contentsjmaj, january 2004—vol. 47, no. 11 jma’s basic policy to ensure safety in health care...

Vol.47, No.1 January 2004

CONTENTS

JMA Policies

Basic Policies of the Japan Medical Association

Eitaka TSUBOI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Interferon Therapy

Basis and Clinical Applications of Interferon

Jiro IMANISHI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

Interferon Therapy for Leukemia

Michihiko MASUDA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Practice of Interferon Therapy—Brain tumor—

Toshihiko WAKABAYASHI and Jun YOSHIDA . . . . . . . . . . . . . . . . . 18

Interferon Therapy in the Field of Dermatology

Kazuko MATSUMURA and Hiroshi SHIMIZU . . . . . . . . . . . . . . . . . 24

Practice of Interferon Therapy—Multiple myeloma and other related hematological malignancies—

Akihisa KANAMARU and Takashi ASHIDA . . . . . . . . . . . . . . . . . . . 32

Sensory Organ Disorders

Olfactory Disturbances—Pathophysiological findings and

the development of new therapeutic procedures—

Mitsuru FURUKAWA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

Housewives’ Eczema

Treatment of Housewives’ Hand Eczema—Touching on recent topics—

Hiroko NANKO . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

JMAJ, January 2004—Vol. 47, No. 1 1

JMA’s Basic Policy to Ensure Safetyin Health Care

The medical accidents that have successivelyoccurred in recent years have greatly shockedthe nation; and it is a source of deep remorsethat these accidents have led to the loss of pub-lic trust in our health care system.

Although some of these medical mistakesfall within the realm of highly advanced medi-cal technology, these incidents are unforgivableirrespective of the causes, given the reality thatthere has been the loss of precious lives com-pletely contrary to the promise of a more fulfill-ing life by the progress that has been made inmedical technology.

We all know that the Hippocratic Oath for-bids physicians from injuring patients throughmedical acts, and this is not limited to the field ofadvanced medical technology. Safety in healthand medical care is the fundamental principleof medical ethics. Health and medical care per-sonnel in charge of blood transfusions, medi-cation, clinical tests, and a variety of othertechnical tasks must be stringently forced torecognize the ironclad rule that patients mustnot be injured or harmed through medical acts.The situation must be quickly remedied against

�JMA Policies

the outbreak of such mistakes and the utmosteffort must be made to appeal to health carepersonnel to take preventive measures againstthe reoccurrence of such accidents. Thus, inview of the situation, it is time for the JMA toactively propose specific measures to securesafe medical and health care. Emergency con-sultations have been held with the membersof the self-improvement committee that wasquickly created within JMA, the committee onhealth care safety, the committee on improvingethics, and various other relevant committees.Opinions on specific accident prevention mea-sures will be solicited, a draft plan will beprepared, and following a decision by theexecutive board, it will be publicly announcedto specialist medical societies, the government,politicians, and to the general public. JMA’sreadiness to take medical accident preventivemeasures and its action policy on this issuemust be communicated; and it must take ac-tions that will win back the public trust that hasbeen lost.

In the past, the JMA expressed its concernwhen it pointed out the possibility that medicalethics might be undermined in the draft revi-sion of the Declaration of Helsinki that wassubmitted to the Council meeting of the WorldMedical Association (WMA). JMA actively

Basic Policies ofthe Japan Medical AssociationJMAJ 47(1): 1–6, 2004

Eitaka TSUBOI

President, Japan Medical Association

The following is a main part of the address of Dr. Eitaka Tsuboi, President of the JapanMedical Association, which was presented at the 109th Extraordinary General Assem-bly of the JMA House of Delegates that was held in Tokyo on October 12, 2003.

2 JMAJ, January 2004—Vol. 47, No. 1

Eitaka TSUBOI

expressed its opposition against putting a priceon human life under any circumstances and tosafeguard the dignity of citizens of economi-cally weaker nations, notably the developingcountries against its elimination in the name ofglobalization or economic efficiency.

High quality health care, highly safe healthcare is what humanity throughout the worldyearns for at present. Thus, the JMA, whichholds a position of leadership within inter-national medical associations, must upholdsteadfastly the principle and action that pro-mote safe health care in Japan. JMA’s pro-posals to secure safe medical and health caremust be publicly announced as quickly as pos-sible, and we must foster the public’s senseof security.

Issues of Clinics with Beds,Retirement Age, etc.

