Management of Rheumatoid Arthritis: Principles and Strategies for Antirheumatic Pharmacotherapy

Laura came into my office as the last patient that day. She had got an acute appointment. A bright, young woman of 25 years of age, university student, the future at her feet. Until suddenly one morning, she could not get out of bed and was unable to dress because her fingers and wrists were swollen, tender, and stiff. She had spent some days in bed, then moved back to her parents because she was unable to manage on her own. When I first saw her, she had been ill for about a month, and was just getting worse and worse day-by-day. She had lost 3 kg of body weight and was pale, desperate, and tired.

She had rheumatoid arthritis (RA). Tender synovitis was present in several joints of the hands. She was rheumatoid factor positive, had elevated C-reactive protein and slight anemia. Erosions appeared on her radiographs. No one else in the family had the disease.

Without delay, she was included in our then ongoing study of early, disease-modifying antirheumatic drugs (DMARD)-naïve RA, the CIMESTRA study. I injected the four most swollen and tender finger joints with glucocorticoids and started methotrexate (MTX) 7.5 mg per week. A fortnight later, when I saw her in the clinic, she was smiling. She was no longer staying in her parents’ home and had returned to the university. She had, she said, still one swollen joint, which she would like me to inject, because the four that had been injected the previous time had gone into remission. She got the injection, and we increased the dosage of MTX. The following months, the specially trained nurses and I saw Laura monthly in the clinic to ensure treatment compliance and complete disease suppression with no evidence of inflammation. She also knew that she could request an appointment within 2 days in case of any swollen joints.

Two years passed quickly. She was in remission. No disease activity apart from one swollen joint 6 months later, which was silenced with an intra-articular injection. MTX 20 mg weekly gave her some discomfort, so she was switched to subcutaneous administration, which she handled herself. No progression was shown on radiographs. She lived a normal life, resumed her fitness training and enjoyed her life as a student.

And then her condition became worse the fall she had graduated from university. She had morning stiffness, fatigue, and new swollen and tender joints at each visit. We added sulfasalazine (SSZ) and hydroxychlorochine, but they had no effect. She was facing sick leave in her new job. She was lucky; the tumor necrosis factor (TNF) inhibitors had been marketed by then, and she was started on etanercept (Enbrel) in combination with MTX. It worked. She went into remission again. The patient still needed a single joint injection once every 1 or 2 years. Apart from that, there were no symptoms and no progression of joint damage. Four years passed, and the disease flared again. Many joints were affected, and the patient had severe problems in her daily life. She was switched to infliximab (Remicade), which was efficacious for 18 months, and then the arthritis showed its ugly face again.

CASE STUDY

For many rheumatologists, this case is not atypical. RA is a challenge to treat because it lasts life-long, so although a treatment works at some time point, there is no guarantee that it will continue to do so.

The treatment strategy that is outlined in this case focuses on disease-modifying treatment right after diagnosis with MTX in monotherapy or in combination with other DMARDs, intensive care with frequent visits in the clinic, individualized treatment aiming at remission, biologic therapies as second-line drugs, intra-articular glucocorticoids as bridging therapy, and parental MTX in patients with poor tolerance for oral treatment.

Among the factors that have the greatest impact on prognosis in RA, pharmacologic intervention is probably the most significant. Treatment strategies have changed dramatically during the past decades from a concept of symptom control (with the rheumatologist in a “reactive” position) to one of disease control, in which the rheumatologist is proactive and aims at bringing the patient into remission, that is without any sign of the disease being active. This shift is the result of several significant advances in the field. These include move away from toxic or nonefficaceous DMARDs to the use of MTX as the anchor drug in RA treatment, better designed and conducted randomized controlled trials (RCTs), and biologic drugs with high efficacy (but also a potential for severe side effects and a substantial burden on economic resources in health care systems around the world).

