patient for example deformity of hand affects the movement of hand or handicap. According to Young et al. (2002), 30% of RA patient were withdrawn from their job within five years due to their condition6 whereas Barrett et al. (2000) shows that one out of seven working people resigned on first year of diagnosis7. Furthermore, the effect of RA does not limit to joints but also cause complications in other organs for example lung fibrosis, inflammation of the lining in the lungs and heart as well as inner lining of blood vessel3. These complications are significant and severe and sometimes lead to mortality, fortunately, these are uncommon. However, there are evidences showing that long term inflammation and loss of function in the body increases risk of heart condition, infections and lead to premature death3. This increases the National Health Service (NHS) and supporting organisations expanses directly and also burden the economic costs indirectly due to the decreases productivity and manpower also increases of medical expenses for other complications.
Although RA is a common disorder, the main causes still remain unknown; therefore making the treatment of RA difficult. Cigarette smoking is believed to be the crucial underlying reason as well as some potential factors for example infections, injuries and genetic inheritance5. Treatment of RA should start as early as possible, preferably within the first six months of the beginning of the disease to achieve better outcome of disease control.
The main aims of RA treatment are to improve patient quality of life by relieve symptoms, minimise the persistent pain and inflammation and also to delay or prevent the progression of joints destruction. According to SIGN guideline4, basic analgesics for example paracetamol and codeine are recommended as an alternative for nonsteroidal anti-inflammatory drugs (NSAIDs) to control the pain in RA. However, NSAIDs therapy is more effective in RA for symptomatic control as NSAIDs exhibit anti-inflammatory effects by inhibit the cyclooxygenase (cox) pathway selectively or non-selectively. NSAIDs do not prevent the progression of joints destruction and should always use with caution as NSAIDs could potentially interacts with many drugs and they have well-documented side effects especially gastrointestinal (GI) problems. Nevertheless, the GI problems could be prevented with concomitant use of gastroprotective drugs like proton pump inhibitors (PPIs).
2.1 Treatment options
The important class of drug in RA treatment is disease modifying anti-rheumatic drugs (DMARDs). DMARDs are commonly prescribed as first line drug and should be sustained in RA patients and they are relatively cheap. Current available DMARDs that are used in UK clinical practice are shown in table 2.
Table 2: Different drug classes for treatment of RA with their advantages and disadvantages
Prevent radiological damage8
Reduce the development of new erosions8
Cumulative toxicity: Osteroporosis, immunosuppression, adrenal suppression, GI bleeding4
Local corticosteroid injections
Rapid local symptomatic relief4
Increase mobility and reduce deformity8
Intra-articular injections may cause flushing and affect hyaline cartilage therefore, each joint should be treated less than 3 times in a year8
Improvement in 3-4 weeks9
Can be used in renal disease4
Bone marrow suppression9
Possible neutropenia or thrombocytopenia8
Less bone marrow suppressive, renal and hepatic toxicity9
Delayed onset (6 weeks up to 6 months)9
Ocular examination must be carried out before treatment8
Deep intramuscular (IM) injection Sodium aurothiomalate
Equally effective as MTX, SASP and Penicillamine
Delayed onset (3-6 months)
Weekly injection for 22 weeks before initiate maintenance regime9
Renal, haematological disorder, nitritoid reaction
Less effective than IM
As above except nitritoid reaction
Similar action to gold, MTX and SASP4
Delayed onset (at least 6-12 weeks, most within 6 months)8
Proteinuria, potentially induce serious autoimmune disease9
Contra-indicated with lupus erythematosus8
Rapid onset (6-10 weeks)8
Contain anti-inflammatory activity9
Contra-indicated or caution in liver disease, pregnant or breast feeding, pulmonary toxicity, haematological disorders, renal disease, immunodeficiency8
Rapid onset (8-12 weeks)4
Beneficial effect in anti-inflammatory activity4
May cause haematological abnormalities in the first 3 to 6 months (require close monitor of blood counts and liver function tests)8
Often limited by side effects9
Reserved for severe active RA when other DMARDs therapy failed8
Additional cautions in RA (contra-indicated with infections, malignancy, renal failure and uncontrolled hypertension)8
Efficacy similar to MTX and SASP (as alternative)9
Onset starts after 4-6 weeks and improvement may extent for further 4-6 months8
Specialist use only
Washout procedure is required before switching to other DMARDs8
The choice of DMARDs used should be appropriate and meet patient requirements as effective early therapy is vital to achieve better prognosis of the disease. Patient should always be counselled on the pros and cons of DMARDs and understand about the essential of disease monitoring. According to a survey conducted by Jobanputra P et al.10 on May 2002, MTX (46.5%) or SASP (43.5%) or either one of both (5%) appeared to be the favour first choice of DMARDs for 331 British rheumatologists. The subsequent choices were leflunomide, IM gold then only biological agents. In addition, the preferred combination was found to be MTX and SASP if either MTX or SASP monotherapy failed. Hydroxychloroquine (8%) also appeared to be the add-on drug into MTX and SASP combination in active disease. In this survey, important clinical influences of DMARDs choice were found to be the poor prognosis of disease, rapid symptom control and their side effects profile. Based on another journal published on July 2005 by Edwards CJ et al.11, SASP (46.3%) and MTX (31.4%) were the regular prescribed DMARDs in RA patients between year 1987 and 2002 from United Kingdom General Practice Research Database. Besides that, the use of gold has found to be fallen from 13.2% to 2.3%.
