Pyramids to myriads: The combination conundrum in rheumatoid arthritis
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Pyramids to myriads: The combination conundrum in
rheumatoid arthritis
D. O’Gradaigh1, D.G.I. Scott2
1Donncha O'Gradaigh, Specialist ABSTRACT Pathogenesis of RA
Registrar in Rheumatology, Department Rheumatoid arthritis continues to be a Our understanding of the immunopatho-
of Rheumatology, Box 204, Addenbrook cause of significant morbidity and dis- genesis of RA continues to expand (7),
Hospital, Cambridge CB2 2QQ, UK; ability. Increased understanding of the with improved understanding of the role
2Professor David G.I. Scott, Consultant immunopathogenesis of the disease, of of T cells (8) and other cells in the in-
Rheumatologist, Honorary Professor, its progression over time, and of patient flammatory infiltrate (9, 10), as well as
University of East Anglia, Department characteristics which correlate with out- of leucocyte adhesion to endothelial cells
of Rheumatology, Norfolk and Norwich come, have allowed more appropriate (11), and definition of the actions of cy-
Hospital, Norwich NR1 3SR, UK. therapy. However, currently available tokines (12). Monocyte infiltration (13),
Please address correspondence and disease-modifying therapy fails to ade- matrix metalloproteinase and cathepsin
reprint requests to Dr. Donncha quately control disease in many patients, production (14, 15), and osteoclast ac-
O’Gradaigh. and many combinations of these drugs tivity (16) all may play a part in the ero-
Clin Exp Rheumatol 1999; 17 (Suppl. 18): have therefore been described. In this sion of cartilage and bone, resulting in
S13 - S19. review, we critically evaluate the exist- the deformity and loss of function which
© Copyright CLINICAL AND ing literature, identifying combinations characterise this disease. Markers of ac-
EXPERIMENTAL RHEUMATOLOGY 1999. for which reasonable evidence of efficacy tive disease are now well established, the
exists, and highlighting important issues most valuable being the C-reactive pro-
Key words: in interpreting such evidence as well as tein (CRP) (17). Novel therapeutic strat-
Rheumatoid, treatment, combination, issues of drug monitoring in such pa- egies have been identified with mixed
DMARD. tients. results (18), primarily directed at cyto-
kines and their receptors. The more re-
Introduction cent inhibitors of tumour necrosis factor
Rheumatoid arthritis (RA) is increas- α (TNFα) show promise (19). There is
ingly recognised as a cause of signifi- also increased, albeit still incomplete, un-
cant disability and morbidity, with mor- derstanding of the mechanisms of action
tality comparable to that of three-vessel of drugs already known to be effective
coronary artery disease or stage IV Hodg- in RA (20). In the context of combina-
kin’s lymphoma (1). Information from tion therapy, the hope would be to iden-
the Norfolk Arthritis Register (NOAR), tify drugs which will act synergistically
a large prospective population-based sur- without overlapping and/or without in-
vey of arthritis, has shown that within teraction of adverse effects.
the first year, 14.4% of newly diagnosed
patients with RA have ceased work. This When to treat - A window of
figure rises to 30.6% (compared with opportunity
2.6% in a control population) over a There is convincing evidence that RA is
mean follow up of 41 months (2). Rec- at its most aggressive, but also most re-
ognition of the impact of RA on health sponsive to disease-modifying therapy,
has led to earlier and more aggressive in the first two years. Brook and Corbett
therapy (3), research leading to new bio- (21) have shown that almost 70% of RA
logic and immunomodulatory therapies, patients develop erosions, with 90% of
and much debate as to the best strate- those occurring in the first two years. In-
gies to apply. As a result, the conven- deed, more sensitive imaging modalities
tional “pyramid” has been inverted (4) such as magnetic resonance imaging
and re-invented (5), while others iden- (MRI) detect erosions within 4 months
tify new paradigms such as “stepping- in RA (22). The rate of radiological pro-
up” and “saw-toothing” (6). This thera- gression may be significantly higher in
peutic conundrum requires careful study the first year (23, 24), although this de-
to make the most appropriate choices for pends to some extent on the scoring
our patients. method used (25).
S-13The combination conundrum in RA / D. O'Gradaigh & D.G.I. Scott
When function is assessed, for example, As mentioned above, MRI scanning fre- implications of these observations have
with health assessment questionnaires quently detects erosive disease sooner yet to be established.
(HAQs), the “window of opportunity” than conventional radiography (CR), and
is again apparent. Wolfe and colleagues recently high-resolution ultrasound What treatment ?
