623
RELATIONSHIP BETWEEN CLINICAL EFFICACY AND LABORATORY CORRELATES O F INFLAMMATORY AND IMMUNOLOGIC ACTIVITY IN RHEUMATOID ARTHRITIS PATIENTS TREATED WITH NONSTEROIDAL ANTIINFLAMMATORY DRUGS JOHN J. CUSH, HUGO E. JASIN, REGINA JOHNSON, and PETEK E. LIPSKY Eighteen rheumatoid arthritis (RA) patients, who had been treated with nonsteroidal antiinflammatory drugs (NSAIDs) only, were enrolled in a 12-week, open-label, randomized protocol to determine whether clinical responses might be associated with improvement in laboratory measures of inflammation and immunologic activity in RA patients treated with NSAIDs. Following a 2-week drug washout period, patients were given either long-acting ibuprofen (2,400 mg/day) or flurbiprofen (200 mglday); clinical, laboratory, and immunologic assessments were done biweekly for 10 weeks. A clinical efficacy index, utilizing a combination of measures of disease activity, identified 7 “responders” and 10 “nonresponders” (1 patient discontinued therapy because of a rash). Flow cytometric analysis revealed no abnormalities in the numbers of circulating CD3+, CD4+, or CD8+ lymphocytes in the 17 patients. The density of these T cell markers at enrollment was similar in patients and control subjects. However, following the 2-week drug washout, significant worsening of morning stiffness, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) was accompanied by a significant decrease (P 5 0.05) in the density of these T cell surface determinants, as is characteristic of activated T cells. After 10 weeks of NSAID therapy, increased density of CD3, CD4, and CD8 was observed in 47%, 73%, and 50% of the patients, respectively. ~-
From the Harold C. Simmons Arthritis Research Center, University of Texas Southwestern Mcdical Center, Dallas. Supported by USPHS grants AR-09989 and AR-39169. John J. Cush. MD; Hugo E. Jasin, MD; Regina Johnson, RN: Peter E. Lipsky, MD. Address reprint requests to Peter E. Lipsky. MD. University of Texas Southwestern Medical Center, Department of Internal Medicine. 5323 Harry Hines Boulevard, Dallas, TX 75235. Submitted for publication August 21, 1989; accepted in revised form November 21. 1989. Arthritis and Rheumatism, Vol. 33, No. 5 (May 1990)
However, in only the responders was the density of these T cell surface markers increased significantly ( P 5 0.04). The responders, but not the nonresponders, also demonstrated significant reductions in the ESR, CRP level, serum IgM rheumatoid factor (RF) titer, and spontaneous synthesis of RF by lymphocytes in vitro ( P 5 0.05). There were significant correlations between improvements in the clinical parameters (50-foot walk time, joint score, and global assessment) and reductions in the ESR, CRP level, and serum RF titer ( P I0.05). These findings demonstrate that clinical improvement in RA patients treated with NSAIDs may be associated with the disappearance of phenotypically activated circulating T cells and functionally activated B cells, as well as with reductions in acute-phase reactants and serum RF titers.
Treatment of rheumatoid arthritis (RA) involves the use of nonsteroidal antiinflammatory drugs (NSAIDs) that are often regarded as symptomatic therapy and disease-modifying antirheumatic drugs (DMARDs) that are thought to exert a more profound effect on rheumatoid inflammation (1-3). Decreases in disease activity as a result of the administration of DMARDs. such as gold salts or D-penicillamine, are often associated with improvement in or normalization of levels of acute-phase reactants and titers of serum rheumatoid factor (RF) (3-6). Although clinical improvement is frequently associated with DMARD therapy, the onset of therapeutic benefit is often delayed, taking weeks to months to achieve the desired effect. By contrast, NSAIDs have historically served as rapid-acting, first-line analgesic and antiinflammatory drugs that are not thought to exert a disease-modifying effect. as evidenced by their inability to lower serum RF titers and acute-phase reactant
CUSH ET AL
624 levels (6-9) or t o alter the clinical or radiographic progression that is characteristic of RA (10). By inhibiting prostaglandin biosynthesis, NSAIDs have been shown t o display a variety of immunomodulatory effects in vitro (1 1-15). However. there is only limited evidence that the therapeutic administration of these agents may affect the abnormalities in cellular or humoral immunity associated with RA (14-20). NSAIDs are therefore thought t o be incapable of suppressing the immunopathogenic mechanisms operative in RA and thereby of altering the progression of the disease. T h e current studies were undertaken to determine whether improvement in clinical symptoms during NSAID therapy might be associated with alterations in circulating activated T cells and B cells. We also attempted to determine whether clinical efficacy was associated with changes in serologic correlates of inflammation (erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP]) and serum RF titers. T h e results indicate that patients who improve clinically while being treated with NSAIDs exhibit evidence of decreases in the number of circulating activated T cells and B cells, along with a diminution in the ESR, CRP, and RF levels.