Besides DMARDs, biological agents have recently become one of the treatment choices for RA. Current biological agents including Adalimumab, inflixmab and etarnercept also known as tumour necrosis factor-alpha (TNF-Î±) inhibitors, are used under supervision of specialist and they act by inhibit the action of TNF-Î±8. Although there are discussions about the increase risk of cancer and infection, more trials should be carried out to clarify the doubts. They can be used as monotherapy or combination (mainly with MTX) when more than two DMARDs agents failed to have good respond8. However they are not widely used yet as they are costly and their actual anti TNF-Î± activity and long term complications have not fully understood.
Non pharmacological interventions play an important role in the management of RA patients by multidisciplinary team although there is lack of evidences from trials. Occupational therapy including daily routine activity advice and joint protection, physiotherapy, splinting, podiatry as well as dietary advices on weight management, supplements and nutritional are the non pharmacological interventions that can be used in RA patients4.
2.2 Assessment of treatment
There are different types of scoring systems or assessments used to assess patient's response to the treatment. Disease activity score (DAS) is a clinical indicator of RA disease activity which include data from Ritchie articular index (RAI), 44 swallow joints count, acute phase response as well as the general health12. DAS 28 is a modified version of DAS but include only 28 tender and swallow joint count, erythrocyte sedimentation rate (ESR) and general health12. Both DAS can be calculated using formulae as shown in table 3.
Table 3: DAS and DAS28 formulae and their respective disease activity level12
4 variables (DAS4)
DAS4 = 0.53938Ã-âˆš(RAI) + 0.06465Ã- (SJ) + 0.330Ã-ln (ESR) + 0.00722Ã- (General Health)
4 variables (DAS28-4)
DAS28-4 = 0.56Ã- âˆš (TEN28) + 0.28Ã- âˆš (SJ28) + 0.70Ã-ln (ESR) + 0.014Ã- (General Health)
3 variables (DAS3)
DAS3 = 0.53938 Ã-âˆš (RAI) + 0.06465Ã- (SJ) + 0.330Ã-ln (ESR) + 0.224
3 variables (DAS28-3)
DAS28-3 = [0.56Ã- âˆš (TEN28) + 0.28Ã- âˆš (SJ28) + 0.70Ã-ln (ESR)] 1.08 + 0.16
Disease activity level:
Remission - DAS < 1.6
Low - DAS â‰¤ 2.4
moderate (2.4 < DAS â‰¤ 3.7)
high (DAS > 3.7)
Disease activity level:
Remission - DAS28 < 2.6
Low - DAS28 â‰¤ 3.2
moderate (3.2 < DAS28 â‰¤ 5.1)
high (DAS28 > 5.1)
RAI -graded assessment of 26 tender joint count13
SJ (swallow joints) - 44 swallow joint count
TEN28 - 28 tender joint count
SJ28 - 28 swallow joint count
Besides DAS and DAS 28, another two widely used assessments in clinical trials are the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) improvement criteria as shown in table 4. ACR 20, 50 and 70 means there is a 20%, 50% and 70% improvement in criteria shown below.
