British Journal of Dermatology 2001; 144: 1101±1104.

editorial comments

Are we going OTT about ITT?

H.C.WILLIAMS

Centre of Evidence-Based Dermatology, Queen's Medical Centre, Nottingham NG7 2UH, U.K.

The article by Schiffner and colleagues in this month's

British Journal of Dermatology provides some importantdata on the difference between analysing clinical trial

data in study participants who comply fully to a study

protocol and those who do not.1 In the context of alarge multicentre uncontrolled open study of Dead Sea

salt and UVB ultraviolet light for treating people with

psoriasis and atopic dermatitis, Schiffner et al. presentthe relative improvement for each disease in two ways.

One was for patients who completed and fully complied

with the protocol: the according-to-protocol populationor ATP. The other was for the entire recruited study

population, i.e. including those that subsequentlydropped out or failed to fully comply: the intention-to-

treat population or ITT. They found that improvement,

as measured objectively by the PASI score for psoriasisand SCORAD for atopic dermatitis, was considerably

higher for the ATP than the ITT populations for both

diseases (68% vs. 57% for psoriasis and 55% vs. 39%for atopic dermatitis).

The implications from this study are clear: when

trying to generalize treatment effects or cost-effective-ness from clinical trials, there is a marked difference in

the result according to which dataset one uses. The ITT

population dataset should preferably be used as it mostclosely represents the target population that one hopes

to generalize to. Despite this, per-protocol analyses are

still the norm for many clinical trials published in thedermatology literature. For example, in a recent

systematic review of 284 randomized clinical trials for

atopic dermatitis, less that 12% had reported an ITTanalysis.2

In addition to estimating treatment effects that are a

more realistic approximation to the populations thatdoctors end up treating, the other key reason for

conducting an ITT analysis in the context of a

randomized controlled clinical trial is to minimize thepotential for bias.3 Thus, excluding participants from

the final analysis simply because they were `dropouts',

without giving detailed reasons for such `non-compli-ance', is likely to result in a biased estimate of treatment

benefit. Reasons for dropping out of a study may be

complex, but unpleasant adverse effects, lack of efficacyor a treatment protocol that is just too demanding for a

busy person are just some. It is essential to capture this

sort of information in an overall analysis of an inter-vention's efficacy because such dropouts are often

enhanced in one of the treatment arms, and a per-

protocol analysis may result in an inflated estimate oftreatment benefit. Sometimes, this bias can result in

claiming an effect where none might have existed.4

This is the reason why looking to see if an intention-to-

treat analysis has been done is used as a major criterion

for rating the quality of clinical trials reports.3 It is alsothe reason why journals such as the British Journal of

Dermatology have signed up to the CONSORT (con-

solidated standards of reporting trials) policy for betterreporting of clinical trials.5

Yet we must not `go over the top' in condemning per-

protocol analyses. They can be, and usually are,performed as exploratory analyses in order to provide

information on potential treatment benefit in those

who comply fully. This information may be importantfor those developing drugs. Thus, if a preliminary trial

evaluating a new acne gel with high treatment efficacy

(as shown in a per-protocol analysis) is marred by adropout of 50% due to local irritation, the developers

may be encouraged to persist with the product and

conduct further work on lowering irritancy or educatingpatients on how to reduce it by other measures.

Some readers may also regard the study by Schiffner

and colleagues as a rather harsh test on which togeneralize the ITT principle to all dermatology clinical

trials. The fact that 68% of the people with psoriasis

and 79% of those with atopic dermatitis had to beexcluded as they were `protocol violators' suggests that

the protocol was quite difficult to follow for most of

the study participants. Perhaps this was the most

q 2001 British Association of Dermatologists 1101

Correspondence: E-mail: hywel.williams@nottingham.ac.uk

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q 2001 British Association of Dermatologists, British Journal of Dermatology, 144, 1101±1104

important finding to emerge from their study. In

addition, even as a clinician with an interest inevidence-based practice, I still find it impossible to

judge whether the differences in the PASI and SCORAD

scores in the ATP and ITT populations are really thatclinically important. For example, does a PASI of 20

imply psoriasis that is `twice as bad' as a PASI of 10? If

such a fall in PASI is mainly due to a reduction in bodyextent, a patient may be just as disabled if his/her

original main problem was psoriasis on areas such as

the face and backs of the hands. Less emphasis shouldbe made on these so called `objective' composite

continuous non-linear scales, and more credence

should be given to simple patient-derived outcomemeasures and quality of life in chronic skin diseases.6

Many trials nowadays try to bridge the chasm

between generalizing from explanatory clinical trialswhich often includes homogeneous, motivated, healthy,

young individuals to everyday patients of all ages and

comorbidity by conducting pragmatic trials, i.e. theystrive to measure treatment effectiveness rather than

efficacy.7 Such trials are typically large and expensiveto perform as they reflect variations between patients

that occur in real clinical practice. Until more pragmatic

trials are done in dermatology, we have to make thebest use of what we have.