PATIENTS AND METHODS Patient selection. Eighteen patients from the arthritis clinics of Parkland Memorial Hospital who had definite or classic RA (21) of at least 3 months duration were enrolled in a 12-week study. All patients met the American Rheumatism Association 1987 revised criteria for the diagnosis of RA (22). ’This study was carried out as part of a multicenter trial of NSAIDs that has been reported separately (23). Inclusion criteria were active RA (Table 1). a positive test result for serum RF, and n o therapy with DMARDs (gold, penicillamine. etc.) or glucocorticoids (oral or intraarticular) in the 3 months prior to study entry. One patient withdrew after 2 weeks of therapy because of a rash, which was not believed to be drug-related. Data from this patient are not included in this report. Twenty-two healthy adult volunteers who were not taking NSAIDs served as normal controls for the cytofluorometric studies. Study design. After giving informed consent, the patients were enrolled into a prospective, randomized, openlabel study utilizing flurbiprofen (8 patients) and a longacting ibuprofen preparation (10 patients). At enrollment, all patients were receiving only NSAID therapy (naproxen in 8 patients, ibuprofen in 4 patients, salicylates in 4 patients, and piroxicam in 1 patient). Initially, each patient underwent a clinical, laboratory, and immunologic assessment. Following enrollment, a 2-week drug washout period was initiated. During the washout period, patients discontinued all NSAID therapy and utilized only analgesic agents (acetaminophen, propoxyphene, and/or acetaminophen plus codeine) as re-
Table 1. Clinical profile of 17 rheumatoid arthritis patients at enrollment and at baseline*
Enrollment values
Male:female ratio Disease duration (years) 50-foot walk time (seconds) Joint score Duration of morning stiffness (minutes) Global assessment ESR (mmhour) CRP (mg/dl) RF (Irglml)
Baseline values
P
22.4 t 2.3
0.13
3 : I4 4.8 ? 1.2 18.9 t 1.6 40.1 122.5
? ?
3.9 24.0
46.1 197.1
? ?
4.3 27.6
0. I7 0.02
9.7 54.7 3.1 280.4
?
0.4 R.9 0.7 46.3
10.4 2 66.0 ? 4.0 ? 294.9 t
0.4 9.6 0.7 56.8
0.31 0.02 0.02 0.46
2 ?
5
~~
* Baseline values were obtained after a 2-week drug washout period. Values are the mean ? SEM. ESR = erythrocyte sedimentation rate (Westergren);CRP = C-reactive protein; RF = rheumatoid factor (normal
RELATIONSHIP BETWEEN CLINICAL EFFICACY AND LABORATORY CORRELATES O F INFLAMMATORY AND IMMUNOLOGIC ACTIVITY IN RHEUMATOID ARTHRITIS PATIENTS TREATED WITH NONSTEROIDAL ANTIINFLAMMATORY DRUGS JOHN J. CUSH, HUGO E. JASIN, REGINA JOHNSON, and PETEK E. LIPSKY Eighteen rheumatoid arthritis (RA) patients, who had been treated with nonsteroidal antiinflammatory drugs (NSAIDs) only, were enrolled in a 12-week, open-label, randomized protocol to determine whether clinical responses might be associated with improvement in laboratory measures of inflammation and immunologic activity in RA patients treated with NSAIDs. Following a 2-week drug washout period, patients were given either long-acting ibuprofen (2,400 mg/day) or flurbiprofen (200 mglday); clinical, laboratory, and immunologic assessments were done biweekly for 10 weeks. A clinical efficacy index, utilizing a combination of measures of disease activity, identified 7 “responders” and 10 “nonresponders” (1 patient discontinued therapy because of a rash). Flow cytometric analysis revealed no abnormalities in the numbers of circulating CD3+, CD4+, or CD8+ lymphocytes in the 17 patients. The density of these T cell markers at enrollment was similar in patients and control subjects. However, following the 2-week drug washout, significant worsening of morning stiffness, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) was accompanied by a significant decrease (P 5 0.05) in the density of these T cell surface determinants, as is characteristic of activated T cells. After 10 weeks of NSAID therapy, increased density of CD3, CD4, and CD8 was observed in 47%, 73%, and 50% of the patients, respectively. ~-
From the Harold C. Simmons Arthritis Research Center, University of Texas Southwestern Mcdical Center, Dallas. Supported by USPHS grants AR-09989 and AR-39169. John J. Cush. MD; Hugo E. Jasin, MD; Regina Johnson, RN: Peter E. Lipsky, MD. Address reprint requests to Peter E. Lipsky. MD. University of Texas Southwestern Medical Center, Department of Internal Medicine. 5323 Harry Hines Boulevard, Dallas, TX 75235. Submitted for publication August 21, 1989; accepted in revised form November 21. 1989. Arthritis and Rheumatism, Vol. 33, No. 5 (May 1990)
However, in only the responders was the density of these T cell surface markers increased significantly ( P 5 0.04). The responders, but not the nonresponders, also demonstrated significant reductions in the ESR, CRP level, serum IgM rheumatoid factor (RF) titer, and spontaneous synthesis of RF by lymphocytes in vitro ( P 5 0.05). There were significant correlations between improvements in the clinical parameters (50-foot walk time, joint score, and global assessment) and reductions in the ESR, CRP level, and serum RF titer ( P I0.05). These findings demonstrate that clinical improvement in RA patients treated with NSAIDs may be associated with the disappearance of phenotypically activated circulating T cells and functionally activated B cells, as well as with reductions in acute-phase reactants and serum RF titers.
