EDITORIAL - Another DMARD option in rheumatoid arthritis?

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Journal of Rheumatology

October 2003

Another DMARD Option in Rheumatoid Arthritis?

HILARY A. CAPELL, MB, Mch, MD, BA, FRCP,

Consultant Rheumatologist;

RAJAN MADHOK, FRCP, MD,

Centre for Rheumatic Diseases,

Wards 14/15,

Glasgow Royal Infirmary,

Castle Street,

Glasgow G4 0SF Scotland.

Address reprint requests to Dr. Capell.

E-mail: hilary.capell@...

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Rheumatologists have ample evidence that early treatment with disease

modifying antirheumatic drugs (DMARD) slows or may even halt radiological

progression and that disability is also reduced. Most rheumatologists, while

using DMARD early in the course of rheumatoid arthritis (RA), also recognize

the importance of sustained suppression of synovitis and that many available

options are poorly tolerated. As in hypertension evidence is accumulating

that using combinations of DMARD has an additive benefit rather than using

more of the same DMARD or class of drug. In those with an inadequate

response, the use of anti-tumor necrosis factor-a (TNF-a) agents provides

additional clinical benefit in a proportion of patients, and even in the

absence of clinical benefit there may be a radiological advantage. However,

biologics are prohibitively expensive for widespread clinical use and

exploring alternative uses for an existing agent is of value. It is in this

context then that we need to examine the data for tetracyclines.

Initial interest in the use of tetracyclines in RA arose from the belief

that a mycoplasma-like organism was implicated in its etiology. Subsequent

studies, however, showed that both minocycline and doxycycline are

metalloproteinase inhibitors in vitro. So, could such readily available

agents that are relatively non-toxic and cheap provide us with a rational

approach to inhibiting the final common pathway for cartilage breakdown and

bone erosion? The metaanalysis published in this issue of The Journal

suggests that there is some evidence for the efficacy of the available

tetracycline compounds but that minocycline data provide the most convincing

evidence of clinical benefit. Clinical trial evidence disappointingly

suggests that despite the findings that tetracyclines inhibit

metalloproteinase synthesis in vitro, this is not achieved in patients. Are

the tetracyclines therefore more like nonsteroidal antiinflammatory drugs

(NSAID) than DMARD because they have no effect on radiographs?

That tetracyclines do not affect radiological disease was noted in the MIRA

study1. In this multicenter randomized placebo-controlled trial over 48

weeks, 219 patients received either 200 mg/day of minocycline or placebo.

Using an intention-to-treat analysis, no difference in the progression of

erosions or joint space narrowing was seen. Although there was a trend

toward the appearance of newly eroded joints being less frequent in the

active group, this too failed to achieve statistical significance.

One of the most comprehensive studies of radiological outcome in RA is the

study by Wolfe and Sharp2. Their study showed, using hand radiographs, that

the rate of progression of joint space narrowing increases with time but

that the rate of progression for erosions does not change with time. There

was no difference in the rate of progression on radiographs and disease

duration. It was also observed that joint space narrowing and erosions are

not good markers to accurately document progression in patients with milder

disease. The rate of progression in the MIRA cohort appears to be slower

than that described in the Wolfe and Sharp study, an aspect noted by the

investigators. In part this may have been due to fewer patients in both the

active and placebo groups being seropositive for rheumatoid factor (56%),

and the mean erythrocyte sedimentation rate (ESR) at the outset in both

groups being similar, 34 mm/h. The initial ESR as a single reading, however,

is a poor correlate of radiological progression, whereas cumulative

inflammatory burden as measured by the mean ESR or as an area under the

curve calculation is better associated. Seventy percent of patients in the

MIRA study had erosive disease and joint space narrowing at onset. To detect

a significant difference the investigators calculated that to achieve 80%

significance, 376 and 478 patients would have to show a change in erosive

disease and joint space narrowing, respectively.

The failure to show beneficial effect on radiological progression may be due

to a true lack of effect, a lack of study power, or biases in patient

selection.

Is disease duration of importance in predicting likelihood of response?

Median disease duration in the report from Tilley, et al3 was 8.6 years and

convincing evidence of response to minocycline was seen in that study. It is

of interest, however, to compare the American College of Rheumatology (ACR)

responses in early RA with a drug such as minocycline4 and those achieved by

Dougados, et al5 with sulfasalazine or methotrexate (MTX) and with MTX

versus etanercept (Bathon, et al6) (Table 1). The numbers studied by O'Dell

were relatively small but the effects achieved with hydroxychloroquine are

much as one would expect clinically and from other studies. By contrast the

benefits he and his colleagues reported with minocycline were similar in

terms of ACR 20 response compared with sulfasalazine, MTX, and etanercept

and greater in terms of ACR 50. Confirmation of such results and evidence of

tolerability beyond the short to medium term will be of importance.

Is there a niche market for minocycline in RA?

Despite recent advances in managing RA including the evidence relating to

the benefit of early DMARD introduction and an increasing range of options,

not all patients tolerate available agents or are suitable for new drugs

such as anti-TNF-a options. An additional hurdle for many is the US

dollar/euro cost of therapies. Hence, the evidence relating to minocycline,

which costs just 3% of a TNF-a blocker, is of importance.