In this chapter, I review some of the evidence found in the literature for the treatment principles and strategy that was illustrated in the case. Such a review cannot be complete; rather, I have instead selected some studies to illustrate my points. My focus is on the prevention of structural joint damage and clinical treatment response in early RA. Other important aspects, such as the impact of treatment strategy on cardiovascular disease, early death, malignancies and osteoporosis, and treatment of established RA, are outside the scope of this chapter.

EARLY VERSUS DELAYED TREATMENT?

The principle of early treatment is based on the concept of a therapeutic window of opportunity early in the disease. By acting in this window, it is assumed that one gets a short-term effect of better treatment response and a long-term effect altering the disease permanently to a milder course. Even a delay of 8 to 9 months in starting DMARD therapy has a significant impact on disease parameters years later.

A recent meta-analysis addressed this issue. A total of 12 studies met the inclusion criteria. The pooled estimate of effects from these studies demonstrated a significant reduction of radiographic progression in patients treated early (standardized mean difference) of −0.19 ( Fig. 1-1 ), which corresponded to a 33% reduction in long-term progression rates compared with patients treated later. Patients with more aggressive disease seemed to benefit most from early DMARD initiation. It was concluded that the effect size from early DMARD initiation was almost half the effect size observed from MTX therapy, and that it was sustained for several years regardless of subsequent treatment. This is an impressive impact and strongly supports the importance of early intervention in newly diagnosed RA.

There is little or no controversy in the rheumatologic field regarding the importance of early intervention. However, the referral of patients to a rheumatologist is often delayed several months for several reasons (patient-related factors, general practitioner hesitation and waiting lists at the hospitals). Therefore, although the establishment of “early arthritis” clinics has been beneficial, it has proven difficult to implement this important aspect of treatment into common clinical practice.

MONO- OR COMBINATION TREATMENT WITH CONVENTIONAL DRUGS?

Some earlier trials of mono- versus combination therapy such as the COBRA and the FinRACo studies showed that SSZ as monotherapy was inferior to SSZ in combination with other conventional drugs (DMARDs). SSZ as monotherapy is now used less frequently (but is still the first choice in women with a pregnancy wish), and MTX has become the first drug of choice in the treatment of RA. Therefore, a clinically more relevant question is whether MTX in combination with other conventional drugs is superior to MTX given alone as first-line therapy. The answer remains open, because studies that compare MTX as monotherapy to combinations of MTX with other conventional drugs (DMARDs) are scarce. Many of the studies do not reflect modern treatment strategy, either because the MTX dosage is too low (maximum dosages 5–10 mg per week) or because they include obsolete drugs such as oral or parenteral gold.

The CIMESTRA trial investigated the issue in a strategic study aimed at remission with intra-articular glucocorticoids, together with either MTX (up to 20 mg) alone or MTX combined with cyclosporine (2.5–4 mg/kg) ( Fig. 1-2 ). All patients were closely monitored (monthly visits with joint counts and adjustment of therapy in case of any swollen joints). The major finding was a very rapid and good clinical response in both groups, with 60% achieving 50% improvement or more ( Fig. 1-3 ), and minimal radiographic progression ( Fig. 1-4 ) with no progression after 2 years in two thirds of the patients ( Table 1-1 ). The clinical response was higher in the combination therapy group, but there was no difference in radiographic progression between the two groups. All in all, the results are comparable to what is achieved with TNF inhibitors.

Table 1-1

Clinical Outcome Measures, Drug Doses and Disease Activity at Baseline, After 1 Year and After 2 Years in the CIMESTRA Study

