therapy for rheumatoid arthritis: combinations of disease-modifying drugs and new paradigms of...

Therapy for Rheumatoid Arthritis: Combinations of Disease- Modifying Drugs and New Paradigms of Treatment

By William S. Wilke and John D. Clough

The last 10 years have witnessed a change in the way rheumatologists view rheumatoid arthritis (RA). It is no longer considered a slowly progres- sive disease limited to the joints, but rather an aggressive systemic disease that results in clinically significant morbidity early in its course and can contribute to excess mortality. Heightened awareness of the health impact of RA has spurred a search for effective therapy to be applied early in the course of disease for patients with moderate to severe RA. Combinations of disease-modifying antirheumatic drugs (DMARD) have become an increasingly popular alternative to sequential monotherapy. In this report, we review published series of patients with RA who have been treated with combinations of DMARDs, sometimes including chemotherapeutic agents, with some critical comment. Published paradigms of treat-

“The basic program of rest, salicylates, and physical therapy is the most sensible beginning of therapy.

The combination of more than two antiinflammatory drugs is not recommended. ”

John A, Goldman, Evelyn B. Hess, 1970.’

“You know something’s happening But you don’t know what it is For the times they are A ‘changin’ ”

Bob Dylan, circa 1965.

C ONSERVATIVE THERAPY for rheumatoid arthritis (RA) was the recognized and

popular approach advocated by rheumatologists in the 1960s and early 1970s. This position was eminently defensible. Treatment with medica- tions in common usage, especially parenteral gold and D-penicillamine (DPN), was by no means universally effective, and resulted in significant adverse effects in at least one third of treated patients.2*3 Trials of chemotherapeutic agents, such as the controlled study of methotrexate (MTX) by Black et aJ4 while demonstrating the efficacy of this drug class, proved that in high doses these drugs were very dangerous. Gradually, over the last 10 years, chemotherapeutic drugs have gained acceptance, first as third-line agents and more recently, in the case of MTX, as a possible second- line drug of choice for the treatment of RA.5,6 In addition, rheumatologists have adopted a more aggressive approach to the treatment of this dis-

ment are also reviewed and a new strategy is presented. The “step-down bridge” strategy allows early treatment with at least four DMARDs, but may place some patients with mild disease at an inappropriately high risk of adverse effects. The “sawtooth” strategy gives little guidance as to which DMARD(s) should be chosen for initial treatment. We describe a “graduated-step” strategy that provides numerical grading to match disease severity and disease activity with appropriate initial therapy and that facilitates therapeutic decisions throughout the course of treatment. Copyright 0 1991 by W.B. Saunders Company

INDEX WORDS: Rheumatoid arthritis; combination therapy; strategies of treatment; “graduated- step” strategy.

eaSe and are willing to initiate disease-modifying antirheumatic drugs (DMARDs) earlier in the course of disease than in the past.’ This evolution in therapeutic thought has been driven by some recent changes in our understanding of RA and the therapeutic agents used to treat it.

RA is no longer considered a benign disease that only has an impact on function. Severe rheumatoid disease has been shown to confer both long-term morbidity and early mortality.*,’ In addition, the high frequency of severe adverse effects expected with chemotherapeutic agents used early in the course of disease has not been realized. lo

Although these agents are effective when they are used in low-dose monotherapy, disease may

From the Department ofRheumatic and Immunologic Dis- ease, The Cleveiand Clinic Foundation, Cleveland, OH.

William S. Wilke, MD: Staff; Department of Rheumatic and Immunologic Disease, Head, Section on Subspecialty Clinics, The Cleveland Clinic Foundation; John D. Clough, MD: Sta& Department of Rheumatic and Immunologic Dis- ease, Director of Health Affairs, The Cleveland Clinic Foun- dation.

Address reprint requests to William S. Wilke, MD, De-

partment ofRheumatic and Immunologic Diseases (Desk AjO), The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195-5028.

Copyright 0 1991 by W.B. Saunders Company 0049-0172/91/2102-1004%5.00/0

Seminars in AIthriri.. and Rheumetism, Vol2 1, No 2, Suppl 1 (October), 199 1: pp 2 l-34 21

22 WILKE AND CLOUGH

not be well controlled in every patient.“,” Higher doses of these agents not only increase their effectiveness, but also result in at least a trend toward a higher frequency of adverse effects.‘3-‘5 To minimize the incidence and severity of adverse effects from high doses of individual agents, relatively low doses of two or more drugs are given simultaneously.

WHICH DRUGS SHOULD BE COMBINED?

An informed decision about which DMARDs to combine requires detailed information about the pharmacology and mechanisms of action of each separate drug. For instance, a renal-toxic drug such as cyclosporine A probably should not be combined with another drug that depends al- most entirely on renal excretion for its elimina- tion, such as MTX. Drugs that are combined ought to have different mechanisms of action that might lead to potentiation, as one drug acts more “proximally” in the inflammatory cascade, thereby allowing lower doses of other drugs that act more “distally.” The ideal combination would include drugs with actions that allow intracellular potentiation.