Next, I would like to discuss issues related tothe health care provision system.

The debate about abolishing Article 13 ofthe Medical Service Law that threatens thecontinued existence of clinics with beds, whichhas been a traditional aspect of Japan’s healthcare culture, has been an ongoing debate forseveral decades. The viewpoints of the govern-ment administration and on-site clinics haveconstantly been at odds over the regulationrestricting the hospitalization period at clinicsto 48 hours despite the supplementary clausethat allows this restriction to be extended atthe discretion of the physician-in-charge. As aresult, these clinics have not been efficientlyoperated. Thus, the JMA is currently in nego-tiations with the Health Policy Bureau ofthe Ministry of Health, Labour and Welfare(MHLW) over the complete abolishment ofthis Article. Although an in-depth study andconcrete discussions have been conducted bymembers of JMA’s committee in charge ofreviewing this issue, it has been a difficultundertaking. But we are determined to con-tinue the ongoing discussions and to achieve

our goal. I believe that a potential solution canbe reached if we study countermeasures thatare fundamental structural reforms of thehealth care system of our country. This is theardent wish of the JMA, and we would like toresolve the issue on abolishing Article 13 of theMedical Service Law that limits the hospital-ization period of patients and other problemsrelated to clinics with beds.

At the last House of Delegates meeting, Ipromised that the JMA would establish a com-mittee to study its bylaws and provisions andcomprehensively discuss the issues concerningclinics with beds, the integration of member-ship qualifications, and a retirement system forboard members and delegates of 70 years andolder. A committee was immediately created,and a committee report was submitted basedon the subsequent discussions that have takenplace. This report has been sent to each localmedical association. As you are aware, theirconclusion was that it was extremely difficult toimplement an integrated membership qualifi-cation and retirement system. And I have justexplained the situation about the issue regard-ing clinics with beds.

Based on an exchange of opinions with eachregional block, we received your viewpointsabout issuing medical certificates for variouslicenses and qualifications. We discussed themajority viewpoint with relevant MHLW per-sonnel that in principle, doctors should refuseto issue a medical certificate if they cannotmake an accurate diagnosis of the patient onhis/her first visit. The MHLW has also indi-cated that they will set up a study team with thecooperation of the JMA at early date, and itwill work towards compiling an intermediateposition within this fiscal year. Therefore, wewill have to wait a short while longer before aconclusion can be reached.

Nursing System

Next, I would like to discuss our nation’snursing care system.


BASIC POLICIES OF THE JMA

As a nation with the world’s most rapidlyaging society and low birth rate, the remark-able progress that has been made in medi-cal science has greatly improved and rapidlychanged community health care both quanti-tatively and qualitatively. Under these circum-stances, it is only natural that well-defined andspecific improvements are being demanded ofour nursing care system. Issues about whatnursing and care for the elderly should be aboutor what improvements should be made in nurs-ing to keep up with the progress that has beenmade in advanced medical technology are someof the many notable demands of the generalpublic. I believe that the JMA must endeavorto build a nursing system that is in sync with thetimes, while simultaneously respecting the pro-fessionalism of nurses who are the partners in acommunity health care system.

Lately, the JMA has advocated the introduc-tion of a team of nurses based on a three-tieredsystem of nurses, assistant nurses, and nurse aidesin community health care as recommended bythe ILO. JMA has especially pointed out therising significance of the existing system ofassistant nurses that is being re-acknowledgedin the face of increasing care duties in an agingsociety. Moreover, in conjunction with the leg-islation of laws in recent years, caseworkers,nursing care workers, and personnel in a vari-ety of health related occupations have arrivedon the scene creating a multi-tiered nursingand care structure. This phenomenon is antici-pated to diversify even more as social valueschange. Despite the shift into a new stage ofdevelopment, the importance of a three-tierednursing and care structure should not to betaken lightly. Physicians and nurses have beengiven the added task of jointly building a sys-tem based on an action plan with a mutual goalthat will integrate the many personnel engagedin diverse occupations with different healthand nursing concepts and achievements and toimplement these myriad tasks effectively inthe community.

The JMA, which has always advocated the

importance of assistant nurses within a three-tiered structure, will continue to advocate theirimportance within a new social milieu; and itbelieves that creating such a nursing and caresystem is an urgent task. Specifically, a jointproject team will be established by the JMAand the Japan Nursing Association aimed atcompleting a nursing system in Japan.

International Activities

Next, I would like to report on the inter-national status of the JMA.