	Baseline (Week 0)			Year 1 (Week 52)			Year 2 (Week 104)
	MTX + Cyclosporine	MTX + Placebo-Cyclosporine	p Value *	MTX + Cyclosporine	MTX + Placebo-Cyclosporine	p Value *	MTX + Cyclosporine	MTX + Placebo-Cyclosporine	p Value *
No. of tender joints, range 0–10	14 (1–20)	14 (8–20)	0.48	0 (0–1)	1 (0–5)	0.004	0 (0–2)	1 (0–4)	0.23
No. of swollen joints, range 0–40	12 (6–14)	11 (6–15)	0.47	0 (0–0)	0 (0–2)	0.11	0 (0–0)	0 (0–1)	0.61
Doctor’s global assessment, 0–100 mm VAS	54 (37–65)	61 (39–71)	0.15	1 (0–7)	5 (0–18)	0.02	2 (0–6)	3 (0–11)	0.60
Patient’s assessment of gain, 0–100 mm VAS	46 (28–70)	48 (29–63)	0.96	11 (2–23)	15 (5–35)	0.13	8 (3–23)	10 (1–29)	0.80
Patient’s global assessment, 0–100 mm VAS	50 (28–70)	52 (32–73)	0.31	11 (2–27)	15 (4–43)	0.20	12 (2–25)	8 (1–34)	1.00
Serum CRP, mg/L	21 (10–42)	19 (8–46)	0.54	7 (3–10)	8 (4–13)	0.07	7 (3–13)	7 (4–13)	0.61
ESR, mm/h	28 (10–48)	27 (10–47)	0.67	13 (7–23)	10 (5–23)	0.42	10 (6–19)	10 (4–19)	0.26
DAS28 score, ESR based	5.4 (4.6–5.1)	5.7 (4.7–6.2)	0.35	2.1 (1.6–2.9)	2.4 (1.6–3.5)	0.33	2.0 (1.6–3.0)	2.2 (1.5–3.2)	0.92
HAQ score, range 0–3	1.0 (0.4–1.5)	0.9 (0.5–1.4)	0.51	0.1 (0–0.5)	0.4 (0–0.8)	0.18	0 (0–0.4)	0.1 (0–0.8)	0.17
ACR20, % of patients	–	–	–	85	68	0.02	88	73	0.04
ACR50, % of patients	–	–	–	58	53	0.08	79	62	0.03
ACR70, % of patients	–	–	–	59	44	0.08	59	54	0.6
EULAR remission, % of patients	0	0	–	43	34	0.33	51	50	1.00
ACR remission, % of patients	0	0	–	35	28	0.39	41	35	0.52
Max. MTX dose, mg/week	0	0	–	12.5 (10–17.5)	15 (12.5–20)	0.08	17.5 (12.5–20)	17.5 (12.5–20)	–
Max, cyclosporine/Placebo-cyclosporine dose, mg/kg	0	0	–	2.5 (2.5–2.5)	2.5 (2.5–2.5)	–	2.5 (2.5–2.5)	2.5 (2.5–3.0)	–
Cumulated dose of intra-articular betamethasone (ml)	0	0	–	9 (6–17)	12 (6–18)	0.09	1.5 (0–5.125)	2 (0–7.25)	0.18
Blood pressure, mmHg	130/50 (120–140/78–88)	130/50 (120–139/72–85)	0.14–0.35	135/82 (120–140/77–88)	127/81 (117–140/75–88)	0.10–0.63	130/81 (120–140/74–86)	131/80 (120–140/77–86)	0.68–0.71
Serum creatinine, µmol/L mean (SD)	75.4 (11.0)	75.3 (12.2)	0.90	81.5 (13.6)	78.0 (14.1)	0.008	81.0 (13.7)	76.5 (12.9)	0.09

Values are median (integrated range) unless otherwise stated.

From Hetland ML, Stengaard-Pedersen K, Junker P, Lottenburger T, Hansen I, Andersen LS, et al; CIMESTRA study group. Aggressive combination therapy with intra-articular glucocorticoid injections and conventional disease-modifying anti-rheumatic drugs in early rheumatoid arthritis: second-year clinical and radiographic results from the CIMESTRA study. Ann Rheum Dis 2008;67;815–822, Table 1.

* Mann Whitney U test for non-dichotomous variables, X3 test for dichotomous variables. ACR, American College of Rheumatology; CRP, C-reactive protein; DAS28, Disease Activity Score in 28 points; ESR, erythrocyte sedimentation rate; EULAR, European Leagus Against Rheumatism; HAQ, Health Assessment Questionnaire, MTX, methotrexate; VAS, visual analogus scale.