Combined DMARDs also should have separate toxicity profiles, which ought to reduce the likelihood of potentiated toxicity. Distinctly separate toxicities also allow blame for adverse reactions to be correctly assigned so that the of- fending agent may be reduced in dose or discontinued. The toxicity profile of the combination should be acceptable.

Differing durations of onset might be exploited. Because the onset of action of MTX generally occurs within 3 to 6 weeks, it might be combined with oral gold, which has a delayed onset of action.16 Patients treated with this combination should experience early improvement of the disease process with MTX. Later, as oral gold takes effect, the dose of MTX may be lowered or the drug may be discontinued.

Unfortunately, knowledge about drug interactions and mechanism(s) of action is incom- plete. The combination of DPN, which inhibits T-cell function,‘7 and hydroxychloroquine (HCQ), which inhibits macrophage function,‘* would seem appropriate. In fact, as we will see, this combination shows little promise.

COMBINATION THERAPY IN THE LITERATURE

Combinations of DMARDs Excluding Chemotherapeutic Drugs

Six series have reported experience with “con- servative” DMARDs in combination (Table 1). Four separate series have reported the combination of antimalarials with other DMARDs.

HCQ combined with DPN was compared with each drug alone in a 2-year double-blind controlled study of 56 patients.lg At 6 months, 43% of patients taking DPN alone were markedly improved, as were 17% of patients taking HCQ alone, whereas only 7% of patients who received combination therapy were markedly improved. This pattern of response continued throughout 24 months of therapy. Moderately severe adverse effects that resulted in lowering the dose of one or the other agent or in discontinuing an agent occurred in 29% of patients receiving combination therapy, 43% of patients receiving DPN alone, and 22% of patients receiving HCQ alone.

In another study, 72 patients were given chloroquine phosphate 250 mg/d, DPN, or the combination of these two drugs, and monitored for 1 year2’ Chloroquine alone was the least effective treatment in this study. At 12 months, radiographs of the hands were compared. Forty-one percent of patients taking DPN and 45% of patients taking the combination were judged to have x-rays that were unchanged or improved. Only 12% of the patients taking chloroquine showed x-ray changes that were unchanged or improved. Adverse effects occurred in 57% of patients taking the combination, 42% taking DPN alone, and 15% of patients taking chloroquine alone.

Neither of these series recommends the combination of antimalarials and DPN. In the first study, patients actually fared worse with combination therapy. In the second study, the addition of chloroquine to DPN may have resulted in mildly additive improved efficacy, but also contributed to a higher incidence of adverse effects.

Other series have combined HCQ with parenteral gold. In a placebo-controlled 12-month prospective study that compared 52 patients receiving parenteral gold and HCQ with 49 patients receiving parenteral gold and placebo, the group that received the combination showed a trend toward greater improvement in all measures.2’

COMBINATION THERAPY FOR RHEUMATOID ARTHRITIS 23

Table 1: Series in Which Combinations of DMARDs Without Chemotherapeutic Agents Were Used

Reference No. of

Patients DMARDs Efficacy Toxicity

BunchJg 56 HCQ 2.2 mg/kg/d

DPN 7 mg/kg/d

Gibson*’ 72 Chloroquine 250 mg/d

DPN maximum of 750 mg/d

Scot? 101 HCQ 400 mg/d

P. gold 50 mg/wk

Singletot? 10

Taggart23 30

HCQ 200 mg/d P. gold

SSZ 2 g/d

DPN 500 mg/d

Farr24 38 SSZ 1.5-3.0 g/d + either

DPN 500 mg/d or

P. gold 50 mg/wk

DPN alone more effective

DPN and combination

“equally effective”

Trend favoring

combination

Response in 80%

Combination significantly

better than SSZ alone

9 (24%) “good”

17 (46%) partial

remission in 2 patients

Led to D/C in:

Combination-2g%

DPN-43%

Combination-57%

DPN-42%

Chloroquine-15%

Withdrawals:

Combination-25

Gold alone- 17 .> safer than gold

alone”

Withdrawals:

Combination-7/l 5

ssz-3115

At 12 months-withdrawal:

DPN-3 1%

P. gold-33% 1 Abbreviations: HCQ, hydroxychloroquine; DPN, o-penicillamine; P. gold, parenteral gold; SSZ, sulfasalazine

Only improvement in C-reactive protein (CRP) showed significance at the 1% level. Unfortu- nately, there was a higher incidence of adverse effects in patients receiving combination therapy, and although they were generally nuisance toxicities, such as rash or gastrointestinal upset, the investigators felt that adverse effects limited the usefulness of this combination.

A lower incidence of adverse effects was seen in an earlier series presented only as an abstract.** In this study, parenteral gold was added after 13 months of therapy with HCQ 200 mg/d. After a mean total dose of 750 mg of parenteral gold, eight of 10 patients improved or remitted. All patients experienced at least a one-tube dilution decrease of rheumatoid factor titer. Therapy was continued for 3 years, and no patient was withdrawn due to adverse effects. The investigators speculated that HCQ somehow protected patients from the toxicity of parenteral gold therapy.