JMA’s contribution to the WMA has increasedyearly and recognition of its contribution con-tinues to rise within the international commu-nity. This is because the JMA has activelystressed medical ethics; and its proposed state-ments that focused on improving medical safetywere adopted. In addition, a working groupwas created to prepare a WMA declaration onwater and health care that was proposed bythe JMA.

Meanwhile, the JMA will host the CMAAOCongress from December 11 to 12, 2003 inTokyo and the WMA Tokyo General Assem-bly on October 6, 2004 for a five-day period.The Board of Trustees has already approvedthe establishment of a preparations committee.Thus, JMA’s record of achievements as aninternational medical association continues togrow. As an international medical association,I would like the JMA to contribute Japan’svery outstanding expertise in health care to theprosperity of humanity throughout the world.

In addition, the progress made by the JMAmedical assistance project in Nepal has beensatisfactory. We are presently in the stage oftransferring the management of the project’shealth activities to the Nepalese staff members.The success of the school education activity inNepal can be attested to the fact that the lit-eracy rate of the community has risen greatlyand our efforts have been highly appraised bythe Nepalese government.

The Takemi Program conducted jointly with


Eitaka TSUBOI

the Harvard School of Public Health in theUnited States continues to make progressiveachievements thanks to the enthusiasm anddedication of all those involved in this program.

Revision of Medical Fees

I would like to extend my deep apologiesand regrets as the head of the executive boardfor the truly grievous state of affairs for themore than anticipated damages that have beencaused by the deficit revision of medical feesand the increased payments of patients. Thenegative effect on the operations of clinics andhospitals has been extensive.

Although some progress has been made torecover from these damages, the aftereffectshave not disappeared and greater effort isneeded.

The recovery of the remaining unadjustedsegment in conjunction with the FY2004 revi-sion of the medical fee schedule will be funda-mentally debated through ongoing discussionswith the Central Social Insurance Medical Coun-cil to ensure that the revision is consistent withthe demands of the clinics and hospitals. Pro-curing financial resources is the most importantfactor in revising the medical fee schedule. Wehad begun negotiations with the Ministry ofFinance, the MHLW, and relevant branchesimmediately after the previous revision hadbeen announced, but we will begin lobbyingactivities with regard to the next revision offinancial resources in tandem with our discus-sions with the Central Social Insurance Medi-cal Council. Formidable effort will be made toconvince the relevant ministries and divisionsof our standpoint.

Difficulties in Health Reform

The Koizumi Cabinet’s reform strategy, whichpromulgates “structural reforms without sanc-tuaries”, has left the health care sector withnumerous scars. The content of the KoizumiCabinet’s health care reforms are mainly char-

acterized by the following two desires. Firstly,there are the health care reforms based onmarket principles that are aimed at making aprofit by putting a price on human life. Specifi-cally, the management of hospitals by privatecompanies, the introduction of a combined pay-ment system for diagnosis and treatment, andreforms that allow the Federation of HealthInsurance Societies to select and sign directcontracts with health and medical institutionsare some of the notable measures that are beingpromoted. The Cabinet’s stance is that suchderegulation measures are needed in order toimprove the quality of Japan’s health care.However, this stance may potentially violatethe fundamental freedom of patients to selectthe medical institution of their choice as well asdestroy the impartial system of health care thathas been maintained thus far. Put in extremeterms, it is the same as saying, “we’ll get ridof the pain of the rich, but poor people mustendure”. Such a system is completely unaccept-able to the Japanese people.

Secondly, the Koizumi Cabinet would like toplace the control of health care costs underthe leadership of the government bureaucracy.They are trying to control the growth rate ofelderly health care costs and the overall frame-work of controls for health costs through mea-sures that require the least effort and exertion.Burgeoning health care costs are an acute prob-lem, but policies by the Ministry of Finance thatincrease or decrease benefits according to theirfinances are not measures that have the welfareof the Japanese people in mind.

Presently, health care costs are estimated at31 trillion yen. Market principle supportersbelieve that the greater this amount is the bet-ter, whereas the bureaucrats believe that thelesser these costs are the better. These com-posite contradicting poles of thought character-ize health care reforms. Thus, health reformsin Japan have progressed without any consis-tency and only superficial reforms or changesthat have been for the worse have been imple-mented, while radical structural reforms remain


unimplemented. Real structural reforms of thesocial security system are just beginning.

