In patients with recently diagnosed rheumatoid arthritis, does treatment with methotrexate guided by a strict, step-wise computerised protocol improve disease remission in comparison to standard care?
Using an intensive and strict step-wise dosing protocol for methotrexate guided by a composite disease activity score in early rheumatoid arthritis with monthly assessments promotes disease remission and improves several measures of disease activity more rapidly than dose adjustments based on clinician opinion with assessments every three months.
Aggressive treatment of early rheumatoid arthritis (RA) is thought to prevent decline in long-term functional status through prevention of joint damage. The use of disease modifying anti-rheumatic drugs (DMARD) early in disease onset was thought to lead to higher rates of clinical remission. Particularly, the 2004 TICORA study published demonstrated that monthly follow up visits with step-wise treatment using a predefined protocol guided by a composite disease activity score (DAS28) significantly improved remission rates and disease score compared to standard care with follow up visits every three months and treatment guided by clinical opinion. Whether a more regimented, computer-assisted protocol could improve disease remission rates was unknown. Further, TICORA employed glucocorticoids as the backbone therapy. The use of a methotrexate backbone was unknown.
Published in 2007, the Computer Assisted management in Early Rheumatoid Arthritis (CAMERA) study randomized 299 patients with early RA who were DMARD and glucocorticoid-naive to intensive treatment (monthly follow-up and computer decision support) or conventional treatment (q3mo follow-up) to drive methotrexate and add-on cyclosporine therapy. Patients in the intensive arm had a greater rate of remission than those in the conventional therapy arm (50% vs. 37%, P=0.03). Both groups had high rates of adverse events.
The CAMERA trial further supports that early, aggressive treatment of RA. This study also confirmed that methotrexate is an appropriate and potent "anchor" treatment for RA, with the ability to titrate dosing in order to achieve a response.
ACR RA guidelines (2015, adapted)
- If symptomatic early RA:
- Use treat-to-target strategy over a non-targeted approach (strong recommendation, LOE low)
- If low disease activity and no prior DMARD medication use, prescribe DMARD monotherapy, preferably methotrexate, over double or triple therapy (strong recommendation, LOE low)
- If moderate or high disease activity and no prior DMARD medication use, prescribe DMARD monotherapy over double therapy (conditional recommendation, LOE moderate) or triple therapy (conditional recommendation, LOE high). Note: Methotrexate was not recommended as the preferred agent.
- Open label, randomized, prospective, multicenter treatment strategy trial
- Intensive computerized treatment protocol (n=151)
- Conventional strategy (n=148)
- Setting: 6 treatment centers in Utrecht, the Netherlands
- Enrollment: 1999-2003
- Follow-up: 2 years
- Analysis: Intention-to-treat
- Primary outcome: Number of patients in remission for at ≥3 months at any time during the 2 years
- RA, defined by the revised 1987 American College of Rheumatology Criteria
- Onset of RA symptoms <1 year
- Age >16 years
- Prior use of glucocorticoids or DMARD
- Use of cytotoxic or immunosuppressive drugs within three months
- Alcohol abuse (>2 units/day)
- Psychological problems affecting adherence
- Demographics: Female 69%, age 54 years
- Disease characteristics: ESR 36 mm/h, RF positive 89%, morning stiffness 87 min, # swollen joints 14, # tender joints 15
- Visual analogue scale (out of 100 mm, higher is worse): General well being 54 mm, pain 51 mm
- Functional ability on Health Assessment Questionnaire (out of 3, higher is worse): 1.2
- Radiographic damage score (out of 448, higher is worse): 1.6
- Randomized to intensive or conventional treatment
- A complex titration strategy of methotrexate monotherapy + add-on cyclosporine therapy is depicted in Figure 1 on page 1445. In brief, both groups started with methotrexate 7.5 mg PO/week.
- Dosing was not changed in either group if patients had improvement in their disease since the prior visit
- If no improvement, the dose increased by 5 mg/week to a maximum of 30 mg/week
- For those on maximum tolerable dose of methotrexate, the medication was changed from oral to subcutaneous administration
- If inadequate response on methotrexate subq dosing, cyclosporine 2.5 mg/kg/day was added and methotrexate was reduced to 15 mg/week, with uptitration of the cyclosporine to a maximum of 4 mg/kg/day.
- If sustained response, methotrexate was decreased at 2.5 mg/week until there was no sustained response, at which point intensification resumed.