These reports suggest that the combination of HCQ and parenteral gold may benefit patients. Divergent opinions about the safety of this combination might be answered by further long-term prospective trials.

Sulfasalazine (SSZ) also has been used in combination with other DMARDs.23 A 6-month open trial of SSZ 2 g alone in 15 patients or in com-

bination with DPN 500 mg/d in 15 patients showed moderately increased efficacy with the combination. With SSZ alone, only the eryth- rocy-te sedimentation rate (ESR) and grip strength showed statistical improvement. With the combination, the ESR, grip strength, and articular index all showed statistically significant improvement. Unfortunately, adverse effects including rash, dysgeusia, and thrombocytopenia were much more common in patients treated with the combination and led to seven withdrawals from combination therapy versus three withdrawals with SSZ alone.

In another study, 38 patients established on a constant dose of SSZ were given either DPN or parenteral gold.24 During the first year, approximately one third of the patients in each group withdrew due to toxicity. However, compared with baseline, the entire group experienced an overall clinical response of 70%, which indicated to the investigators that both combinations were more effective than SSZ alone.

Both of these studies suggest that the combination of parenteral gold or DPN with SSZ is relatively safe, and that this combination is more effective than SSZ alone. Whether these combinations are more effective than parenteral gold or DPN alone is unknown. If the combination is

24

more effective, it lends itself to further study because the typical adverse effects of SSZ differ from those of either DPN or parenteral gold.

Combinations Using One Chemotherapeutic Agent

All of the chemotherapeutic agents commonly used to treat RA have been combined with at least one other DMARD (Table 2). In addition, prednisone has been combined with a cytotoxic drug in a controlled study.25 High-dose cyclophosphamide (CTX) (1.7 mg/kg/d) in 19 patients was compared with low-dose (CTX ( 1.1 mg/kg/ d) combined with low-dose prednisone (7.7 mg/ d) in 13 patients. Improvement in the number of affected joints and grip strength was similar in both groups. Walking time and ring size showed greater improvement in high-dose CTX patients. On the other hand, 19 patients in the high-dose

WILKE AND CLOUGH

CTX group experienced 25 occurrences of adverse effects, including serious infection in two. Only one of 13 patients in the low-dose group experienced an adverse effect. In this series, prednisone was CTX-sparing.

CTX was one of the chemotherapeutic agents used in combination in an open trial of 21 patients.26 Eleven RA patients were treated with parenteral antilymphocyte globulin 750 mg/d administered on 15 consecutive days and simultaneous prednisolone 20 mg/d for 12 months. At 12 months, CTX 50 mg/d was added in one patient, chlorambucil 4 mg/d in two patients, and azathioprine (AZA) 2.5 mg/kg/d in eight patients, At 6 and 12 weeks’ follow-up, the duration of morning stiffness, grip strength, and active joint count showed significant improvement for the group when compared with previous prednisolone alone. Unfortunately, this improvement was

Table 2: Series in Which One Chemotherapeutic Agent Was Combined With Another DMARD

No. of Chemotherapeutic Reference Patients Agent DMARDs or Other EffiCaCy Toxicity

Smyth=k 13 CTX 1.1 mg/kg/d Prednisone 7.7 mg/d Equal to 1.7 mg/kg/d CTX -8% Binda?’ 11 AZA 2.5 mg/kg/d (8) Initial antilymphocyte globulin Overall significant at 3 mo 91%

Prednisolone 20 mg/d CHL 4 mg/d (2) CTX 50 mg/d (1 j’

Bittef’ 30 CHL 5 mg/d l Gold sodium thiomalate or Gold 30%

+ DPN 100 mg/d or + Levamisole 45 mg/wk

17 CHL 5 mg/d l DPN 100 mg/d or + 20%

+ Levamisole 450 mg/wk DPN best Let.+? 70 AZA 2.1 mg/kg/d Gold sodium thiomalate “Well controlled” (47.1%) No worse than gold

50 mg/mo alone

Shiroky” 4 MTX 11.25 mg/wk SSZ 2.3 g/d -88% improvement in None active joints

Lee” 18 MTX 10 mg/wk DPN 750 mg/d 8/l 2 achieved complete “. no dropouts”

remission Pred 10 -, 2.5 mg

Brawe?’ 7 MTX 11.5 mg/wk P. gold 75 mg/wk Recapture of good “No toxicity was response or remission observed”

in all

FtauJ2 48 MTX 7.5-15 mg/wk P. gold 50 mg/wk Overall reduction in No worse than MTX

disease activity alone

William+ 335 MTX 7.5 mg/wk AUR 8 mg/d Similar response for More withdrawals in

combination v. MTX combination for ADR

alone. Lack of response withdrawals = AUR 13%. MTX 7%. combination 2%

Kantor’O 287 MTX “standard dose” AUR “standard dose” 49% of pts taking AUR - 12% withdrawals alone after combination due to worsened clinically ADR with

combination

l Numbers in parentheses indicate number of patients treated.