I announced my support for Mr. Koizumi inthe last LDP presidential election; and therewere many voices around me that opposed mysupport. I have been criticized and asked why Ihave supported Mr. Koizumi when the JMAhas been thoroughly battered by his structuralreforms. The health reforms that have beenpursued by the Koizumi Cabinet are very infe-rior and I am aware of this fact. My reason forsupporting him is that our social security sys-tem has reached its limits due to the haphazardmeasures that have been taken in the past. Toseriously reform our system, I have acutely feltthe need for the kind of drive displayed by Mr.Koizumi’s reforms. We are in the stage wheretotal social security reforms cannot be achievedwithout fundamental reform. It is importantthat there is a clear vision of our country’sfuture before we put a scalpel to the existingsocial security system. When I scrutinized theother leaders in our political system, I did notsee one political leader whom I thought wouldpush furiously ahead with reforms. I believethat the increasing momentum to legislatenational reforms provides a singularly uniqueopportunity to enact health care reforms.

Social Security System as Part ofNational Strategy

A national viewpoint and a perspectiverooted in medical ethics are needed to imple-ment fundamental health reforms. If the con-cepts of a new social security system are notbased on these perspectives, the direction ofthese reforms will waver. As I stated at the pre-vious House of Delegates meeting, the socialsecurity system must be expanded as part of thegovernment’s national strategy.

Employment must be secured and pensionsmust be properly paid to the elderly. Thesecomponents of the social security system areissues that the government must address withjust as much responsibility and earnestness as

national defense. Politicians have traditionallyviewed social security as a form of charity forthe economically disadvantaged. What is evenmore frightening is that they believe that thenational strategy is to utilize the financial re-sources set aside for the social security systemfor other policies. Social security as a means ofrelief for the economically disadvantaged ismost certainly one aspect of the system, but it isnot limited to this function alone. The goal is tocreate a social welfare system that benefitsboth the younger generation and the elderly.

What is needed in future is a social securitysystem that provides for all stages of an indi-vidual’s life cycle from birth, education, employ-ment, pension, to the end-of-life care. The kindof social security system that we aim for is muchbroader in concept than UK’s social securitysystem, which is based on a concept of security“from cradle to grave”.

However, living in an age where life valuesgreatly change and in an advanced informationsociety where we live under the illusion that wehave reached the ultimate stage of develop-ment, a multifaceted information network thatexceeds conventional methods must be estab-lished in order for each citizen to be convincedof a social security concept that is based onmedical ethics according to his or her senseof values.

However, it is difficult to pursue this tasksuccessfully utilizing solely JMA’s conventionallatitude of professional knowledge; and abroader spectrum of expertise and technol-ogy from other sectors is needed. I acutely feelthat the course that the JMA must adopt tocope with the strong public demand for diversehealth care will require much energy and accu-mulated technology.

However, to realize this ideal and to build asociety where social security is viewed as a partof the national strategy, the government ad-ministration and legislators must be persuadedof this fact based on public consensus. Thus,I believe that JMA’s foremost responsibility isto strive untiringly toward this goal.

BASIC POLICIES OF THE JMA


Extraordinary devotion and an exception-ally broad perspective will be required to suc-cessfully accomplish this important and diffi-cult task. Superior leadership of the presidentand the resilient unity of all JMA members arevital factors. Thus, standing at this juncturetoday and with an awareness of my limitations,I have decided not to run for the office of presi-dent in the next JMA presidential election.

I have worked as an executive member ofthe JMA for the past 15 years since I was

elected to the Executive Board of Trustees inOctober 1988. During this 15-year tenure, Ihave served in the office of president for fourterms or eight years since 1996. I am confidentthat the JMA will make a giant leap forwardwith the understanding of the Japanese publicto help build our nation into the foremosthealth care nation in the world. With thesewords, I would like to conclude the president’spolicy speech for the 109th JMA ExtraordinaryHouse of Delegates meeting. Thank you verymuch.

Eitaka TSUBOI


Introduction

Interferon was first discovered by Naganoand Kojima1) in Japan as a virus inhibiting fac-tor in 1954. It was also discovered by Isaacs andLindenmann2) in 1957 as a substance respon-sible for virus interference. About a half cen-tury has passed since its discovery. It has beenclinically applied to treat various diseases formore than 20 years. This paper outlines inter-feron and explains the results of the basicresearch toward its clinical application.