Table 4: EULAR response criteria and ACR improvement criteria
EULAR response criteria12
ACR improvement criteria14
Analysis of improvement in DAS or DAS28 (Î”) from baseline:
No response: Î” â‰¤ 0.6
Moderate response: 0.6 < Î” â‰¤ 1.2
Good response: Î” > 1.2
Tender joint count
Swollen joint count
Improvement in a minimum of three of:
Patient's global disease activity
Practitioner's global disease activity
Patient's pain assessment
Acute phase response
3.0 Recommendation and evidences
As written in the scenario above, this female patient has failed to respond to 6 months of treatment with SASP. There are two straight forward options such as to add another or more drugs into the current treatment or to switch the SASP to another drug. As MTX is the favoured drug and effective as SASP so MTX is the drug of choice to either add on or switch to. There are many clinical trials and reports that compare the efficacy of single drug therapy and the combination therapy in early RA15-17 however in this scenario, the comparison of MTX-SASP combination with MTX monotherapy in patient who failed SASP will be focused.
A randomised open clinical trial has been carried out by Haagsma et al. (1994)18 to compare the effectiveness, adverse effects and the pharmacology of the combination therapy of sulphasalazine (SASP) and methotrexate (MTX) with monotherapy of MTX in patients with RA who failed to respond to SASP therapy. A total of 40 patients who are older than 18 years old, suffered from RA as defined by revised ACR criteria (1987) with a DAS score more than 3.0 and failed to respond with their current SASP treatment (given for at least 6 months) were assigned randomly to either combination or monotherapy but only 38 patients completed the trial. Patients who already had MTX or contraindicated with MTX were excluded. Patients were then examined openly by an examiner 2 weeks before trial start and every 4 weeks until week 24. Mean change of DAS score in both groups was measured as primary outcome where the change of DAS between week 0 (baseline) and week 24 (end) was used as secondary outcome. Besides that, adverse events were checked every 4 weeks by patient interview and laboratory results. On the other hand, 15 patients who received the combination therapy were involved in the study of effect of constant SASP administration on the pharmacokinetics of weekly MTX dose. Results of this clinical trial showed that the mean change and change from baseline for both therapies group were decrease but the differences in combination group were significantly superior to the monotherapy group. There was no notably difference on the adverse events between two groups and SASP showed no effect on the pharmacokinetic of MTX. Therefore, this study has concluded that MTX-SASP combination therapy is clinically better than MTX monotherapy. Nonetheless, it has some limitations for example small sample size, short duration and study was conducted openly.
Moreover, a randomised, double-blind, placebo controlled methotrexate and sulphasalazine combination therapy (MASCOT) study which compare the efficacy of MTX or SASP monotherapy and combination therapy with MTX-SASP in patient who has inadequate response to 6 months SASP treatment was conducted by Capell HA at el.19 in Scotland. This study was divided into 2 phases where 687 patients received 6 months SASP treatment in phase 1 and accessed by DAS score then those who had unsatisfactory response (DAS â‰¥ 2.4) after treatment were recruited into phase 2. A total of 165 patients were recruited into phase 2 after selections and they were randomly allocated into 3 treatment groups which include MTX-SASP combination, SASP monotherapy with placebo and MTX monotherapy with placebo. The secondary outcome measures were the EULAR and ACR 20, 50 and 70 scores. Besides that, side effects experienced by each patient were recorded to compare the toxicity between three treatment groups. At the end of this study, only 118 patients have completed the study as 47 patients were dropped out due to side effects or lack of efficacy. Results showed that DAS scores of three treatment group decreased while the combination group was significantly superior to both monotherapies (combination versus MTX, P = 0.039; combination versus SASP, P = 0.023). In addition, combination group appeared to have more patients in the good response as well as remission level. As for the ACR 20, 50 and 70, although combination group seemed to have greater proportion in 20%, 50% and 70% respond groups, there was no statistically significant different compared to both monotherapies group. Thus, this study proved that the MTX-SASP combination treatment after failure to 6 months SASP treatment has significant clinical improvement and cost effective with no extra adverse effects.