Abbreviations: CTX, cyclophosphamide; AZA, azathioprine; CHL, chlorambucil; DPN, b-penicillamine; MTX, methotrexate; SSZ, sul-

fasalazine; P. gold, parenteral gold; AUR, auranofin; ADR, adverse drug reaction.


not seen at 6 and 12 months. The lack of continued statistically significant improvement may be due to the fact that prednisolone was reduced from 20 mg/d at the start of combination therapy to a mean of 13 mg/d at 6 months, and to 11 mg/d at 12 months.

In another open trial, chlorambucil was added to previous DPN 1 g/d or to previously initiated parenteral gold. 27 Other combinations included levamisole with DPN, and parenteral gold with DPN. Remission was most often seen in the parenteral gold plus DPN and levamisole with DPN patients, during a follow-up of 38 to 113 weeks. Unfortunately, the number of patients in each group was small (five to 12), which makes claims of efficacy less certain. Approximately 25% of patients treated with these combinations experienced adverse effects, including herpes zoster infection in one patient.

The combination of AZA 2.1 mg/kg/d and parenteral gold 50 mg/mo administered to 70 patients was reported in abstract form.28 Forty- seven percent of patients were “well controlled.” Adverse effects with this combination were reported to be no worse than with parenteral gold alone.

MTX has been combined with three different DMARDs. A short report of four patients treated for a mean period of 24 months with MTX mean dose 11.3 mg/wk and SSZ mean dose 2.3 g/d in patients who had not responded to SSZ in three cases and to MTX in one case, suggested that the combination was more effective than either drug alone.29 The authors reported no adverse effects. This combination of two folic acid inhibitors should be monitored carefully, because of a report of potentiated MTX toxicity in a patient receiving simultaneous trimethoprim-sulfamethoxazole.30

The combination of DPN and MTX was reported in abstract form.31 Sixteen patients who failed to respond optimally to DPN were given weekly oral MTX, mean dose 10 mg/wk. Dis- continuation due to drug intolerance did not occur. Three patients were lost to follow-up and one patient died of unknown causes. Of the re- maining 12 patients, eight achieved complete remission, which was sustained for 7 months in seven of eight patients. The other four patients achieved 50% or greater improvement in impor- tant efficacy measures. The combination of MTX

and DPN was also shown to be corticosteroid- sparing compared with DPN alone.

MTX was added to background parenteral gold therapy. 32 Seven patients who received parenteral gold for a mean of 4 years in a dose of 75 mg/mo were given MTX, mean dose I 1.5 mg/wk, for an average of 19 months. This abstract reports either good response or remission in all treated patients. Toxicity was not encountered.

In the European literature, Rau and Karger treated 46% of 10 1 RA patients with simultaneous parenteral gold and MTX 7.5 to 15 mg/ wk.33 This combination resulted in a reduction of active joint count and daily corticosteroid re- quirement. The toxicity encountered was no worse than with MTX alone.

Two recent abstracts report divergent results observed with the combination of auranofin (AUR) and MTX. In the first double-blind, randomized study, 335 patients initially were given AUR 6 mg/d or MTX 7.5 mg/wk alone.34 A third group was given the combination of AUR 6 mg/ d and MTX 7.5 mg/wk. Two hundred eleven patients completed the trial. The investigators found no statistically significant differences in response among the groups. Withdrawals for lack of response were less frequent in the group receiving both active agents; however, there were more withdrawals due to adverse effects in that same group.

In the second abstract, 267 patients with active RA initially received a combination of AUR and MTX for 6 months. I6 At 6 months, 89% of eval- uable patients showed clinical benefit defined as greater than 50% reduction in joint count and physician’s global assessment. In a second blinded phase of this trial, placebo was randomly substituted for MTX in half the patients. Previous ben- efits were maintained in 74% of patients who re- mained on combination therapy and 5 1% of patients taking AUR alone. At 6 months’ follow- up, only 14% of patients who received both active agents withdrew because of adverse effects. The investigators believe that the risks of combination therapy were not greater than the risks of either agent alone.

The combination of MTX and HCQ has also been reported. We found that this combination was no more toxic than MTX alone in a retro- spective review of 87 RA patients monitored for

26

a mean of 42 months.35 More recently, Fries et al reported an unexpected benefit when MTX was combined with HCQ.36 In a computer-gen- erated review of nearly 2,600 RA patients, the percentage of patients with elevated serum transaminase levels was statistically significantly lower in those receiving MTX 8.8 mg/wk combined with HCQ (0%) than in patients receiving MTX 9.6 mg/wk alone (2.7%). Figure 1 contrasts serum transaminase levels in a subset of patients from that study.

Among these combinations, those that include CTX run the risk of long-term oncogenesis3’ The combination of MTX and low-dose oral gold is well tolerated. Our own unpublished anecdotal experience suggests that the addition of oral gold to background MTX and HCQ is more effective than MTX and HCQ alone. As with the combination of MTX and HCQ, further studies are needed.