Insisting on data relating to an intention-to-treat

analysis is not a statistical game for enthusiasts thathas little to do with routine clinical practice. Far from

being `over the top', it is one of the most important

aspects of good clinical trial practice and reporting.8

Clinicians should insist on seeing an intention-to-treat

analysis if they are to be reassured that bias has been

minimized and if they are to begin to generalize the

study results to the patient sitting in front of them.

Acknowledgment

The author wishes to thank Dr John English for proof-

reading the manuscript.

References

1 Schiffner R, Schiffner-Rohe M, Gerstenhauer F, et al. Differences inefficacy between intention-to-treat and per-protocol analyses for

patients with psoriasis vulgaris and atopic dermatitis: clinical and

pharmaco-economic implications. Br J Dermatol 2001; 144: 1154±

1160.

2 Hoare C, Li Wan Po A, Williams H. Systematic review of treatments

of atopic eczema. Health Technol Assess 2000; 4: 1±203.

3 Hollis S, Campbell F. What is meant by intention to treat analysis?

Survey of published randomised controlled trials. Br Med J 1999;319: 670±4.

4 Chene G, Morlat P, Leport C et al. Intention-to-treat vs. on-

treatment analyses of clinical trial data: experience from a study ofpyrimethamine in the primary prophylaxis of toxoplasmosis in HIV-

infected patients. Controlled Clin Trials 1998; 19: 233±48.

5 Cox NH, Williams HC. Can you COPE with CONSORT? Br J Dermatol

2000; 142: 1±3.

6 Ashcroft DM, Li Wan Po A, Williams UHC, Griffiths CEM. Clinical

measures of disease severity and outcome in psoriasis: a critical

appraisal of their quality. Br J Dermatol 1999; 141: 185±91.

7 Roland M, Torgeson DJ. What are pragmatic trials? Br Med J 1998;

316: 285.

8 Cunliffe WJ, Poncet M, Loesche C, Verschoore M. A comparison of

the efficacy and tolerability of adapalene 0.1% gel versus

tretinoin 0.025% gel in patients with acne vulgaris: a meta-analysis of five randomized trials. Br J Dermatol 1998; 139

(Suppl.52): 48±56.

Paraneoplastic pemphigus: the role of tumours and drugs

G.J.ANHALT

Johns Hopkins University, School of Medicine, Room 771 Ross Research Building, 720 Rutland Avenue, Baltimore, MD, USA 21205

It has now been 10 years since paraneoplastic

pemphigus (PNP) was first described.1 The originallyproposed features of the syndrome have proven to be

quite accurate, although clarification of some points

has occurred. The disease is associated with a smallnumber of lymphoproliferative disorders. Approximately

80% of cases are linked to just three neoplasms:

Non-Hodgkin's lymphoma (NHL), chronic lymphocytic

leukaemia (CLL), and Castleman's disease.2 Some cases

are less commonly associated with retroperitonealsarcomas, thymoma and Waldenstrom's disease. The

most constant clinical feature is the presence of

intractable stomatitis. The autoantibody response ischaracterized by antibodies against desmoglein 13 and

3, as well as antibodies against proteins of the plakin

family of desmosomal proteins. Of the various plakin

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q 2001 British Association of Dermatologists, British Journal of Dermatology, 144, 1101±1104

antigens recognized by individual patients, the most

constant serological findings are autoantibodies againstperiplakin and envoplakin.4 Some patients with CLL

might respond to immunosuppressive treatment,5 but

virtually all patients with NHL die from their diseaseor the complications of treatment. Many die from

pulmonary involvement, which is a unique feature of

PNP.6

The three cases described by Gooptu et al.7 clearly

demonstrate many of these findings. The authors were

concerned about the temporal relationship betweenadministration of fludaribine, and the development of

PNP. They also correctly note that cases of PNP have

developed in temporal association with radiationtherapy and treatment with interferon-alfa. Over the

years, I have participated in the characterization of

more than 140 cases of the disease, and no consistentpattern has arisen regarding chemotherapeutic treat-

ment and development of the autoimmune disease. One

must also recognize that about one-third of cases ofPNP arise in patients with occult neoplasms, so that no

therapeutic agent can be implicated. In the early 1990s,I suspected that treatment with cyclophosphamide,

then a commonly used cytotoxic and immuno-

modulatory drug, may have initiated autoimmunityin PNP patients. This association did not bear out.

When fludaribine was introduced as a new agent, it

then became suspect. I feel that any newly introduceddrug that is useful in the treatment of NHL and CLL

will have the risk of being implicated in inducing

the development of PNP. There is no registry forcomprehensive data acquisition about this disease, so

adverse events occurring with the use of new drugs will

be affected by reporting bias. As new biological agentssuch as monoclonal antibodies are introduced for

treatment of these neoplasms, the same questions

may be raised as cases of PNP are identified in patientsreceiving these agents. Without clear data showing

the risk of PNP developing in patients treated with

older regimens vs. those treated with newer chemo-therapeutic or biological agents, the association is only

speculative.

