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IJPMR 12, April 2001;11-18
Treatment of Rheumatoid Arthritis with
Combination of Disease Modifying Anti-Rheumatic
Drugs: A Three-year follow-up study
Dr. N. Romi Singh, DNB (PMR), .MNAMS, Assistant Professor
Dr. Kunjabasi Wangjam, MS (Ortho), DNB (PMR), Associate Professor & Head, Department of
Physical Medicine & Rehabilitation, Regional Institute of Medical Sciences, Imphal Abstract
Rheumatoid arthritis is a multisystem disease causing substantial morbidity. Disease
modifying anti-rheumatic drugs induce clinical remission in such patients. The study aims to find
out the efficacy of these drugs in producing disease remission in patients of rheumatoid arthritis
reporting even at the later stage of illness.

A prospective study was carried out in 61 patients of rheumatoid arthritis. Mean duration
of illness was 2.9 years, age ranging from 20-65 years. The patients were followed up for a mean
period of 20.29 ± 9.79 months (range 6-36 months). Chloroquine phosphate - 150 mg/day,
Methotrexate -7.5 to 15.0 mg/week Sulfasalazine 500-2000 mg/day were given in saw-tooth
strategy regime. Clinical response was measured for clinical markers of synovial inflamation.
Disease control was achieved in 39 % of the patient at 6 months and in 60% of patients in 24
months, still maintaining at 50% improvement in clinical markers. Chloroquine and Methotrexate
was the most commonly used combination (52.5%) for achieving remission,without any major
adverse effects.

Disease modifying anti-rheumatic drugs have a role in achieving disease remission even
in comparatively later stages of illness. Methotrexate and Chloroquine can be safely given for
longer period. Side effects can be monitored by periodic check up.
Key words :
Rheumatoid Arthitis, Disease Modifying Anti-Rheumatic Drugs, Saw-tooth strategy,
Disease remission, Outcome measures, Adverse effects.

of disease modifying anti-rheumatic drugs(DMARDS) are not clearly understood3,4.
However, there is strong evidence that DMARDS multisystem disease causing substantial morbidity can alter the short-term course of the disease5,6.
Treatment of RA with DMARDS is problematic demonstrated that 50% of the patients suffering because of various adverse effects and drugs also from RA will have significant impairment of their tend to loose their effectiveness with time.
work activities after 10 years of diagnosis1,2. Sincethe pathogenesis of RA is obscure, the treatment It is also reported that only 5 - 15% of the remains emperical and the mechanisms of action patients of RA in whom there was initial responseto a DMARD will continue benefit from the drug Address for correspondence : Dr. N. Romi Singh, Assistant therapy after 5 years4,7,8. Increasing knowledge Professor, Department of Physical Medicine & Rehabilitation, about the pathogenesis and long-term morbidity and Regional Institute of Medical Sciences, Imphal-795004, the importance of early treatment in RA has led to a more aggressive approach9. And, clinical trials with DMARDS in early RA indicate definitedecrease in radiographic progression when Study design
inflammation is effectively suppressed, suggesting Assessment for the clinical variables was that the inflammatory process is at least the major done at entry (baseline), at 1 to 2 months interval factor in joint destruction10. Individual DMARDS for the first 6 months and thereafter at 3 to 6 have to be changed repeatedly, in order to find out months interval. The clinical variables tested were the most effective and least toxic drug for the swollen joint count (JS), tender joint count (JT), individual patient. Since the traditional pyramid range of motion (ROM) of the joints, grip strength approach has become ineffective in suppressing in Kg/cm2 (using grip dynamometer), duration of the rheumatoid inflammation and in preventing joint morning stiffness in minutes and pain using visual destruction in most RA, new treatment strategies have been proposed11-13. In our set up, we find the investigations for RA factor, C-Reactive protein, majority of the cases of RA reporting to us in the haemogram, liver function test (LFT), kidney later stage of illness. Hence, the present study function test (KFT) and radiological investigations aimed to find out the efficacy of DMARDS in viz. X-ray of the wrist and hand, chest X-ray were producing disease remission and arresting progression of disease process in RA patients even haemogram were done at 3 months interval if no at the later stage of illness and to find out the toxicity untoward adverse effects were reported.
and tolerance of DMARDS used thereof.