(26) compared the 5-year follow up of (HRUS) was found to be intermediate There is insufficient knowledge of the
patients treated within 2 years to groups in sensitivity between CR and MRI (32). mechanisms of action of DMARDs to
of patients with a disease duration of 2 - It is unclear whether tests must identify date to allow an entirely rational selec-
20 years treated later, and found a sig- all erosions, or simply find any erosion tion of DMARD combinations. Early
nificant improvement in the early treat- in a particular patient to identify that pa- studies with cyclosporin suggested that
ment group compared with the other tient's disease as “erosive” and indicate methotrexate should be stopped for a
groups, who then showed continuing appropriate treatment. Therefore, the role minimum period before cyclosporin was
functional loss despite (later) treatment. for earlier use of these more sensitive started, and the combination was dis-
In another study (27), the “area under the imaging modalities is not yet established, couraged (38), but now these drugs are
curve” (severity over time) for all func- and only CR is currently included in the a well-established combination (v.inf).
tion and disease process variables was American College of Rheumatology cri- Similarly, both methotrexate and sala-
less for early versus delayed therapy in teria for RA (33). zopyrin are known to inhibit folate me-
a cohort of patients with early RA pro- tabolism, implying increased toxicity
spectively followed for five years. Combination therapy without benefit from such a combination.
Juxtarticular and generalised osteoporo- The case for combination therapy is However, this combination has also
sis are important early systemic features made on several grounds. Firstly, many proved useful, although folate supple-
of RA. Patients with disease for less than patients continue to decline, functionally mentation is usually recommended.
six months have higher bone mineral and radiologically, despite treatment The results of two meta-analyses of ef-
density (BMD) than those with disease with successive single DMARDs (34). ficacy (39) place methotrexate (MTX),
of longer duration, and the rate of BMD However, it would be desirable to main- intramuscular gold (i.m. gold), and sal-
loss is higher in patients with early RA tain any partial response obtained with azopyrin (SZP) on an equal footing,
compared with controls or with patients a tolerated treatment, and combination though gold had the highest rate of dis-
whose disease is adequately controlled therapy is therefore a logical step. Sec- continuation. These drugs were found to
by disease-modifying antirheumatic ondly, the success of combination ther- be superior to oral gold and to antimalar-
drugs (DMARDs) (28, 29). apy in oncology, and more recently for ials. Prednisolone (PRD) was not inclu-
human immunodeficiency virus (HIV) ded in this study. Kirwan (40) showed
Whom to treat patients, is evident. The remission of RA an early symptomatic benefit and delay-
While most patients do require aggres- in a patient treated with combination ed progression of radiographic change
sive second-line therapy, a proportion chemotherapy for acute myelogenous with fewer new erosions in a group treat-
remain well controlled with antiinflam- leukemia reported by Roubenoff and ed with 7.5 mg PRD, although the role
matory therapy alone, and up to 30% of colleagues (35) is taken as evidence sup- of long-term oral corticosteroids is still
patients do not develop erosive RA. Can porting this strategy. (However, single contested (41). Cyclosporin A (CYA) is
we identify these patients in advance so cytotoxic drugs have also been used to at least as efficacious as the antimalar-
that only those with potentially progres- good effect, and it is not clear whether ials and has low toxicity (42). Other stu-
sive disease need be exposed to the risks the potency of the drugs, rather than their dies show delayed radiographic progres-
of the more potent second-line thera- combination per se, brought about remis- sion (43, 44), an important effect asso-
pies ? An algorithm has been developed sion in this case.) Nonetheless, whether ciated with the more potent DMARDs.
from the NOAR data allowing the accu- RA is regarded as an infective process, We have experienced no difficulties in
rate prediction of patients who will de- or as a proliferative disorder of synovial substituting the new micro-emulsion-
velop erosions (30). The variables used or immune-competent cells, the parallel based formulation of CYA, Neoral, in
are similar to those previously found to is striking and supports the early use of mono- or in combination therapy [unre-
have prognostic value (17). Patients with combination therapy. ported data, (45)].
