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).

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The 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-

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Hypothalamus-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-

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The 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

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Hypothalamus-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.
though its application to a group of early   A frequently more important interaction               6. FRIES JF : Re-evaluating the therapeutic ap-
                                                                                                      proach to rheumatoid arthritis: the “sawtooth”
RA patients has not yet been demon-          which is often overlooked occurs be-                     strategy. J Rheumatol 1990; 17 (Suppl. 22): 12-
strated.                                     tween NSAIDs and DMARDs. We com-                         15.
The role of PRD in combination with          monly see raised transaminase levels in               7. AREND W: The pathophysiology and treatment
other DMARDs is difficult to assess          patients on NSAIDs, particularly diclo-                  of rheumatoid arthritis. Arthritis Rheum 1997;
                                                                                                      40: 595-7.
from the current literature. It does seem    fenac, which is of importance when mon-               8. FOX DA : The role of T cells in the immuno-
to be of value in achieving rapid symp-      itoring MTX. Caution is required in the                  pathogenesis of rheumatoid arthritis: new per-
tomatic relief, and may slow the progres-    use of NSAIDs in patients taking CYA,                    spectives. Arthritis Rheum 1997; 40: 598-609.
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;
for adjunctive intraarticular cortico-       therapy should be that of the individual                 40: 5-18.
steroid in early RA patients commenc-        drugs. It will be easier in the add-on regi-         10. FIRESTEIN GS : Invasive fibroblast-like syno-
                                                                                                      viocytes in rheumatoid arthritis; passive re-
ing MTX (71). In general, when patients      mens to identify the likely cause of a new               sponders or transformed aggressors ? Arthritis
present with early disease we use the        adverse effect, although knowledge of                    Rheum 1996; 39: 1781-90.
depot (i.m.) injection of methylpredni-      each drug in a combination and their                 11. MOJCIK CF, SHEVACH EM: Adhesion mol-
solone while awaiting the effect of          typical toxicity profiles should facilitate              ecules: A rheumatologic perspective. Arthritis
                                                                                                      Rheum 1997; 40: 991-1004.
DMARDs, and this appears to be very          appropriate action.                                  12. TAK PP, SMEETS TMJ, DAHA MR, et al.: Ana-
effective in the short term (unpublished                                                              lysis of the synovial cell infiltrate in early rheu-
data). In effect it mimics the step-down     Conclusion                                               matoid synovial tissue in relation to local dis-
approach, though not exactly replicating     While advances have been made in the                     ease activity. Arthritis Rheum 1997; 40: 217-
                                                                                                      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
still undergoing trials as monotherapies     ease in many of our patients. In particu-                joint erosion in rheumatoid arthritis. Ann
to establish their efficacies, although      lar, the evidence of a “window of oppor-                 Rheum Dis 1994; 53: 39-44.
                                                                                                  14. KEYSER G, REDLICH A, HAUPL T: Differen-
combinations of these agents have been       tunity” must focus our attention on the                  tial expression of cathepsins B and L compared
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-
                                                                                                      vial bone destruction. J Rheumatol 1998; 25:
posed (19).                                  of desperation, but it is increasingly be-
                                                                                                      1887-94.
                                             ing recognised as a logical option.                  16. GRAVALLESSE EM, HARADA Y, WANG J-T,
Monitoring patients on combination                                                                    GORN AH, THORNHILL TS, GOLDRING SR :
therapy                                      “Diseases desperate grown                                Identification of cell types responsible for bone
The majority of clinical trials showing       By desperate appliance are relieved,                    resorption in rheumatoid arthritis and juvenile
                                              or not at all”                                          rheumatoid arthritis. Am J Pathol 1998; 152:
benefit from combinations have also                                                                   943-51.
found little additional adverse effects                                 Hamlet
                                                                                                  17. VAN DER HEIJDE DM, VAN RIEL PL, VAN
from an interaction between the various                                                                 LEEUWEN MA, VAN’T HOF MA, VAN RIJS-

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Hypothalamus-pituitary-adrenocortical and -gonadal axis in RA /The combination conundrum in RA / D. O'GradaighEDITORIAL
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