RA is also associated with an increased risk of major sepsis or comorbidity

such as bronchiectasis, and in these circumstances caution is often

necessary when using high dose MTX or contemplating an anti-TNF-a drug.

Utilization of agents with antibacterial properties is an attractive option

both theoretically and practically.

What is the extent of toxicity?

A disappointing aspect of the report by Stone and colleagues was the

relative lack of information relating to toxicity in the primary studies.

The first question many patients with RA ask when offered additional therapy

relates to the risk of side effects. While the consort structure of

reporting clinical studies is relatively recent, the lack of toxicity

information from some studies is a concern (an indictment of investigators

and also of peer reviewers who have assessed such studies). Information

about toxicity should be routinely and meticulously documented in any

prospective study and all clinicians need to maintain vigilance when using a

new drug or initiating therapy for an unlicenced indication.

Table 2 lists the side effects recorded in those studies where this

information is available. However, use of minocycline in clinical practice

reveals far more side effects than these studies have reported. The British

National Formulary, for instance, includes anorexia, pancreatitis,

dizziness, tinnitus, vertigo (more common in females), acute renal failure,

pigmentation that may be irreversible, discoloration of conjunctivae, tears

and sweat, drug induced systemic lupus erythematosus (SLE), and

hepatotoxicity as possible side effects. Known rare adverse events

attributed to tetracycline include benign intracranial hypertension7,8.

Gastrointestinal upset, dizziness, skin pigmentation, and hepatitis are

thought to be dose-related whereas rashes, headache, SLE, benign

intracranial hypertension, or s- syndrome are more likely to be

idiosyncratic.

In their study of 40 patients receiving minocycline, Kloppenburg, et al

noted that 2 patients developed dizziness of such severity that they fell,

leading to fracture of elbow in one and fracture of humerus in another9.

Although total discontinuations because of toxicity were relatively low in

that study (12.5%), there was a life-threatening allergic pneumonitis in one

patient. Other study toxicity reports are noted in Table 2.

In view of the potential usefulness of minocycline, rheumatologists need

answers to issues of toxicity. For instance, does gradual dose escalation

mitigate the dizziness? Could onset of skin pigmentation be delayed by using

a smaller dose? Similarly, can one predict which individuals are more likely

to develop skin problems? The extent to which this slate gray skin

discoloration is of concern to patients varies greatly. Some will tolerate

extensive discoloration, others are less willing to do so despite a good

effect from the drug.

Clinicians caring for such patients need to be committed to full blood count

and biochemistry checks every 3 months while therapy is continued.

Tetracyclines are known to be teratogenic and therefore appropriate

pre-pregnancy advice should be given. There are also potential interactions

with warfarin, oral contraception, antacids, iron preparations, and

penicillins. It is of importance to be alert to these possible side effects.

While data relating to adverse events may be sparse, this metaanalysis

provides a useful summary of the value of tetracyclines in RA for the

practicing physician considering their use. The finding that drugs in the

same class differ in vivo despite similar in vitro effects suggests that

further study may be useful. Minocycline appears to achieve benefit similar

to drugs that we accept as useful DMARD. It is important, however, to

recognize that to show radiological change, significantly larger studies

than rheumatologists usually undertake will be necessary.

REFERENCES

Search PubMed for:

1. Bluhm GB, Sharp JT, Tilley BC, et al. Radiographic results from the

minocycline in rheumatoid arthritis (MIRA) trial. J Rheumatol

1997;24:1295-302. [MEDLINE]

2. Wolfe F, Sharp JT. Radiographic outcome of recent-onset rheumatoid

arthritis. Arthritis Rheum 1998;41:1571-82. [MEDLINE]

3. Tilley BC, Alarcon GS, Heyse SP, et al. Minocycline in rheumatoid

arthritis. Ann Intern Med 1995;122:81-9. [MEDLINE]

4. O'Dell JR, Blakely KW, Mallek JA, et al. Treatment of early seropositive

rheumatoid arthritis. Arthritis Rheum 2001;44:2235-41. [MEDLINE]

5. Dougados M, Combe B, Cantagrel A, et al. Combination therapy in early

rheumatoid arthritis: a randomised, controlled, double blind 52 week

clinical trial of sulphasalazine and methotrexate compared with the single

components. Ann Rheum Dis 1999;58:220-5. [MEDLINE]

6. Bathon JM, RW, Fleischmann RM, et al. A comparison of etanercept

and methotrexate in patients with early rheumatoid arthritis. N Engl J Med

2000;343:1586-93. [MEDLINE]

7. Digre JB. Not so benign intracranial hypertension. BMJ 2003;326:613-4.

[MEDLINE]

8. Lochhead J, Elston JS. Doxycycline induced intracranial hypertension. BMJ

2003;326:641-2. [MEDLINE]

9. Kloppenburg M, Breedveld FC, Terwiel JP, Mallee C, Dijkmans BAC.

Minocycline in active rheumatoid arthritis: A double-blind,

placebo-controlled trial. Arthritis Rheum 1994;37:629-36. [MEDLINE]

10. O'Dell JR, Haire CE, Palmer W, et al. Treatment of early rheumatoid

arthritis with minocycline or placebo. Arthritis Rheum 1997;40:842-8.

[MEDLINE]

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