Ophthalmologic examination was carried out everysix months for all the patients receiving Chloroquine Patients and Methods
for its potential ocular toxic effects.
sixtyone patients of classic RA fulfilling the revised DMARD therapy
criteria of American College of Rheumatology 198714, attending the Department of Physical strategy regime11 using Chloroquine phosphate 150 Medicine and Rehabilitation, Regional Institute of Medical Sciences, Imphal. The inclusion criteria Sulfasalazine 500-2000 mg/day. As has been were RA patients with duration of illness more than outlined in the objective of the present study, most 6 months with history of unsuccessful treatment of our patients have reported in the later stage of but without history of any DMARD therapy.
illness. Single DMARD was instituted for mild and Patients with functional classification stage IV of moderate disease activity while double or triple American College of Rheumatology, pregnant drugs combination was instituted for severe disease woman or woman of childbearing age group without activity and for those reporting at later stage of contraceptive cover were excluded from the study group. So also, the patients with history of liver, Concurrent therapy
renal, haematological, cardio-pulmonary or active Non-steroidal anti-inflamatory drugs were peptic ulcer disease and with visual difficulties were given on regular basis for the initial period of 10 to 14 days and thereafter as and when needed basis.
There were 5 male and 56 female patients.
Intra-articular steroid injection was also given, if The patient characteristics were given in table 1.
required to control acute local inflammation of the The period of study was from January 1997 to joint. But no systemic corticosteroids were administered during the study period.
for all the variables were put at p<0.05.
Outcome measures
The main end point was the improvement of patients’ condition by at least 50 per cent among the clinical variables measured with special therapy with the number of patients recieving themare shown at Table 2. Chloroquine and consideration to joint counts, pain, and morning Methotrexate were the most frequently used stiffness and grip strength. We have considered 50 percent improvement as clinically relevant and patients (52.5%). 18 patients i.e. 30% received the treating physicians could readily recognise the either Chloroquine or Methotrexate while only 6 change. We have taken into consideration of the patients [10%] needed all the three drugs viz.
Chloroquine, Methotrexate, Sulfasalazine for the preliminary improvement criteria of American College of Rheumatology16 for measuring the Table 2. Showing number of patients (%) recieving
decreased by 50 percent, JT decreased by 50 percent, absence of morning stiffness or less than30 minutes duration. Besides, the evaluations of additional measures like grip strength and pain improvement in patients’ and physician’s global assessment in VAS was also considered.
Table 1: Showing patient characteristics (n = 61).
CQ = Chloroquine, MTX = Methotrexate, SLZ= receiving treatment with each specific DMARD at a specific period of time. Chloroquine was the commonest initial DMARD instituted in 46 patients Methotrexates as the initial single DMARD. For lack of therapeutic response, combination of DMARDS were instituted in the following 3 to 6months. Mean cumulative time of DMARDS used in combination for achieving disease remission was 9.6 months without any significant adverse effectsin 43 patients (70%).