This article is a revised English version of a paper originally published inthe Journal of the Japan Medical Association (Vol. 128, No. 7, 2002, pages 1013–1017).

Types and Properties

Interferon (IFN) is generally classified into 3types (Table 1). First, IFN-� is produced whenleukocytes are infected with a virus. It is alsocalled leukocyte interferon. Second, IFN-� isproduced when fibroblasts are infected with avirus or treated with synthetic double-strandedRNA (polyinosinic acid/polycytidylic acidcomplex; poly I :C). It is also called fibroblastinterferon. Third, IFN-� is produced when lym-phocytes are stimulated with a mitogen or sen-sitized lymphocytes are bound to an antigen. Itis also called immune interferon.

Basis and Clinical Applications ofInterferonJMAJ 47(1): 7–12, 2004

Jiro IMANISHI

Professor, Kyoto Prefectural University of Medicine

Abstract: Interferon (IFN) is an antiviral substance that was discovered about 50years ago. The advance in the basic research of IFN has revealed the actionmechanism of its antiviral effect at a molecular level and provided wide clinicalapplications. It is roughly divided into 3 types: IFN-�, IFN-�, and IFN-�. IFN-� isrelated to IFN-�, but IFN-� is completely different. Any type of IFN is a (glyco)protein with a molecular weight of about 20,000kDa. IFN is known to have variousbiological activities including antiviral effects. Major biological activities include cellgrowth inhibition and immune regulation. Anti-tumor effect of IFN develops byintegration of the various biological activities. IFN is considered to exert its antiviraleffect by not only directly inhibiting viral proliferation, but also stimulating cytotoxicT cells, natural killer cells, and macrophages.

Key words: Interferon; Inhibition of viral proliferation;Immunomodulating effect; NK cell; Helper T cell

� Interferon Therapy


J. IMANISHI

IFN-� is similar to IFN-� because both have166 amino acids (some types of IFN-� have 165amino acids) and because there is about 50%homology for their amino acid sequences, orthe nucleotide sequences that code them. Fur-thermore, since the genes for IFN-� are locatedat the same chromosome as that for IFN-� (9p-21 for humans), IFN-� is genetically related toIFN-�. It has been revealed that IFN-� has 14or more subtypes, and that there are 23 or moregenes for IFN-� including pseudogenes. In con-trast, IFN-� has one gene and one subtype.

IFN-�, a subtype of IFN-�, has 172 aminoacids. The genes for IFN-� are also located atthe same chromosome and there is 60% orhigher homology for amino acid and nucleotidesequences.3)

Another type of IFN is produced from pla-

cental trophoblasts and called trophoblast IFN.This type of IFN is also called IFN-�. It is con-sidered to be closely related to the recognitionof pregnancy by the parent body.4)

One recent development is a form of consen-sus IFN-� that has a structure common to thesubtypes of IFN-�. The consensus IFN-� isconsidered to provide higher efficacy than nor-mal IFN-�, with fewer adverse effects.

IFN-� usually exists as a dimer and has 146amino acids, 20 fewer amino acid as comparedwith the 166 amino acids of IFN-� or IFN-�. Ithas one gene located at the chromosome of12q24.1 for humans. These facts indicate thatIFN-� is completely different from IFN-� orIFN-�.

Table 1 Types and Properties of Human (Hu) IFN

Type I Type II

HuIFN-�HuIFN-� HuIFN-�

Normal HuIFN-� HuIFN-�

Molecular weight About 20,000 About 20,000 About 20,000About 20,000 (monomer)About 40,000 (dimer)

No. of amino acids 165–166 172 166 146

23 or higher About 7No. of genes (including (including 1 1

4 pseudogenes) 6 pseudogenes)

Subtype 14 or higher 1 1 1

Intron 0 0 0 3

Gene location 9p21 9p21 9p21 12q24.1

Presence/absence ofNo Yes Yes Yes

sugar chain

Antigenic type � � � �

Main producer cell Leukocyte Trophoblast Fibroblast Th1�NK

Type I Type I Type IType IIReceptor (common to (common to (common to

(specific to �)�, � and �) �, � and �) �, � and �)

Receptor gene21q22.1 21q22.1 21q22.1 6q16-q12location

Species specificity Weak Weak Weak Strong


BASIS AND CLINICAL APPLICATIONS OF INTERFERON

Biological Activity

Many of the various biological activities ofIFN are known and understood (Table 2).Naturally enough, since it was first discoveredas an antiviral agent, we know that it engages inantiviral activity (inhibits viral proliferation).Other known activities include inhibition of cellgrowth and effects on immunological activity.