involvement of at least two large joints, Drug resistance is also encountered in Fries and collegues (46) devised a tox-
a disease duration of 3 months or more, these related fields of medicine, where icity index based on the severity of the
and positive rheumatoid factor (at least combination regimens are used to avert adverse drug events or laboratory abnor-
1:80) had an 89% chance of developing this. The multiple drug resistance gene malities and the frequency of their occur-
erosions. The risk of erosions was also and its product p-glycoprotein 170 (pgp- rence. Hydroxycloroquine (HCQ) was
greater in males, though this was not 170), a transmembrane transporter which the least toxic and oral gold (MYC) the
used in the algorithm. The positive pre- actively excretes drugs from tumour most (diarrhea had a very high weight-
dictive value of this algorithm is similar cells, have been studied in RA (36). ing in this index), while MTX, penicilla-
to that associated with having the HLA- Cyclosporin and hydroxychloroquine are mine (DPen) and azathioprine (AZA)
DR4 antigen (31), and is more practica- found to be competitive inhibitors of were closely grouped. PRD was simi-
ble in most clinical settings. pgp-170 (37), although the therapeutic larly placed, though longterm conse-
S-14Hypothalamus-pituitary-adrenocortical and -gonadal axis in RA /The combination conundrum in RA / D. O'GradaighEDITORIAL
M. Cutolo & D.G.I. Scott
quences such as osteoporosis were like- bination and the regimen must be applied duration of 6 - 10 years who had not al-
ly to have been missed in the relatively if we are to follow “evidence-based med- ready discontinued MTX or SZP because
short follow-up period (mean 2.6 years). icine.” of toxicity and/or “failure.” In a subse-
SZP was not included in this study, but Earlier meta-analyses (38, 48, 49) paint- quent, open-label study (52), HCQ and
the toxicity profiles of MTX and SZP ed a gloomy picture of combination regi- SZP were added in patients with an in-
have been shown to be comparable (39). mens. However, data from only a small adequate (less than 50%) improvement
The main group of DMARDs was found number of trials were analysed, and in on MTX, and significant improvements
to be no more toxic than the commonly some cases the same data appeared in were seen, suggesting that this combi-
used non-steroidal antiinflammatory each meta-analysis, falsely amplifying nation is of value even when not used
drugs (NSAIDs). their significance. Furthermore, there is ab initio. However, it has not been es-
Drug tolerability is also important. Wolfe debate about the acceptability of per- tablished for early RA patients whether
(47) found a high rate of drug discon- forming meta-analysis combining the it is best to start a triple regimen from
tinuation due either to poor tolerability results of trials of different drugs (50). the outset, or whether SZP and HCQ can
or toxicity. HCQ was withdrawn after a Some recent trials have been more prom- be added later (up to 10 years later, re-
mean of only 20 months, and MYC af- ising (Table I). flecting the study cohort) for those inade-
ter 25 months. Exceptions were MTX quately controlled on MTX monother-
and oral PRD, with over 50% of patients MTX, SZP, and HCQ (51) apy.
continuing these drugs for more than 60 This is regarded as a landmark study of Secondly, are both SZP and HCQ re-
months. combination therapy, having been care- quired as additions to MTX ? There are
Different strategies for combining fully conducted, with adequate numbers no studies adding SZP alone to MTX
DMARDs have been proposed. The of patients receiving each treatment and when the latter has failed, and while
“step-down bridge” described by Wilske a two-year follow-up period. This dou- HCQ and MTX have been tried in com-
(4) uses PRD initially, and in non-re- ble-blind study randomly assigned 102 bination, there was no clear advantage
sponders 3 further drugs are added to ob- patients with a disease duration of 6 - 10 to the combination [other than a signifi-
tain remission. The more toxic drugs are years to the combination of all three cant reduction in the number of patients
then withdrawn, aiming to maintain con- drugs, to MTX alone (as the “gold stand- with elevated liver enzymes (53)]. In an
trol with HCQ alone. In the “step-up” ard” control), or to HCQ and SZP com- open-label, randomised study (54) of 40
approaches, further DMARDs are added bined. The triple regimen was clearly su- patients with an insufficient response to
where the existing “anchor” drug fails perior (P = 0.03) in a composite score of SZP (2 gm/day), the addition of MTX in
to achieve predetermined targets. The early morning stiffness, tender or swol- combination was superior to changing to
“saw-tooth” approach (6) changes the len joint count and the erythrocyte sedi- MTX alone. However, this result must
DMARD in the event of a patient reach- mentation rate. A 50% improvement was not be over-interpreted. A randomised
ing a predetermined “disability level.” seen in 77% of the patients in the triple double-blind study (55) of 105 early RA
Drugs may replace, or be combined with, therapy arm, compared with 33% and patients not previously treated with SZP
the drug which has lost efficacy. Both 40% in the other two groups, respec- or MTX found no advantage to the com-
the step-up and saw-tooth strategies in- tively. bination over either drug alone in a one
clude the idea of setting therapeutic tar- Three important questions are raised by year follow-up.
gets for each drug so that “failure” is this study. First, can the results be ex- In an example of the “step-down” ap-
readily identified, thus allowing one to trapolated to early RA (i.e., less than 2 proach (56), a cohort of early RA patients
move promptly on to the next step. It is years’ duration)? O’Dell’s cohort is unu- was treated with MTX, SZP and PRD.
important to recognise that both the com- sual in having patients with a disease Although initially significantly better
than a control group on SZP alone, this
Table I. Summary of combination therapy trials; see text for details. difference was lost on discontinuing the
steroid at 28 weeks, and there was no
MTX SZP CYA HCQ AZA significant deterioration on withdrawal
of MTX after 40 weeks.