A major strength of the study was that the strategy with maximum inflammatory suppression was applied to both treatment arms. Thereby the isolated impact of combination treatment could be identified. This is in contrast to most other studies of combination therapy, in which the design is either open or the two treatment groups differ with respect to certain factors, such as visit frequency or use of concomitant prednisolone. The weaknesses of the study included the use of cyclosporine, which is very limited in today’s treatment palette due to a fear of toxicity, although the low-dose regimen was well tolerated ( Table 1-2 ).

Table 1-2

Adverse Events in the CIMESTRA Study

Type of Adverse Event	Methotrexate Plus Cyclosporine(n = 80)	Methotrexate Plus Placebo-Cyclosporine(n = 80)	P
Dyspepsia	18 (23)	16 (20)	0.85
Hypertrichosis	26 (33)	6 (8)	<0.001
Constipation	3 (4)	9 (11)	0.13
Insomnia	4 (5)	9 (11)	0.25
Antihypertensive agent added due to hypertension (BP > 140/90 mm Hg)	17 (21)	9 (11)	0.13
> 10% decrease in serum albumin versus baseline	6 (8)	9 (11)	0.59
> 30% increase in serum creatinine versus baseline	15 (19)	5 (6)	0.03

Shown are the number (%) of adverse events that occurred in > 10% of patients in either treatment group. P values were determined by Fisher’s exact test.BP, blood pressure.

From Hetland ML, Stengaard-Pedersen K, Junker P, Lottenburger T, Ellingsen T, Andersen LS, et al; CIMESTRA Study Group. Combination treatment with methotrexate, cyclosporine, and intraarticular betamethasone compared with methotrexate and intraarticular betamethasone in early active rheumatoid arthritis: an investigator-initiated, multicenter, randomized, double-blind, parallel-group, placebo-controlled study. Arthritis Rheum 2006;54:1401–9, Table 2.

The MASCOT study reported that the combination of MTX and SSZ was more effective than the use of either drug alone in patients, who had a suboptimal response to SSZ ( Table 1-3 ), but there was no difference in radiologic progression. One study investigated patients with an inadequate response to MTX and found, not surprisingly, that combination with leflunomide was more efficacious than continuing MTX alone.

Table 1-3

The MASCOT Study: Change in Clinical Outcomes Since Baseline in Combination Therapy (MTX and SSZ) and SSZ and MTX Alone

Variable	Combination (n = 56)	SASP (n = 55)	MTX (n = 54)	Comb v SASP * p Value	Comb v MTX * p Value	SASP v MTX * p Value
DAS	−0.67 (−1.38 to −0.21)	−0.3 (−0.8 to 0)	−0.26 (−0.99 to 0)	0.039	0.023	0.29
HAQ	−0.5 (−10.25 to 0.06)	−0.25 (−9.13 to 0.13)	−0.19 (−10.25 to 0.13)	0.51	0.57	0.99
Ritchie articular index	−4 (−7.5 to −0.5)	−3 (−9 to 1)	0 (−6 to 3)	0.43	0.019	0.13
Swollen joint count	−3 (−4 to −0.5)	−3 (−6 to 0)	−2 (−6 to 0)	0.94	0.81	0.74
Pair score	−8 (−27.5 to 2)	0 (−13 to 7)	0 (−23 to 11)	0.071	0.25	0.58
Patient global	−11.5 (−27.5 to 0.5)	0 (−15 to 5)	−7 (−26 to 2)	0.06	0.72	0.14
Physician global	−12.5 (−25 to 0)	−4 (−15 to 5)	−5 (−22 to 0)	0.044	0.62	0.13
ESR	0 (−8.5 to 1)	0 (−4 to 9)	1 (−3 to 6)	0.087	0.033	0.86
CRP	0 (−5.5 to 1)	0 (−1 to 2)	0 (−3 to 2)	0.18	0.24	0.90