Published in IJCP July 2019
Clinical Study
Effect of Adjuvant Atorvastatin Therapy on Disease Activity in Active Rheumatoid Arthritis: A Tertiary Care Center Study in India
July 12, 2019 | H Singh, Rekha Mathur, A Singhania, Kiran B
     


Abstract

Introduction: In current practice, rheumatoid arthritis (RA) patients are being treated with combinations of different disease-modifying antirheumatic drugs (DMARDs). This early aggressive approach halts the progression of disease. Among different drugs being used for treatment of RA, statins provide cardiovascular safety but their role as immunomodulatory drugs in RA is still being studied. In our study, we studied the effect of atorvastatin on disease activity in RA patients. Material and methods: An open-label, prospective, comparative clinical study was conducted with 100 patients. After baseline evaluation, subjects selected for the study were categorized into two groups of 50 each. Subjects in Group I received tablet atorvastatin (20 mg/day) along with their pre-existing DMARD therapy. Group II were those subjects who continued their pre-existing DMARDs, but didn’t receive atorvastatin so was considered as control group. Results: The study results showed that Group I had higher level (6.20 ± 1.2) of Disease Activity Score-28 (DAS28) at baseline than Group II (5.50 ± 1.24), which was statistically insignificant (p = 0.06). At 4 weeks, DAS28 was improved significantly from baseline in both groups. There was significant improvement in DAS28 by 2.52 and 1.53 from baseline to 12 weeks in Group I and Group II, respectively (p < 0.001). Similarly, the Clinical Disease Activity Index (CDAI) was higher in Group I (35.48 ± 16.72) than in Group II (27.56 ± 14.45). At 4 weeks, CDAI was improved significantly from baseline in both groups. There was significant reduction in CDAI by 23.32 and 12.84 from baseline to 12 weeks in both groups (p < 0.001). Conclusion: In our study, the results showed that atorvastatin, when used as adjuvant therapy with DMARDs, had beneficial effects on parameters of disease activity in RA patients and also was well-tolerated when given in combination with DMARDs.

Keywords: Atorvastatin, CDAI, DAS28, rheumatoid arthritis

Rheumatoid arthritis (RA) is associated with increased cardiovascular mortality and morbidity.1 In well-established RA, the median life expectancy is less than in control populations.2,3 Infection, renal disease and respiratory failure traditionally have been the primary factors contributing to excess mortality in RA patients, although it has been belatedly recognized that congestive heart failure, ischemic heart disease and peripheral atherosclerosis deserve the appellation as the prime killers of rheumatoid patients.4 It may be that chronic systemic inflammation in RA contributes to excess cardiovascular disease (CVD) in this population either by potentiating and/or accelerating atherosclerosis or by other mechanisms such as diffuse subclinical vasculitis.5 Parallels between the inflammatory and immunological mechanisms operating in atherosclerotic plaque and rheumatoid synovitis have been highlighted and atherosclerosis is widely considered to be an inflammatory disease.6 Arterial stiffness is a marker of vascular dysfunction and an independent risk factor for CVD.7

Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have demonstrated benefit in the primary and secondary prevention of CVD.8 The protective effect of statins appears to be greater than can be explained by their cholesterol reduction property9 and the benefit of statins appears to be even greater in the presence of higher C-reactive protein (CRP) levels.10 Statins are known to have a number of immunomodulatory effects, which may affect vascular function, plaque stability and thrombosis.11 These immunomodulatory effects of statins may be especially important in patients with RA who have systemic immune activation. Statins have been demonstrated to reduce disease activity and inflammatory responses in a murine model of inflammatory arthritis and in patients with RA.

Many data indicate effects for statins in innate immune response including effects on endothelial function,12 macrophage, natural killer cell and neutrophil effect or functions.13 Similar effects on acquired immune responses via suppression of antigen presentation14 and T-cell polarization have been shown in vitro and in vivo. Synovial inflammation in RA is characterized by activated components of both innate and acquired immune responses. Thus, postulated effects for statins might reasonably operate within the synovial membrane. Findings of an in vitro study15 showed suppression of synovial T-cell and fibroblast-like synoviocyte cytokine release, which tends to support to this notion.

Data suggest that modulation of inflammation can be achieved by atorvastatin in a proportion of patients with RA, suggesting that some of the above pathways may indeed be tractable to HMG-CoA reductase inhibition.16 Moreover, in vitro cytokine release by RA synovial mononuclear cells and by synovial fibroblasts was also reduced by statins.15 Statins have a satisfactory safety profile and relatively few adverse effects. In the absence of side effects and contraindications, it may be reasonable to consider statin use in selected cases particularly in patients with a long history of active RA that are at increased cardiovascular risk.