Statistical analysis:
There were 37 patients (60%) who recieved combination of 2 DMARDS at a single point of outcome variables were evaluated by using two- time. 18 patients (30%) took only one DMARD tailed student’s t-tests, after putting the data in a for achieving clinical remission. Of the total patients computer using dbase. The statistical significance only 6 patients discontinued DMARD therapy due values of JS and JT at 3, 6, 24 months of DMARD to adverse effects requiring temporary withdrawal therapy. Mean value of the number of JS got of DMARD. 10 patients needed addition of another significantly reduced from 2.61±1.58 to 0.87±1.05 DMARD or change to another DMARD for lack at 3 months (p<0.01) and to 0.39±0.88 (p<0.001) of response in 3 to 6 months period, as shown in at 6 months. After 24 months, the improvement in the mean JS was still significant (p<0.05). Mean Table 4. We observed improvement in the clinical value of number of JT also significantly reduced at markers of the disease viz. JS, JT, ROM of the 3 months (p<0.001). Reduction in mean value of joints, grip strength, morning stiffness duration and JT was still significant at 24 months follow-up improvement in pain scored by 3 to 6 months of the DMARD therapy. Significant improvement wassustained at the end of 24 months with thecontinuation of DMARDS. Table 5 shows changes Fig. 1. Showing changes in mean Swollen Joint
Count (JS)/Tender Joint Count (JT)
in the mean values in the clinical variablesmentioned above.
Table 4 : Showing number of DMARDS
prescribed, DMARDS discontinued due to adverse effects or needing addition of another DMARD Swollen Joint Count/
Tender Joint Count
for lack of efficacy in the study group ( n= 61 ) of the joints was also significant by the end of 6 months (p<0.001) and the significance was still maintained at the end of 24 months (p<0.01). We also observed significant improvement in the mean values of grip strength at 3 months (p<0.05) and still more significant at the end of 6 months (p<0.001) as shown at figure 2. Moreover, the improvement in the mean scores of morning CQ = Chloroquine, MTX= Methotrexate, SLZ= Sulfasalazine, stiffness and pain remained significant from 3 Table 5: showing change in mean value ± standard
deviation in clinical variables at the end of 3,6,24 (p<0.001) as shown in figure 3 and figure 4.
Fig. 2. Showing mean Grip Strength
115.97 ± 60.40 173.06 ± 89.43 203.22 ± 108.90177.33 ± 70.40 49.35 ± 16.57 31.29 ± 26.45 36.33 ± 29.30 were maintained in these patients. However, Fig. 3. Showing mean duration of
morning stiffness (in hrs.)
remission was temporary if DMARDS was stopped after the remission, as was observed in 4 such patients showing relapse of signs and symptoms within 2 months of stoppage of DMARDS therapy.
Toxicity and adverse reactions:
temporarily or switch to another DMARDS due to adverse reactions .1 patient receiving Chloroquinedeveloped blurring of vision at 3 months and Fig. 4. Show ing m ean pain scores (in VAS)
switched to Methotrexate. 1 patient recieving Methotrexate developed anaemia at 6 months , for which 2 units of whole blood transfusion was given . The patient had a history of dependance on non- steroidal anti-inflamatory analgesic drugs before being admitted into the present study. 2 patients combination developed severe nausea and liverfunction abnormalities at 6 months. Liver function Table 3. Showing number of patients receiving
test alteration was in the form of altered Albumin and globulin ratio but with SGOT and SGPT levels maintained within 2 times the normal value. 2 paitents recieving combination of all the three drugs developed nausea, loss of appetite and dizziness at6 to 10 months. 1 paitent recieving Chloroquine and Methotrexate developed vasculitis which was rather an extra-articular manifestation of the Discussion
In the present series, 31 patients (51%) were now a days started early in the course of the disease followed up for 6 to 12 months while 24 patients with the aim to achieve clinical remission as early (39%) were followed up for 24 to 36 months. The as possible. However, complete remission of RA patients have been followed up for a mean duration is rare, inspite of the currently available DMARDS of 20.29 ± 9.79 months (range 6 to 36 months).
therapy modalities17,18. Although early treatment Out of the total 61 patients, 24 patients i.e. 39% seems to be the common denominator in all newer achieved clinical remission at the end of 6 months strategies, it is also generally agreed that aggressive follow up. Out of 24 patients followed up for two therapy should be used in severe RA and even in years 15 patients (60%) maintained clinical comparatively later stage of illness19.
remission. 50% improvement in clinical markers In the present study disease remission was achieved in 39% of patients at the end of 6 months.