MTX ——— Parallel Add-on Add-on Parallel trial
Thirdly, at what dose should one regard
E=; T= E +; T = E=; T= E =; T +
(see M + S + H) (see M + S + H)
MTX as having “failed” ? The mean dose
of MTX in O’Dell’s blinded study was
SZP Add-on ——— NRT (see MTX + SZP NRT 16.6 mg in the monotherapy group and
E +; T = + HCQ) 16.4 mg in the triple-therapy group. In
the latter, open-label study patients were
I.m. Gold Add-on Add-on Add-on Add-on Add-on
E +; T = E+; T? E+; T= E +; T+ E+; T=
taking a median dose of 17.5 mg when
they were converted to triple therapy.
Notes: Parallel means both drugs were given simultaneously; in add-on trials, the drug in the first Haagsma’s studies (54, 55) used a maxi-
column is the “anchor drug” to which the other was added. mum of 15 mg MTX. Others (57) have
E: efficacy, T: toxicity, (+) increased, (=) unchanged, NRT: no reported trials.
found an optimum dose (efficacy vs. tol-
S-15The combination conundrum in RA / D. O'Gradaigh & D.G.I. Scott
erability) for MTX monotherapy of 18 while improving control. small study of this combination (but with
mg. Since there is considerable variation MTX and i.m. gold (60): MTX was gold added to previous HCQ), reported
across individual patients, a useful guide added to i.m. gold in those with incom- only in abstract form, showed improved
therefore would be to consider combi- plete response. A good response, reduced response in 8 of 10 patients, with no in-
nation therapy for most patients when steroid requirement, and reduced tender creased toxicity (66).
MTX alone in a weekly dose between joint count, or remission were reported AZA has been added to i.m. gold but is
15 mg and 20 mg is insufficient, although in all patients. A combination of oral gold only described in a textbook. On this
some patients may tolerate higher doses. and MTX was not beneficial (61). While combination, 47% of patients were well
One cannot generalise about the use of these trialists used their own evidence controlled with no increase in toxicity,
MTX/SZP/HCQ combinations, and must (62) to show that oral and parenteral gold but there was no clear comparison be-
tailor one's decision, depending on the were comparable, Felson (39) found i.m. fore and after combination therapy, or
study which most closely represents the gold to be more efficacious than the oral with a control group (67).
patient in question. preparation, and i.m. gold is continued MTX and AZA (68, 69): These studies
considerably longer than oral gold in reported the initial 24-week and later, 48-
MTX and CYA clinical practice (63). Therefore these week results of a randomised study com-
Tugwell et al. (58) used an add-on ap- two combination studies of gold appear paring either drug alone to the combina-
proach, randomly assigning 148 patients consistent with data concerning mono- tion. Three different dosage “levels”
(mean disease duration 9.8 years) with a therapy. were used, the maximum dose of MTX
partial response to MTX (up to 15 mg/ CYA and i.m. gold (64): In an uncon- being 15 mg/week as monotherapy, but
week) to the addition of placebo or CYA trolled, non-randomised add-on study, 20 only 7.5 mg/week in the combination
(2.5 - 5.0 mg/kg). At 24 weeks, outcome patients with partial response to i.m. gold arms. The AZA dosage ranged from 50
measures including the tender joint received CYA with improvement in early mg/day to 150 mg/day. More patients on
count, swollen joint count, and HAQ, morning stiffness (from 95% to 74% of combination drugs discontinued treat-
were improved by at least 50% in 45% cases) and moderate-to-marked im- ment due to adverse effects, without any
of patients from the combination group, provement seen in both the physician and benefit of increased efficacy. Furst (70),
compared to 27% of the controls. This patient assessments of disease (in 89% arguing for the rational selection of com-
study was extended (59), with a follow and 79% of the patients, respectively). binations, has suggested that this com-
up of the original combination group Six patients withdrew from the study, bination is unlikely to be of additive
over a total of 48 weeks, in which pa- three due to typical CYA toxicity (rising benefit.