Treatment of rheumatoid arthritis (RA) involves the use of nonsteroidal antiinflammatory drugs (NSAIDs) that are often regarded as symptomatic therapy and disease-modifying antirheumatic drugs (DMARDs) that are thought to exert a more profound effect on rheumatoid inflammation (1-3). Decreases in disease activity as a result of the administration of DMARDs. such as gold salts or D-penicillamine, are often associated with improvement in or normalization of levels of acute-phase reactants and titers of serum rheumatoid factor (RF) (3-6). Although clinical improvement is frequently associated with DMARD therapy, the onset of therapeutic benefit is often delayed, taking weeks to months to achieve the desired effect. By contrast, NSAIDs have historically served as rapid-acting, first-line analgesic and antiinflammatory drugs that are not thought to exert a disease-modifying effect. as evidenced by their inability to lower serum RF titers and acute-phase reactant
CUSH ET AL
624 levels (6-9) or t o alter the clinical or radiographic progression that is characteristic of RA (10). By inhibiting prostaglandin biosynthesis, NSAIDs have been shown t o display a variety of immunomodulatory effects in vitro (1 1-15). However. there is only limited evidence that the therapeutic administration of these agents may affect the abnormalities in cellular or humoral immunity associated with RA (14-20). NSAIDs are therefore thought t o be incapable of suppressing the immunopathogenic mechanisms operative in RA and thereby of altering the progression of the disease. T h e current studies were undertaken to determine whether improvement in clinical symptoms during NSAID therapy might be associated with alterations in circulating activated T cells and B cells. We also attempted to determine whether clinical efficacy was associated with changes in serologic correlates of inflammation (erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP]) and serum RF titers. T h e results indicate that patients who improve clinically while being treated with NSAIDs exhibit evidence of decreases in the number of circulating activated T cells and B cells, along with a diminution in the ESR, CRP, and RF levels.
PATIENTS AND METHODS Patient selection. Eighteen patients from the arthritis clinics of Parkland Memorial Hospital who had definite or classic RA (21) of at least 3 months duration were enrolled in a 12-week study. All patients met the American Rheumatism Association 1987 revised criteria for the diagnosis of RA (22). ’This study was carried out as part of a multicenter trial of NSAIDs that has been reported separately (23). Inclusion criteria were active RA (Table 1). a positive test result for serum RF, and n o therapy with DMARDs (gold, penicillamine. etc.) or glucocorticoids (oral or intraarticular) in the 3 months prior to study entry. One patient withdrew after 2 weeks of therapy because of a rash, which was not believed to be drug-related. Data from this patient are not included in this report. Twenty-two healthy adult volunteers who were not taking NSAIDs served as normal controls for the cytofluorometric studies. Study design. After giving informed consent, the patients were enrolled into a prospective, randomized, openlabel study utilizing flurbiprofen (8 patients) and a longacting ibuprofen preparation (10 patients). At enrollment, all patients were receiving only NSAID therapy (naproxen in 8 patients, ibuprofen in 4 patients, salicylates in 4 patients, and piroxicam in 1 patient). Initially, each patient underwent a clinical, laboratory, and immunologic assessment. Following enrollment, a 2-week drug washout period was initiated. During the washout period, patients discontinued all NSAID therapy and utilized only analgesic agents (acetaminophen, propoxyphene, and/or acetaminophen plus codeine) as re-
Table 1. Clinical profile of 17 rheumatoid arthritis patients at enrollment and at baseline*
Enrollment values
Male:female ratio Disease duration (years) 50-foot walk time (seconds) Joint score Duration of morning stiffness (minutes) Global assessment ESR (mmhour) CRP (mg/dl) RF (Irglml)
Baseline values
P
22.4 t 2.3
0.13
3 : I4 4.8 ? 1.2 18.9 t 1.6 40.1 122.5
? ?
3.9 24.0
46.1 197.1
? ?
4.3 27.6
0. I7 0.02
9.7 54.7 3.1 280.4
?
0.4 R.9 0.7 46.3
10.4 2 66.0 ? 4.0 ? 294.9 t
0.4 9.6 0.7 56.8
0.31 0.02 0.02 0.46
2 ?
5
~~
* Baseline values were obtained after a 2-week drug washout period. Values are the mean ? SEM. ESR = erythrocyte sedimentation rate (Westergren);CRP = C-reactive protein; RF = rheumatoid factor (normal