were in Steinbrocker functional class II to IV) and Burhoo AM20 reported that at 8 to 10 weeks all injectable gold (sodium aurothiomalate) being the the 20 patients had shown complete remission with most common initial DMARDS used in 82% of low dose Methotrexate at 7.5 to 15mg /week with patients. The above findings indicate that it is not encouraging results till 6 months follow up period.
too late to institute DMARDS treatment in RA In our series, out of 24 patients followed up for 2 patients, even in whom erosions have appeared years, 15 patients (60%) showed maintenance of remission of the disease with the continuation of DMARDS. In a 2 year double blind randomised interesting study where 121 patients who had study, O’Dell and colleagues21 compared responded to a combination of Methotrexate and Hydroxy Chloroquine were randomized to one of Sulfasalazine (1gm/day) with hydroxyChloroquine three continuation therapy protocols for control of 400 mg /day combination or all the three drugs.
flare of the disease activity viz., (group I - 40 The primary endpoint of their study was also 50% patients) on hydroxychlroquine with pulse improvement in the composite symptoms of arthritis Methotrexate, (group II - 41 patients) on as comparable to those of our study. Fifty of 102 Hydroxychlroquine with placebo pulse, (group III- paitents had a 50% improvement at 9 months and 40 patients) on placebo with pulse Methotrexate.
maintained at least the same degree of improvement They observed that patients improved on a for the two year period without evidence of major side effects. Of these, 24 of 31 patients recieved Chloroquine. And continuation of Methotrexate or all the three drug combination, 14 of 35 patients Hydroxy Chloroquine delayed the onset of flares.
In our study also, after clinical remission was hydroxyChloroquine and 12 of 36 patients were achived we continued with either Chloroquine or treated with Methotrexate alone. In our study, 37 Methotrexate. As such combination therapy of 2 of 61 patients (70%) needed combination of DMARDS, out of which 6 patients recieved all cumulative period of 9.6 months only. Other series the three drugs while 32 patients ( 52.5%) recieved also recorded the mean duration of combination Methotrexate and Chloroquine combination. 60 % of patients in our series maintained 50% clinical In our series, 6 patients out of 61 patients improvement at the end of two years as compared (10%) needed to stop DMARD therapy because to 49% of patients in O’Dell et al series21.
of adverse reaction as comparable to that of 0’Dell Mottonen et al22 carried out a prospective et al21 which has similarity of DMARDS used and study in 142 patients treated according to saw- moreover the moderate duration of follow-up as tooth strategy using gold sodium thiomalate, well, upto 24 to 36 months duration. The higher Sulfasalazine, Methotrexate, hydroxy Chloroquine, percentage (29%) of adverse effects encountered d-penicillamine etc. They observed clinical in Mottonen T et al series22 may be because of remission in 20% of patients at end of first year different drug combinations and probably also for and in 27% of patients after 2 years of DMARDS comparatively longer period of follow-up (mean 6.2 therapy. The difference in the percentage of patients who achieved clinical remission at 2 years( i.e 27% ) in the series of Mottonen et al22, may be initial DMARD in 46 patients (64%) while 23 because of the severity of the cases (51% of them patients (32%) recieved Methotrexate as initial and psychological impact of musculoskeletal DMARD in the present study. One important conditions. Arthritis Rheum 1995; 38:1351-1362.
observation we have found in our series was that Yelin E, Henke C. Epstein WV. The work dynamics patients taking Chloroquine decreased to 18 of the person with rheumatoid arthritis. Arthritis patients at 1 year while patients taking Methotrexate kept on increasing by 6 months (40 patients) and Cash JM, Klippel JH. Second line drug therapy at 1 year (28 patients). It appears that Methotrexate for rheumatoid arthritis. N Engl J Med. 1994;19:1368-1375.
has moderate potency in controlling the dieasese activity as compared to Chloroquine. Better clinical rheumatoid arthritis affect outcome? J Rheumatol remission was achieved in patients recieving combination therapy taking Chloroquine and Van der Heijde DMFM, Van Riel PL, Nuver-Zwart IH, Van de Putte LBA. Sulphasalazine versus hydroxyChloroquine in rheumatoid arthritis : 3 Conclusions
years follow up (letter). Lancet 1990; 335:539.