A previous study “Trial of Atorvastatin in Rheumatoid Arthritis16 (TARA)” showed significant improvement in Disease Activity Score-28 (DAS28) (-0.5, 95% confidence interval [CI] - 0.75 to -0.25) compared with placebo (0.03, -0.23 to 0.28; difference between groups -0.52, 95% CI -0.87 to -0.17, p = 0.004). CRP and erythrocyte sedimentation rate (ESR) declined, swollen joint counts also fell (-2.69 vs. -0.53; mean difference -2.16, 95% CI -3.67 to -0.64, p = 0.0058). Although, authors found only modest change but the significant reduction in DAS28 provides proof of concept that pathways targeted by atorvastatin offer therapeutic opportunity in inflammatory disease.

A double-blind trial studied the effect of either increased dose of methotrexate (MTX) from 7.5 mg to
15 mg (Group A) or 7.5 mg MTX plus 40 mg atorvastatin (Group B). This study showed a significant reduction in DAS28, CRP, ESR and swollen joint count in atorvastatin group compared to placebo in patients with RA presenting with active disease despite undergoing disease-modifying antirheumatic drug (DMARD) therapy.

Although not indicative for first-line use, this effect of atorvastatin could prove beneficial in the context of DMARD combination design, in which a statin offers both vascular protective and adjunctive immunomodulatory potential. Based on the above literature, we planned to study the effect of atorvastatin on disease activity of RA as there is scant Indian data available in this regard.

Material and Methods

Patients with diseases like (known or detected on baseline investigations) hepatic, renal diseases, heart failure, endocrinological disorders, hematological disorders, uncontrolled hypertension, coronary heart disease, pregnant or lactating mothers, those belonging to reproductive age group, not willing to practice contraception and who were taking lipid-lowering therapy (statin or fibrate), had hypersensitivity to statin, were excluded from the study. The study was approved by Ethical Committee. After obtaining the informed consent, we recruited 100 patients, meeting the 1987 American College of Rheumatology criteria, with high activity disease (DAS28 >5.5 and Clinical Disease Activity Index [CDAI] >22) despite ongoing DMARD therapy. All participants were informed about all possible side effects of drugs. A detailed history and clinical examination was done in all subjects included in the study. They underwent routine laboratory investigations like serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), blood urea, ESR and baseline radiograph of hands.

After baseline evaluation, subjects selected for the study were categorized into two groups of 50 each by Random No. Table. Subjects in Group I received tablet atorvastatin (20 mg/day) along with their pre-existing DMARD therapy. Group II were those subjects who continued their pre-existing DMARDs but didn’t receive atorvastatin, who were considered as control group.

Disease activity using DAS28 and CDAI in each of the subjects of either group was evaluated at baseline and every 4 weeks for 3 months by the same observer at each visit. Patients were also observed for adverse effects in both the groups. All data collected in the study were analyzed statistically at the end of study using Independent t-test, Paired t-test and Chi-square test. Improvement in disease activity was measured by subtraction from baseline value.

Results

Baseline variables were comparable in both groups (Table 1). There was statistically significant improvement in DAS28 in both groups with DMARD therapy including adjuvant atorvastatin in Group I at 4, 8 and 12 weeks (Table 2). The DAS28 score was comparable (i.e., statistically insignificant) in both groups at 4, 8 and 12 weeks (Table 3). When both groups were analyzed by CDAI, significant improvement in disease activity was observed at 4, 8 and 12 weeks (Table 4). The comparison of CDAI between groups was comparable (i.e., statistically insignificant) at baseline, 4, 8 and 12 weeks (Table 5). Both DAS28 and CDAI showed gradual and significant improvement from high disease activity to moderate disease activity in both groups
(Figs. 1 and 2). No clinical, hematological adverse events were noted. Atorvastatin when given as adjuvant therapy in active RA patients was well-tolerated. No significant liver function or muscle abnormality was detected in those given atorvastatin.

Table 1. Baseline Variables in Both Groups

Variables

Group I

Group II

P value

Age (years)

42.56 ± 13.3

43.12 ± 9.96

0.237

Male

10

10

1.00

Female

40

40

1.00

Disease (mean) Duration

2.08 years ± 1.3

2.00 years ± 1.2

0.590

RF

60.45%

61.33%

0.745

ESR (mm 1st hour)

44.2 ± 19.4

31.92 ± 11.87

0.001

CDAI

35.48 ± 16.7

27.56 ± 14.4

0.01

DAS28

6.20 ± 1.2

5.50 ± 1.2

0.06

TJC

10.88 ± 8.96

11.48 ± 8.41

0.730

SJC

3.2 ± 3.07

2.08 ± 2.13

0.037

PGA

3.2 ± 1.51

3.24 ± 1.22

0.884

EGA

2.96 ± 1.44

3.12 ± 1.28

0.559

GH

32 ± 15.11

32 ± 12.45

1

CDAI = Clinical Disease Activity Index; DAS28 = Disease Activity Score-28; ESR = Erythrocyte sedimentation rate; EGA = Evaluator global assessment; PGA = Patient global assessment; RF = Rheumatoid factor; TJC = Tender joint counts; SJC = Swollen joint counts; GH = Patient’s general health; P = P value (<0.05 = significant).