Also in this issue, Schaeppi et al.8 report the presenceof suprabasilar acantholysis surrounding a primary

melanoma. The authors suggest that the term

`localized paraneoplastic pemphigus' could be appliedto this phenomenon, but there are reasons why this

would not be appropriate. All forms of pemphigus are

associated with antidesmoglein antibodies, and all aresystemic autoimmune diseases. Absent in this case

were the clinical signs of PNP: stomatitis, disseminated

skin lesions, and evidence of antidesmoglein autoanti-

bodies in skin and serum. The patient had autoanti-bodies that identified desmoplakin 1 and plakoglobin by

immunochemical techniques, but antibodies against

desmoplakin I are present in many disorders, includingpemphigus vulgaris and erythema multiforme.9 In PNP,

antibodies against envoplakin/periplakin are the most

unique markers, and these also were absent in thiscase. Additionally, a paraneoplastic syndrome is defined

as a syndrome caused by a remote effect of a neoplasm,

not attributable to invasion by the tumour or bytumour metastases. It is not clear that this patient had

such a syndrome, for the phenomenon was localized to

the tissue immediately surrounding the primary tumour,and was not present distally, even in the face of

recurrent metastatic disease. What is intriguing is the

presence of such clear acantholysis in the absence ofdesmoglein autoantibodies, and the suggestion that

antibodies against plakoglobin or desmoplakin can

induce cell detachment, perhaps in the presence oflocally produced factors, derived from the melanoma.

So, why do patients with these specific neoplasmsdevelop PNP? One must recognize that autoimmunity

in patients with NHL, CLL and Castleman's disease

is well recognized by physicians in haematology/oncology, and knowledge of this predated the descrip-

tion of PNP. More commonly, patients develop auto-

immune cytopenias, with autoantibodies againstplatelets, neutrophils or red cells.10 In these cases, the

autoimmune disease is not influenced by the tumour

burden, does not respond well to immunosuppressivetherapy, and frequently is the cause of death. In some

patients, it seems that these tumours induce an

autoimmune response against epidermal cell proteins,not haematopoietic cells, and these patients present

with PNP. This does not always occur in isolation,

for patients with PNP may also develop additionalautoimmune cytopenias, as documented in case no. 2

by Gooptu et al. This would indicate a complex and

unpredictable effect of the tumour on the immunesystem, with potentially fatal autoimmunity as the end

result. This disease remains a complex and challenging

disorder. It is our expectation that the next decade willprovide further insights into its pathogenesis, and

provide more hope for affected patients.

References

1 Anhalt GJ, Kim SC, Stanley JR et al. Paraneoplastic pemphigus:An autoimmune mucocutaneous disease associated with neo-

plasia. N Engl J Med 1990; 323: 1729-35.

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q 2001 British Association of Dermatologists, British Journal of Dermatology, 144, 1101±1104

2 Anhalt GJ. Paraneoplastic pemphigus. Advances in Dermatology,Vol 12. Philadelphia: Mosby-Year Book, Inc. 1997: 77±97.

3 Amagai M, Nishikawa T, Nousari HC, Anhalt GJ, Hashimoto T.

Antibodies against desmoglein 3 (pemphihgus vulgaris antigen)

are present in sera from patients with paraneoplastic pemphigusand cause acantholysis in vivo in neonatal mice. J Clin Invest

1998; 102: 775±824.

4 Kiyokawa C, Rurhberg C, Nie Z et al. Envoplakin and periplakin

are components of the paraneoplastic pemphigus antigencomplex. J Invest Dermatol 1998; 111: 1236±1238(Letter).

5 StaÊhle-BackdaÈhl M, Hedblad MA, Skoglund C, Fagerholm P,

Anhalt GJ. Paraneoplastic pemphigus: A report of two patients

responding to cyclosporine. Eur J Dermatol 1995; 5: 671±675.

6 Nousari HC, Deterding R, Wojtczack H et al. The mechanism of

respiratory failure in paraneoplastic pemphigus. New Engl J Med,1999; 340: 1406±10.

7 Gooptu C , Littlewood TJ, Frith P et al. Paraneoplastic pemphigus:

an association with fludarabine? Br J Dermatol 144: 1255±1261.8 Schaeppi H, Bauer JW, Hametner R et al. A localized variant of

paraneoplastic pemphigus: acantholysis associated with malig-

nant melanoma. Br J Dermatol 144: 1249±1254.

9 Foedinger D, Sterniczky B, Elbe A, Anhalt G, Wolff K,Rappersberegr K. Autoantibodies against desmoplakin I and II

define a subset of patients with erythema multiforme major.

J Invest Dermatol 1996; 106: 1012±1016.

10 Sallah S, Sigounas G, Vos P, Wan JY, Nguyen NP. Autoimmunehemolytic anemia in patients with non-Hodgkin's lymphoma:

characteristics and significance. Ann Oncol 2000; 11: 1571±17.