In general, IFN stimulates macrophage andnatural killer (NK) activities and plays impor-tant roles in host defense. IFN, particularlyIFN-�, plays a key part in regulating the bio-logical immune response, as described below.It is also considered that IFN exerts its effectson viral infection and malignant tumors, asdescribed in the following sections, by combin-ing all of its diverse biological activities.

1. Antiviral activityThe mechanism of antiviral activity of IFN

(inhibition of viral proliferation) has been gen-erally revealed (Fig. 1). The binding of the IFN

molecule to its receptor activates two enzy-matic systems. One is the 2-5A synthetase sys-tem (2-5A oligosynthetase). When the enzymeis activated, 2-5A is synthesized in the presenceof ATP and double-stranded RNA. 2-5A acti-vates endo-RNase (endonuclease) to degradeviral mRNA, thereby inhibiting viral proteinsynthesis.

The other enzymatic system is protein kinase(PKR), which is also activated in the presenceof double-stranded RNA. When activated, itphosphorylates the initiation factor-2� (eIF-2�) required for starting the synthesis of pep-tide chains on ribosomes, thereby inactivatingeIF-2�. This prevents the virus from commenc-ing protein synthesis on the ribosome, andresults in the inhibition of viral proliferation.

In addition to the two enzymatic systemsresponsible for the inhibition of viral prolifer-ation, other known mechanisms include theinhibition of transcription into viral mRNAand viral inhibition at the viral particle buddingphase. It is considered that appropriate action

Table 2 Various Biological Activities of IFN

1. Anti-tumor effect2. Inhibitory effect on cell growth3. Effects on lymphocytes

a) Stimulation and inhibition of antibody production (B cell)b) Inhibition of delayed-type hypersensitivity (T cell)c) Inhibition of transplantation immune response (T cell)d) Inhibition of blastogenesis and DNA synthesis (T cell)e) Potentiation of killer T cells (T cell)f ) Potentiation of natural killer activity (NK cell)g) Potentiation of ADCC activity

4. Effects on macrophagesa) Potentiation of phagocytosisb) Potentiation of adherence to tumor cellsc) Inhibition of intracellular bacterial proliferationd) MIF activitye) Chemotaxis

5. Other effects on cellsa) Chemotaxis for neutrophilsb) Potentiation of NBT reduction in neutrophilsc) Increased histamine release in basophilsd) Promotion of differentiation of erythroblastse) Induction of differentiation of neuroblastoma cellsf ) Potentiation of expression of MHC Class I and II antigens


J. IMANISHI

Thp Tho

IL2, IL12

IL2, IL4

IFN-�, IL2 TNF-�

IL4, TNF-�

IL4, IL10IL4, IL10

IL2, IFN-gIL2, IFN-�

IFN-gIFN-�

Th1

Th2

IL4, 5, 6, 10

Humoral immunity

Cellular immunity

Fig. 2 Th1 and Th2 cytokine

mechanisms of IFN may function depending onviral type.

2. Effects on the immune systemIFN has been known to have many effects on

the immune system. It is considered to gener-ally inhibit antibody production and delayed-type (Type IV) hypersensitivity. However, itstimulates cytotoxic T cells (killer T cells), NK

cells, killer cells responsible for antibody-dependent cell-mediated cytotoxicity (ADCC),macrophages, and neutrophils.

IFN-� has a regulatory effect on the immunesystem: that is, IFN-� is produced from type 1helper T (Th1) cells. It is also known to stimu-late the growth of Th1 cells. Since Th1 cells areinvolved in cellular immunity, IFN-� is con-sidered to increase cellular immunity. In con-

Fig. 1 Mechanism of antiviral effect of IFN

IFN

� Protein kinase (PKR) system

� 2�-5� oligosynthetase (2-5AS) system

Inactive 2-5AS Active 2-5AS

Double-stranded RNA

Double-stranded RNA

ATP

AMP

2-5A

Inactive endo-RNase

Active endo-RNase Degradation of viral mRNA

Phosphodiesterase

elF-2�

Inactive PKR Active PKR Phosphatase

Phosphorylated elF-2�Inhibition of the start ofviral peptide chain synthesis

IFN receptor

ATP: adenosine triphosphateAMP: adenosine monophosphate


BASIS AND CLINICAL APPLICATIONS OF INTERFERON

Fig. 4 IFN-NK system

NK cell

NK precursor cells

Tumor cell destructionVirus-infected cell destruction

Production

Activitypotentiation

Differentiation IFN

Virus

Infection

Inhibition ofviral proliferation

Infectedcells

Infectedcells

Virus-inducedIFN

Production

Immune IFN

LymphocyteKiller T cellNK cellK cell

MacrophageRe-infection and

recurrence

Healing

trast, since IFN-� suppresses the activity ofTh2 cells, it is considered to suppress humoralimmunity (Fig. 2).