The experience with prednisone and CTX suggests an interesting concept. Both increased efficacy and increased toxicity usually occur as the doses of chemotherapeutic agents are increased.‘2-‘4 The addition of lowdose prednisone (<O. 1 mg/kg) as a chemotherapeutic-sparing agent might be safer38,39 than increasing the dose of the chemotherapeutic agent.

Combinations Using Two Chemotherapeutic Agents

Whether or not the concept of RA as a benign clonal expansion of poorly regulated B cells has merit 40,41 this analogy has led to the use of combinations of chemotherapeutic agents for treatment (Table 3). 42-50 Scherbel and Harrison were among the first clinicians in the United States to

WILKE AND CLOUGH

combine sequential parenteral nitrogen mustard followed by low-dose pulsed MTX, usually in combination with HCQ. Unfortunately, only the details of the nitrogen mustard therapy were published.51,S2 We continue to use these agents in sequence.53

When chemotherapeutic agents are combined to reduce the frequency and severity of adverse effects, they usually are prescribed in lower doses than when used as monotherapy. McCarty and Carrera were the first to publish results of two chemotherapeutic agents combined in low-dose with HCQ.42 They treated 17 patients with resistant RA using roughly */z dose equivalents of CTX and AZA combined with 200 to 400 mg/d of HCQ introduced sequentially. The dose of each chemotherapeutic agent was alternately increased over weeks to months until mild leukopenia occurred. Five patients achieved remission, two near-remission, seven partial response, and three showed no response. In a follow-up report, only four of the 16 patients who achieved remission showed worsening of erosions at 3.5 years’ follow- up.43 This response was remarkable, because all these patients had failed previous DMARD therapy, which often included parenteral gold and/ or AZA. Unfortunately, after 3.5 years of follow- up, four patients developed malignant neoplasms, which were fatal in three; pneumonia developed in five other patients, which necessitated withdrawal of at least one of the chemotherapeutic agents in two patients. 43 These investigators suggested the substitution of another chemotherapeutic agent for CTX. In a recent editorial, the senior author reported that he had successfully treated at least 33 additional patients with the combination of MTX, AZA, and HCQ.S3

Serum Glutamic Oxaloacetic

Traneaminase (SGOT) in units/ml

”

Methotrexate Alone Methotrexate + Hydroxychloroquine

Fig 1: Twenty-six patients taking either MTX alone or MTX combined with HCQ. (Data from Fries et al.36)


Table 3: Series in Which Two Chemotherapeutic Agents Were Used Simultaneously

No. of Chemotherapeutic

Reference Patients Agents DMARDs or Other Efficacy Toxicity

McCa@ 3 1 AZA 74 mg/d HCQ 2 11 mg/d 16 complete remission 4 malignancies

Csuka43 CTX 30 mg/d 14 excellent to good 2 pulmonary

1 no response infections

1 thrombocytopenia

ButleP 16 CTX 25 mg/d HCQ 400 mg/d Radiologic recortication 1 stomatitis

Tiliakos45.4B MTX 5 mg/wk 7/l 2 and 50-90%

improvement in

efficacy measures

in all

Fosdick4’ 16 MTX

I

doses not None 6 complete remission No serious toxicity

CTX specified g partial remission

Biro- 37 MTX g mg/wk HCQ 200-400 mg/d 4 joint count 6 1% 3 leukopenia

Wilke49 AZA 67 mg/d 4 WSR47% 1 herpes roster

1 bacterial pneumonia

LangevitP 12 MTX 5-12.5 mg/wk HCQ 200-400 mg/d J- joint count 59% 3 nausea

AZA 25-50 mg/d J WSR38%

Abbreviations: AZA, azathioprine; CTX, cyclophosphamide; HCQ, hydroxychloroquine; MTX, methotrexate; WSR, Westergren sedimentation rate.

Butler and Tiliakos reported a controlled trial in which two groups of patients, who received either MTX 5 mg/wk, CTX 25 mg/d, and HCQ 400 mg/d or MTX alone 10 to 15 mg/wk, were compared with a third group that continued previous treatment without chemotherapeutic agents.44*45 During a follow-up ranging from 8 to 23 months, patients who received the two chemotherapeutic agents showed the most improvement. This experience was updated and 16 patients were monitored for 2 years4’j These patients experienced 50% to 90% improvement in duration of morning stiffness, grip strength, number of painful joints, and Westergren sedimentation rate (WSR). X-ray evaluation showed recortication in seven patients. Adverse effects were rare; treatment was interrupted in only one patient due to stomatitis.

Fosdick reported 16 patients treated with MTX and CTX. MTX was started after CTX alone failed to produce the desired improvement.47 Few details are given in this abstract. Six patients achieved complete remission and nine, partial remission. Side effects included “self-limited stomatitis” in all patients and elevation of a liver function test in one patient. No irreversible bone marrow depression, thrombocytopenia, or infection were reported.

We reported our positive experience with combination therapy using AZA, MTX, and HCQ in preliminary form in 1987.48 The original 20 patients had failed previous single-agent chemotherapeutic treatment, including MTX in 17 patients and AZA in three. Either AZA or MTX was then added to the other stable chemotherapeutic agent. The majority of patients were also receiving HCQ.