One of the supporting evidences is the concise report published by Schipper LG at el.20 (2009). They have compared the results of four randomised clinical trials (RCTs) for evaluation of the efficacy of MTX-SASP combination in patients who had failed SASP treatment and patient who never expose to any DMARDs previously. Among these RCTs, two were about the add-on trials while two were parallel trials in DMARDs naÃ¯ve patients. Mean change in DAS and ACR improvement criteria were used as the primary outcome measure. As a result, this report showed that MTX-SASP therapy has additive effects in patients who failed SASP therapy but only has sub-additive effects in DMARDs naÃ¯ve patients. It also recommended that the addition of MTX to SASP as a clinical treatment option after SASP has failed.
On the other hand, another recent report compares the efficacy between a complete change to MTX monotherapy and an addition of MTX to SASP in patients who failed SASP treatment was also demonstrated by Schipper LG at el.21 (2009). In this report, they have included large number of patients from Nijmegen Inception Cohort who initiated the treatment with SASP as first or second choice then followed by either an addition of MTX or a complete change to MTX. Exclusion criteria were the concurrent use of other DMARDs and delayed initiation of MTX in patients who change to MTX monotherapy. The final amount of patients involved in this study was 230 where 106 patients underwent combination therapy and 124 patients changed to MTX monotherapy. They were followed up for up to a year and the mean change in their DAS 28 after 6 months was measured as primary outcome. This report found that the decrease of mean change in DAS28 in both of the treatment groups were similar and statistically significant (P< 0.0001) after 24 weeks however the discontinuation of treatment was significantly higher (P< 0.05) in the combination group compared with the monotherapy group after a year. The monotherapy group also showed a greater one year drug survival of MTX (P <0.01) but more frequent adverse events than the combination group. Thus, this report suggested that the clinical efficacy of both treatments is similar and recommended that a complete change to MTX monotherapy is a beneficial choice in patients who failed SASP treatment.
Based on the evidences18-20 above, the MTX add on therapy is found to be a better option than switching the SAPS to MTX. Although Schipper LG at el. (2009)21 failed to prove that the combination treatment is a better option than monotherapy, combination treatment still has significant decrease on the DAS28. Thus, in this scenario, MTX should be initiated with weekly dose of 7.5mg and adjusted according to patient response until maximum weekly dose of 20mg. According to NICE guideline recommendation 20, if the disease is stable after the addition of new drugs, the pre-existing drug may be reduced or stopped. Thus, in this scenario, stepping down treatment can be carried out if this patient condition improved and stable after the introduction of MTX into SASP treatment. However, original treatment regime should be resumed when first sign of a flare is observed during stepping down.
If patient still fail to response to MTX-SASP treatment after 6 months, triple drugs treatment for example MTX, SASP and hydroxychloroquine could be an option. This triple drugs combination has shown superior effect than MTX alone (P<0.001) and SASP-hydroxychloroquine (P=0.003) in a two year, randomised and double blinded clinical trials conducted by O'Dell JR at el.22 (1996) without any increment of toxicity events. The superior effect of MTX-SASP-hydroxychloroquine was seen again in a two year, double blinded, randomised and placebo-controlled clinical trial carried out by O'Dell JR at el.23 (2002) by comparing the efficacy of MTX-SASP-hydroxychloroquine with MTX- hydroxychloroquine combination (P= 0,05) and MTX-SASP combination (P=0.002). These combinations were found to be well tolerated.
Besides the triple treatment, there is another alternative for example, change the MTX-SASP combination to the combination of MTX with TNF-Î± inhibitor as suggested by NICE guideline. NICE stated that TNF-Î± inhibitor can be used when patient failed to response to a minimum of 2 DMARDs. The combination of either one of adalimumab, etanercept or infliximab with MTX was found to have greater effect compared to MTX alone24-26. However this combination is not as cost effectiveness as the triple combination as above.
As a conclusion, RA is a progressive chronic disease that affects patient's quality of life and a poor prognosis can cause further complications. Early effective treatment should be initiated to achieve good symptom control and prevent bone erosion. MTX and SASP are current preferred DMARDs in treatment of RA due to their efficacy and favour side effects profile compared to the conventional DMARDs (gold, penicillamine). Besides that, corticosteriods can be used for specific indications and should be avoid for long term use due to the long term complications. In addition, TNF-Î± inhibitors seem to be a useful agent in future. Besides the pharmacological treatment, non-pharmacological interventions can further improve patient quality of life and patient education on compliance, lifestyle changes and disease knowledge is very important to achieve maximal disease control.