tients who had been randomly assigned serum creatinine), and only one due to
to placebo in the first 24 weeks received lack of effect. A flare occurred in most Overview of combination DMARD
CYA in the second 24-week period. The patients when CYA was withdrawn at six therapy
first treatment group maintained their months, suggesting a true benefit rather This overview does not purport to be an
improved control, while the group con- than simply a placebo response. How- exhaustive summary of all combination
verted to CYA benefitted to a similar de- ever, randomised, controlled studies studies. We have instead concentrated on
gree as the first group. have not been reported. those which appear to be of most rele-
One could argue that comparison with HCQ and i.m. gold (65): In this double- vance to contemporary practice. The re-
placebo in these studies is not clinically blind, randomised controlled study over sults from the trials discussed are some-
relevant since patients with incomplete one year, 52 patients (disease duration times at variance. This may be explained
response to MTX would not be contin- less than 5 years) received i.m. gold and by differences in the patient populations
ued on the same treatment, although HCQ, and 49 patients received i.m. gold studied, by the evidence previously out-
most patients who take monotherapy and placebo. A statistically non-signifi- lined that RA may behave quite differ-
with MTX are not in remission and have cant trend toward increased efficacy was ently in the early and chronic stages, and
incomplete responses. There are strong found, the authors reporting a 20-25% by the fact that “step-down,” “parallel,”
indications and theoretical reasons sug- advantage from the combination on a and “add-on” strategies cannot be di-
gesting the use of this combination ear- broad clinical, laboratory, and radiologi- rectly compared.
lier in the course of a patient’s disease, cal assessment. Perhaps of clinical sig- We feel that combinations of MTX/CYA
although further studies are necessary. nificance, the CRP did fall significantly or SZP/MTX in those patients who are
in the combination group, and this is re- inadequately controlled on monothera-
Gold therapies garded as an important marker of pro- py (with MTX or SZP, respectively) are
A number of patients with longstanding gressive disease. However, there was well supported by trial literature. The ad-
RA initially well controlled by i.m. gold also a trend to increased toxicity, with dition of SZP and HCQ to partially ef-
experience a loss of efficacy of this drug, half of the combination group withdraw- fective MTX is another useful strategy.
typically 1 - 10 years after starting it. A ing due to adverse effects (mainly rash). In patients already on i.m. gold with par-
number of combinations have been used Of note, 17 of the 49 controls also with- tial effect, the addition of MTX or CYA
in patients in whom i.m. gold has some drew due to adverse effects, rash again seems promising. The triple regimen of
benefit, aiming to maintain this effect being the most common. Conversely, a MTZ, SZP, and HCQ at initiation of
S-16Hypothalamus-pituitary-adrenocortical and -gonadal axis in RA /The combination conundrum in RA / D. O'GradaighEDITORIAL
M. Cutolo & D.G.I. Scott
treatment is an important consideration, therapy (76). tis [Ed]. J Rheumatol 1997; 24: 1023-7.
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The role of PRD in combination with monly see raised transaminase levels in 7. AREND W: The pathophysiology and treatment
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40: 595-7.
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to be of value in achieving rapid symp- itoring MTX. Caution is required in the pathogenesis of rheumatoid arthritis: new per-
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sion of erosions pending the action of and this would be particularly important 9. BURMESTER GR, STUHLMULLER B, KEY-
SZER G, KINNE RW: Mononuclear phagocytes
the slower-acting DMARDs (35). A in those on CYA/MTX combinations. As and rheumatoid synovitis: Mastermind or
similar role has recently been described a rule, the monitoring for combination workhorse in arthritis? Arthritis Rheum 1997;
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viocytes in rheumatoid arthritis; passive re-
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25.
Boers’s study (56). treatment of patients with RA, we are 13. YANNI G, WHELAN A, FEIGHERY C, BRES-
Most of the new biological agents are still far short of a firm control of the dis- NIHAN B : Synovial tissue macrophages and
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discussed (72). AZA and mycophenolate aggressive pursuit of optimal control as with matrix metalloproteinases and their re-
mofetil have been used in combination early as possible. The “pyramid” has spective inhibitors in rheumatoid arthritis and
in acute graft rejection (73). More rele- been inverted, re-invented, shuffled, and osteoarthritis. Arthritis Rheum 1998; 41: 1378-
87.
vantly, preliminary reports indicate that cast aside by various experts, creating
15. HUMMEL KM, PETROW PK, FRANZ JK, et al.:
combinations of MTX with anti-TNFα instead a “myriad” of therapeutic choic- Cysteine proteinase cathepsin K mRNA is ex-
therapy are of benefit (74, 75), and a es. Combination therapy is one such idea pressed in synovium of patients with rheuma-
theoretical synergistic role has been pro- “whose time has come,” perhaps borne toid arthritis and is detected at sites of syno-
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