Since then, we have retrieved data on all patients in the department treated with this combination and lengthened the duration of follow- up. We now have information on 37 patients who received AZA (mean dose, 67 mg/d) and MTX (mean dose, 9 mg/wk) for a mean of 30 months. Thirty-one patients simultaneously were taking HCQ 200 to 400 mg/d. Active joint count was reduced from 14 at time zero to 9 at 12 months and 5 at 18 months. The WSR decreased from 48 mm/h at time zero to 36 mm/h at 12 months and 26 mm/h at 18 months. The frequency of serious toxicity was low. Three patients experienced reversible leukopenia, one patient herpes zoster, and one patient bacterial pneumonia. Other adverse effects included gastrointestinal toxicity in seven patients, elevation of serum transaminase level in two, alopecia in one, and hepatic fibrosis in a patient who had previously

28 WILKE AND CLOLJGH

Table 4: Disease Features of Rheumatoid Arthritis and Other Factors That Predict a Poor Outcome

in Selected Prospective Series

Follow- No. of Reference Year Up (vr) Patients IFC t APR AJC t RF Other

DuthieBS 1964 9 200 x X X X

McKonkey@ 1972 0.5-6 987 X

Jacoby6’ 1973 a-14 100 X X

Fleminge’ 1976 4.5 102 X X X X 4 Grip strength

Fcigenbaums* 1979 >5 50 X X 4 Grip strength, psychological

stress

Sjoblomao i 984 2 103 X X 4 Hgb concentration

Raskars2 1984 15 100 X X X 4 Hgb concentration presence

of rheumatoid nodules

Kaarelas3 I 985 a 200 X X Worsening radiographic grade,

symmetric swelling, EMS

> T HR

Sherrers9 1986 11.9 681 X Worsening radiographic grade,

t age, female sex

Scott” 1987 20 112 X X t Age, late presentation

Mottonen” 1988 2 58 X X X “Disease activity”

Erhardtsg i 989 a 64 Extra-articular involvement,

t cryoglobulins, (+) PASCA

Reilly8 1990 25 100 X X f Hgb concentration

Abbreviations: IFC, impaired initial functional capacity or worsening functional capacity; + APR, chronic elevation of acute-phase reactants; AJC, active joint count inversely related to prognosis; t RF, increasing or high titer rheumatoid factor; 4 Hgb, decreased hemoglobin concentration; EMS, duration of early morning stiffness; PASCA, positive test for precipitating antibodies to soluble cellular antigens.

taken MTX for more than 10 years. This low incidence may be due to the trial design, which excluded patients who were intolerant to chemotherapeutic agents. Patients who failed monotherapy had done so after taking MTX for a mean of 58 months or AZA for 15 months, proving they could tolerate chemotherapy. Our treatment also may have been made safer due to concomitant therapy; the majority of patients were receiving HCQ36 and 2 1 of 37 patients were receiving weekly folic acid.s5,56

This same combination was reported in the British literature.50 Of 12 patients observed for 14 to 18 months, the mean joint count before treatment was 11 .O and after treatment was 4.5. The WSR decreased from 45 mm/h to 28 mm/ h. Four patients were withdrawn from treatment, due to nausea in one and inefficacy in three. These results are similar to the Cleveland Clinic experience.

The combination of AZA and MTX seems surprisingly safe in the small number of patients reported. There is theoretical rationale for ex- pecting synergy between these agents at the in-

flammatory cell leve157 and with regard to drug metabolism.58 The de novo pathway of purine synthesis is blocked by MTX. Further purine synthesis is dependent on salvage pathways, which are in turn dependent on the enzyme hy- poxanthine-guanine phosphoribosyltransferase. This enzyme is also necessary for purine activa- tion. As this enzyme becomes more active, it converts a higher percentage of intracellular AZA to its effective form. Above the intracellular level, MTX inhibits xanthine oxidase, the enzyme that

Total - IO-21 months

Fig 2: Time course of therapy based on the

“treatment pyramid.”


catabolizes 6-mercaptopurine, resulting in higher blood levels of active AZA.

If this drug combination is shown to be more effective than monotherapy with either agent in controlled studies, it may be a useful alternative to higher doses of MTX or AZA.

GOALS OF THERAPY

Eficacy Measures

The primary goal of therapy in RA is to improve or at least maintain function. Many ret- rospective and prospective series have attempted to discover which features or other factors present in early RA and/or during the disease process

predict poor functional outcome8,59-70 (Table 4). Older age, high titer of rheumatoid factor, early functional decline, abnormal psychological sta- tus, extra-articular involvement, low hemoglobin level, and poor initial radiographic grade predict later impaired function, morbidity, and sometimes mortality. Clearly, one of the measures that affects function is radiographic change. Unfor- tunately, radiographic studies are expensive and subject to interobserver error.

Two predictive measures common to most long-term studies are the initial active joint count and sustained elevation of acute-phase reactants. That the number of active joints might predict

--A Other Combinations

or CSA or Biologicals or Apheresis or Tidal Lavage

______________

I AU (P) or DPN ! orMTXorAZA I k

I

z 8 w -

I I ! HCQ I + I + +

NSAlDs I + I 1 + (Analgesic?) , + (Analgesic?)