- If no response on maximum tolerable methotrexate and cyclosporine dosing, other DMARDs were used
- Intensive treatment: Monthly follow-ups, clinical decisions aided by a computerized decision support tool
- Response compared to prior visit defined as >20% improvement in # of swollen joints and >20% improvement in ≥2 of: ESR, # tender joints, and VAS general well-being
- Inadequate response defined as ≤50% improvement from baseline in # of swollen joints and ≤50% improvement in ≥2 of: ESR, # tender joints, and VAS general well-being
- Conventional treatment: q3mo follow-ups
- Response compared to prior visit defined as a decrease in # of swollen joints, or if unchanged # of swollen joints, the assessor determined response by assessing # of tender joints, ESR, and VAS general well-being
- Inadequate response defined as # swollen joints ≥6, # painful joints ≥3, ESR ≥28 mm/h, and AM stiffness ≥45 min
- For both groups, sustained response defined as no swollen joints and ≥2 of: # painful joints ≤3, ESR ≤20 mm/h, and VAS general wellbeing ≤20 mm
Comparisons are intensive therapy vs. conventional therapy.
- Number of patients in remission for at ≥3 months at any time during the 2 years
- 50% vs. 37% (P=0.029)
- Mean time until the first period of remission
- 10.4 vs. 14.3 months (P<0.001)
- Mean duration of remission period
- 11.6 vs. 9.1 months (P=0.025)
- American College of Rheumatology 50% response (ACR50)
- 1 year: 58% vs. 43% (P=0.018)
- 2 years: 46% vs. 45% (P=1.00)
- Radiographic progression score over 2 years according to modified Sharp/van der Heijdge method
- 0 units/year (IQR 0-2.0) vs. 0 units/year (IQR 0-2.5) (P=0.9)
Values below are reported as areas under the curve (AUC), with the independent variable being time from randomisation. Data was reported this way to demonstrate that intensive treatment led to a more rapid response in these variable, but not a more drastic response at the two year point.
- Morning stiffness AUC
- 17.0 vs. 23.7 (P=0.009)
- ESR AUC
- 17.7 vs. 21.6 (P=0.007)
- Tender joint count AUC
- 3.6 vs. 5.5 (P<0.001)
- Swollen joint count AUC
- 2.7 vs. 4.7 (P<0.001)
- VAS general well-being AUC
- 19.0 vs. 31.2 (P<0.001)
- VAS pain AUC
- 12.0 vs. 19.0 (P=0.001)
- Functional disability score AUC
- 0.64 vs. 0.80 (P=0.8)
Statistical comparisons of adverse events were not provided.
- Any adverse event
- 94% vs. 87%
- 2378 vs. 873 events
- Elevated liver transaminases: 23.2% vs. 18.6%
- Hematologic abnormalities: 7.1% vs. 4.2%
- Pulmonary symptoms: 2.0% vs. 5.3%
- Gastrointestinal: 24.6% vs. 25.2%
- Neurological disorders: 18.8% vs. 18.8%
- Renal events: 2.4% vs. 2.8%
- Mucocutaneous: 14.8% vs. 18.2%
- Time to withdrawal
- 59 and 25 withdrew from the trial.
- 57 vs. 42 weeks (P=0.02)
- The authors did not report the amount of patients that required cyclophosphamide. However, they did state that cyclophosphamide was no more effective than methotrexate in patients who received it.
- Patients were barred from receiving glucocorticoids in order to control disease activity while awaiting for methotrexate to take effect, which is not representative of standard clinical practice. If patients were allowed to receive glucocorticoids, this may have minimised the more rapid benefit seen with the intensive treatment group.
- Patients in the intensive treatment group were reassessed monthly, compared to every three months in the standard care group. This allowed for medication titration much more rapidly in the intensive care group. Given that both groups achieved similar disease activity scores at the end of two years, the benefit seen with the intervention may be attributable to more frequent rheumatologist visits.
- The protocol lead to reduction in methotrexate dosing among patients in remission, which may have lead to less well-controlled disease and more pronounced radiographic progression.
- Funding not identified.
Study funding was not disclosed. There were no conflicts of interest declared.
- Demoruelle MK & Deane KD Treatment strategies in early rheumatoid arthritis and prevention of rheumatoid arthritis. Curr Rheumatol Rep 2012. 14:472-80.
- Singh JA et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. ' 2016. 68:1-26.
- Bijlsma JW & Weinblatt ME Optimal use of methotrexate: the advantages of tight control. Ann. Rheum. Dis. 2007. 66:1409-10.