Table 2. Analysis and Improvement in DAS28 Over 12 Weeks in Both Groups

Duration

Group I

Group II

4 weeks

1.46

0.83

8 weeks

1.71

1.16

12 weeks

2.52

1.53

P value

<0.001

<0.001

Table 3. Analysis and Comparative Assessment of DAS28 Between Two Groups

Duration

Group I

Group II

P value

Baseline

6.20 ± 1.2

5.50 ± 1.2

0.00

4 weeks

4.74 ± 1.3

4.67 ± 1.1

0.77

8 weeks

4.49 ± 1.2

4.34 ± 1.4

0.59

12 weeks

3.68 ± 1.0

3.97 ± 1.3

0.24

Table 4. Analysis and Improvement in CDAI Over 12 Weeks

Duration

Group I

Group II

4 weeks

15.24

7.64

8 weeks

17.36

9.68

12 weeks

23.32

12.84

P value

<0.001

<0.001

Table 5. Analysis and Comparative Assessment of CDAI Between Two Groups

Duration

Group I

Group II

P value

Baseline

35.48 ± 16.7

27.56 ± 14.45

0.012

4 weeks

20.24 ± 12.9

19.92 ± 10.59

0.892

8 weeks

18.12 ± 11.9

17.88 ± 14.30

0.927

12 weeks

12.16 ± 10.3

14.72 ± 10.27

0.217

Figure 1. Comparative assessment of DAS28 between two groups from baseline to 12 weeks.

Figure 2. Comparative assessment of CDAI between two groups from baseline to 12 weeks.

Discussion

RA is a chronic disease with more predispositions to atherosclerosis owing to its inflammatory state. This increased prevalence of atherosclerosis in RA has made ischemic heart disease, the most common cause of death, followed by infection in RA, thus increasing its mortality two times greater than the general population. Also in RA, the median life expectancy is shortened by an average of 7 years for men and 3 years for women compared to control populations. In the studies, DMARDs to some extent reduced the cardiovascular mortality in RA. Statins have been demonstrated to reduce disease activity and inflammatory responses in a murine model of inflammatory arthritis and in patients with RA.15,16

In present study, Group I had higher level (6.20 ± 1.2) of DAS28 at baseline than Group II (5.50 ± 1.24), which was insignificant (p = 0.06). At 4 weeks, DAS28 was improved significantly from baseline in both groups but the improvement in DAS28 score in Group I (1.46) was more than the Group II (0.83) (Table 2). There was significant improvement in DAS28 by 2.52 and 1.53 from baseline to 12 weeks in Group I and Group II, respectively (p < 0.001) (Table 2). Similarly, CDAI was higher in Group I (35.48 ± 16.72) than in Group II (27.56 ± 14.45) (Table 5). At 4 weeks, CDAI was improved significantly from baseline in both groups but the improvement in CDAI score in Group I (15.24) was more than the Group II (7.64) (Table 4). There was significant reduction in CDAI by 23.32 and 12.84 from baseline to 12 weeks in the two groups (p < 0.001) (Table 4).

This study showed a significant reduction in various variables of disease activity of RA-like tender joint count (TJC), swollen joint count (SJC), patient global assessment (PGA), evaluator global assessment (EGA), ESR, patient’s general health (GH) over a period of 12 weeks in both groups (atorvastatin and control); similar finding was observed for 40 mg atorvastatin in TARA study.16

In our study, the results showed that atorvastatin when used as adjuvant therapy with DMARDs had beneficial effects on parameters of disease activity and also, was well-tolerated when given in combination with DMARDs. Since, the improvement in disease activity was numerically higher in the atorvastatin adjuvant therapy group when compared with DMARD alone group, but this was statistically insignificant; hence, it is suggested that larger and longer trails are needed so as to evaluate the modest but beneficial effect of well-tolerated atorvastatin therapy in patients of RA. But thanks to good safety profile, easy administration and the existence of a broad experience regarding their use in clinical practice, statins are particularly attractive therapeutic agents, so even a modest efficacy in the treatment of RA in association with the reduction of cardiovascular risk can lead to a beneficial therapeutic ratio. This can make statins particularly useful as adjuvant therapy associated with other conventional therapeutic methods used in RA, especially in patients with dyslipidemia, where they should be the first choice of treatment.

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