OTiPTlPt. Ed. ; + I + I + I I i I I

Mild (O-4) Moderate (5-7) Severe (8-l 3)

Disease Severity Classification

Reserved

Fig 3: The initial level of therapy is based on the sum of the disease activity index (Al; Table 5) and the

prognostic factor score (Table 6). Subsequent therapy decisions depend only on the disease Al (see text).

Therapies enclosed in the “consider” block may be used, but are not mandatory. This allows individual

flexibility while maintaining the spirit of the paradigm. The “reserved” step should not be used as initial

therapy and is only used if patients fail step 3, “severe” disease. Al Level 1: joint aspiration, corticosteroid

joint injectkrn, intramuscular administration of corticosteroids and/or corticotropin, and oral corticosteroid

(0.1 mg/kg prednisone equivalent). Al Level 2: includes “induction therapies” with intramuscular or joint

injection of chemotherapeutic agents, intravenous chemotherapeutic agents such as nitrogen mustard,

and intravenous high-dose “pulsed” corticosteroids. HCQ, hydroxychloroquine; NSAIDs, nonsteroidal

antilnflammatory drugs; OT, occupational therapy; PT. physical therapy; ED, patient education; AU (0).

oral gold; SSZ, sulfasalarine; MTX, mathotrexate; AU (P), parenteral gold; DPN, o-penicillamine; AZA,

azathioprfne; CSA, cyclosporine A.

30 WILKE AND CLOUGH

Table 5: Disease Activity

Disease

Activity

Pain

EMS (min)

S/T joints

WSR (min/h)

or

CRP (mg/dL)

Total ooints

Inactive Subacute Active

Marked

Response or Partial Poor

Remission Score Response Score Response Score

None 0 Intermittent 1 Constant 2

<15 0 15-30 1 >30 2

o-2 0 3-5 1 >5 2

<30 30-45 >45

0 1 2

<2.0 2.0-2.6 >2.6

0 4 8

NOTE. Disease activity index has been adapted from a drug response index conceived and tested by Scott et al.*‘,87 One numerical

value is assigned to each efficacy measure. Grip strength was not included because of diurnal variation and the inherent problems of

interpretation due to simultaneous median neuropathy in some patients, and fixed deformities and degenerative changes at the carpal/

metacarpal joint of the thumb in others.

Abbreviations: EMS, duration of early morning stiffness; S/T joints, total count of swollen and/or tender joints, ie, a joint that is swollen

and/or tender is given a value of 1; WSR, Westergren sedimentation rate; CRP, C-reactive protein.

declining functional capacity and worsening of the radiographic index is not surprising. In a sur- vey of 57 experienced rheumatologists, the joint tenderness count was the most popular measure of drug effectiveness. 5g Of interest, the WSR was among the least-preferred measures, despite the ability of “disease-modifying” agents to reduce acute-phase reactants levels5’

The magnitude of elevation of acute-phase reactants correlates well with radiographic grade5%72>73 and with active joint count.8,5g-62,- 65,66,70 Three series have found more severe involvement of peripheral joints72,73 and a higher rate of new bone erosions73 in patients with RA who have persistently elevated acute-phase reactants. In another prospective study of 64 patients who received second-line drugs for an adequate time period, patients who maintained a persistently low WSR showed less radiographic progression than did patients with higher values.74 In a trial of 67 patients with RA, only those who received drugs that lowered the WSR showed a trend toward reduced rate of articular erosions.75

The prospective series by Dawes et al deserves special attention. 76 One hundred fifty patients with RA who received DMARDs were assessed during 1 year of therapy. Radiographs were obtained at the start, at 6 and 12 months. The WSR and CRP were measured regularly. At 12 months, patients were divided into groups based on the values for the WSR and CRP. At 6 months, all

patients showed significant worsening of radiographic scores compared with baseline. However, at 12 months, patients in whom the acute-phase reactants were normalized showed no progression. In contrast, patients in whom these measures were intermittently elevated or always elevated showed radiographic deterioration. This study suggests that in a large population of patients with RA, radiographic deterioration is minimized when acute-phase reactants are normalized.

If the degree of eventual physical dysfunction is directly related to the number of a&&d joints and the height of the elevation of acute-phase reactants, the objective goal of therapy must be to reduce the number of affected joints and to normalize acute-phase reactants. This should be accomplished quickly, soon after the diagnosis of RA is certain and before cartilage is damagecL40 Effective early treatment is necessary, because radiographic damage develops in the fnst 2 years in the majority of patients with moderate to severe disease.77~78 In addition, effective treatment may better control irreversible joint damage, which results in radiographic change.”