Hannonen P, Mottonen T, Hakola M, Oka M.
Sulphasalazine in early rheumatoid arthritis : a 48 like saw-tooth strategy has a role in inducing disease remission even at a comparatively later controlled study. Arthritis Rheum 1993; 36:1501- stage of RA. DMARDS treatment seems to retard the progression of the disease in patients of RA Wolfe F, Hawlay DJ, Cathey MA. Termination of slow acting antirheumatic therapy in rheumatoid substitution can be made safely for those becoming arthritis : a 14-year prospective evaluation of 1017 ineffective or showing toxic effects.The beneficial consecutive patients. J. Rheumatol 1990; 17:994- effects of continued treatment with DMARDS may be extended for longer periods. Methotrexate Situnayake RD, Grindulis KA, McConkey B. Long and Chloroquine can be safely given for longer term treatment of rheumatoid arthritis withSulphasalazine, gold or Penicillamine : a periods (upto 3 years in the present series) without comparasion using life-table methods. Ann any major side effects However, despite initiation of early aggressive therapy, RA may continue to Emery P, Solomon M. Early rheumatoid arthritis progress in some patient. In this group with time to aim for remission. Ann Rheum Dis 1995; progrssive disease, inspite of continued aggressive treatment with DMARDS, treatment with drug van de Putte LBA. Chronic arthritis : Why the combinations should be tried as early as possible.
joint ? Scand J Rheumatol 1995; 24 (suppl 101) : Moreover,the role of newer biological agents and how they will perform as combination therapy in Fries JF. Revaluating the therapeutic approach such patients needs to answer critical questions to rheumatoid arthritis : the ‘’saw tooth’’ strategy.
in near future. For this we need to review the combination therapy and to encourage appropriately Wilske KR, Healey LA. Remodelling the pyramid designed studies to answer these questions.
: A concept whose time has come. J Rheumatol1989; 16:565-567.
Wilske WS, Clough JD. Therapy for rheumatoid Yelin E., Callahan L. The economic cost and social arthritis combinations of disease modifying drugs and new paradigms of treatment. Semin Arthritis Rheum 1991; 21 (suppl 1): 21-34.
Arnett FC, Edworthy SM, Bloch DA et al. The concerning rheumatoid arthritis - lessons from American Rheumatism Association 1987 revised Hodgkin’s disease and coronary artery disease.
criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31 (3):315-324.
Burhoo Ali Mohmad. Methotrexate as remission Paulus HE, Egger MJ, Ward JR, Williams HJ.
inducing agent in rheumatoid arthritis. Indian J Phys Med Rehabil 1997-98; 8-9:31-36.
rheumatoid arthritis patients treated with disease O’Dell JR, Haire CE, Erikson N et al. Treatment of modifying anti-rheumatic drugs based on the rheumatoid arthritis with Methotrexate alone, patients treated with placebo. Arthritis Rheum sulfasalzine and Hydroxy Chloroquine, or a combination of all three medications. New Eng J Felson DT, Anderson JJ, Boers M et al. American College of Rheumatology preliminary definition Mottonen T, Paimela L, Ahonen J et al. Outcome of improvement in rheumatoid arthritis. Arthritis in patients with early rheumatoid arthritis treated according to the ‘Saw tooth’ strategy. Arthritis Alarcon GS, Blackburn WE Jr, Calvo A, Castaneda Clegg DO, Dietz F, Duffy J et al. Safety and Association preliminary criteria for remission in efficacy of Hydroxy Chloroquine as maintenance rheumatoid arthritis: a prospective study. J therapy for rheumatoid arthritis after combination Pinals RS, Masi AT, Larsen RA. Subcommittee Chloroquine. J Rheumatol 1997; 24:1896-1902.
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