NEWER PARADIGMS OF TREATMENT

Strict adherence to a pyramidal approach to therapy may delay the initiation of effective measures for many months to years in patients with moderate to severe RA (Fig 2). Because no rev-


Table 6: Prognostic Factors

Factor Score

Deteriorating functional capacity* 1

Sustained (~6 mo) elevated WSR 1

RF titer 2 1:640 Latex 1 Extra-articular diseaset 1

Radiologic joint damage 1

Total points 5

* Includes worsening functional class, and/or change in employ-

ment capacity.

t Includes rheumatoid nodules, inflammatory eye disease, sicca

complex, vasculitis, and pleural or pulmonary involvement.

Abbreviations: WSR, Westergren sedimentation rate; RF, rheu-

matoid factor.

olutionary new modalities are available, new philosophies of therapy are necessary. Until safer and/or more effective treatments are available, we must use those we have innovatively. Wilske and Healey have suggested a “step-down bridge” paradigm in which an initial dose of prednisone 10 mg/d is administered for 1 month.” Patients who fail to respond adequately are then given the combination of antimalarials, oral gold, parenteral gold, and MTX. Other DMARDs may be substituted. After 3 months of multiple drug therapy, tapering is attempted with the hope that antimalarials will maintain disease control.

Another strategy, the “sawtooth” paradigm, depends on setting a ceiling for disability.‘l Dis- ease-modifying drug therapy is serially changed whenever this ceiling is reached, in an attempt to maintain early disease control.

The step-down bridge paradigm certainly allows vigorous early therapy for RA. Unfortu- nately, it may place some patients with only moderate disease at unnecessary risk of adverse effects from exposure to multiple DMARDs. In addition, long-term maintenance of moderate to severe RA with HCQ alone has not been dem- onstrated.

Table 7: Disease Severity Classification

Score Classification

o-4 Mild

5-7 Moderate

B-13 Severe

NOTE. Disease activity index + prognostic factor score = disease

severity classification.

Table 8: Other Factors That Influence

Treatment Decisions I

A.

8.

C.

D.

E.

F.

G.

Drug allergy or intolerance

Age

Patient expectations

Coexisting disease

1 Peptic ulcer disease

2. Diabetes mellitus

3. Malignancy

4. Macular degeneration

5. Active infection

6. impaired renal function

7. Liver disease

Drug interaction

1. Anticoagulants

2. Anticonvulsants

3. Alcohol

4. Allopurinol

5. Antibiotics

6. Addiction

Noncompliance

Drug failure and need for surgery

The sawtooth paradigm assumes that when monotherapy or combinations of drugs result in disease control, this control will disappear over time. Although that phenomenon certainly occurs with gold therapy, it is usually because over time the dose and frequency of administration are changed. 82 That phenomenon does not ap pear to occur with some DMARDs, including MTX.83 In addition, initial disease control may be difficult to realize. Monotherapy with conser- vative DMARDs is only effective in a small percentage of patients. 2,84,85 Even with chemotherapeutic agents, tight control is rarely achieved. In a long-term prospective study, 16 patients who continued to receive MTX for 36 months showed a mean WSR of 53 mm/h and an active joint count of 8.’ ’ This apparent limited response to monotherapy in some patients dictates that combinations of DMARDs will likely be used early in the sawtooth paradigm. But this paradigm does not provide rationale for specific therapeutic choices.

To expose only those patients with sufficiently active disease to risk the potential adverse reactions of combination therapy, the Cleveland Clinic group has designed a graduated paradigm of treatment: “graduated-step therapy” (Fig 3). In this paradigm, at or near the time of diagnosis,

32

disease activity is computed by summing vari- ables derived from a response index developed and tested by Scott et al86*87 (Table 5). The numerical value for disease activity is then added to another value obtained by summing arbitrarily chosen prognostic indicators (Table 6). This sum is the numerical value for disease severity (Table 7). Patients are then entered into the paradigm and treated with the modalities corresponding to this value (Fig 3).

At 3 to 6 months, patients are reevaluated, but only the disease activity index is computed. Pa- tients with values of 0 to 3 are designated as hav- ing inactive disease and to have responded to therapy. They may be continued at the present treatment level, or it may be reduced. Patients with values of 6 to 8 have active disease that has not responded to therapy and treatment should be escalated. Patients with values of 4 to 5 have subacute disease. Decisions regarding change of therapy for these patients will depend on changes of efficacy measures that have not been included in the disease activity criteria, including time of

WILKE AND CLOUGH

onset of afternoon fatigue, change in grip strength, change in hemoglobin concentration, or the onset or worsening of extra-articular disease. Other factors that might influence treatment decisions are also considered (Table 8).

This paradigm is, in fact, a formalized version of the past and current practice of our group. As we enter and prospectively monitor our patients using this paradigm, we will evaluate efficacy and toxicity on a regular basis. We anticipate that changes in the specific recommendations at each step will be necessary as this concept evolves.

New philosophies of therapy represent the best chance for contemporary “breakthroughs” in the treatment of RA. The early use of compatible combinations of drugs and modalities that are carefully chosen and appropriate for the individual level of disease activity appears to be a rational paradigm to test in well-designed prospective trials.

ACKNOWLEDGMENT

The authors would like to thank Ann W. Fuentes for her technical assistance on the manuscript.

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