Effects on Viral Infections

For the action mechanisms of IFN on viralinfections, IFN directly provides antiviral effectsand indirectly inhibits viral infections throughthe immune system (Fig. 3). IFN enhances theactivities of macrophages, NK, and ADCC toinhibit viral proliferation in infected cells anddestroy infected cells.

It is considered that the same mechanismswork for tumors. IFN directly inhibits the pro-liferation of tumor cells, and generally has astronger growth inhibitory effect on tumor cellsthan on normal cells. IFN is also known toinduce apoptosis in some cells. Thus, IFN notonly directly inhibits the proliferation of tumorcells or destroys them, but also indirectly inhib-its them by stimulating the immune system. Asdescribed above, IFN is known to enhance theactivity of killer T cells, NK cells, and ADCC,

and to stimulate macrophages and neutrophilsto destroy tumor cells.

IFN is known to form a cycle with NK cells.That is, IFN increases NK activity, activatedNK cells produce IFN, and IFN acts on NKprecursor cells to induce the differentiation ofNK cells, thereby increasing NK cells. This sys-tem formed by IFN and NK cells is called IFN-NK system (Fig. 4). The IFN-NK system isdeeply involved in host defense against viralinfection and against tumors. It is well knownthat the IFN-NK system strongly inhibitstumor metastasis.

Conclusions

IFN engages in various biological activitiesincluding antiviral action. It combines all itsactivities to provide protection against viralinfections and tumors. It is important to clini-cally apply IFN by managing both the directand indirect effects of IFN.

REFERENCES

1) Nagano, Y. and Kojima, Y.: Pouvoir immuni-sant de virus vaccinal inactivé par des rayonsultraviolets. C R Soc Biol (Paris) 1954; 148:1700–1702.

2) Isaacs, A. and Lindenmann, J.: Virus interfer-ence. I. The interferon. Proc Roy Soc 1957;B147: 258–267.

Fig. 3 Antiviral effect of IFN


J. IMANISHI

3) Capon, D.J., Shepard, H.M. and Goeddel,D.V.: Two distinct families of human and ovineinterferon alpha genes are coordinately ex-pressed and encode functional polypeptide.Mol Cell Biol 1985; 5: 768–779.

4) Pontzer, C.H., Ott, T.L., Bazer, F.W. et al.:Structure/function studies with interferontau: Evidence for multiple active sites. J Inter-feron Res 1994; 14(3): 133–141.


Introduction

Interferon (IFN) has various biological activi-ties including the inhibition of viral prolifera-tion. The induction of cytotoxic T cells is con-sidered one of the action mechanisms of theantitumor effect of IFN. Tumors of hemato-poietic organs for which IFN is effective in-clude chronic myeloid leukemia (CML), hairycell leukemia (HCL), multiple myeloma, andmalignant lymphoma.


Chronic Myeloid Leukemia

CML increases leukocytes and causes sple-nomegaly and anemia. The chronic phase ischaracterized by increased leucocytes proceed-ing to the blast crisis in 3 to 4 years unlessoptimal treatment is given. The blast crisis ofthe disease shows a pathology similar to acuteleukemia. Since it does not respond to chemo-therapy, it often leads to death within 1 year.Therefore, the target of CML treatment is to

Interferon Therapy for LeukemiaJMAJ 47(1): 13–17, 2004

Michihiko MASUDA

Assistant Professor, Department of Hematology, Tokyo Women’s Medical University

Abstract: Most patients with chronic myeloid leukemia (CML) have leucocytosis,anemia, and splenomegaly. The natural history of CML is progression from abenign chronic phase to a rapidly fatal blast crisis within three to four years. Thediagnosis of CML is usually based on detection of the Philadelphia (Ph) chromo-some. Ph chromosome abnormality is t(9;22). The molecular consequence of thet(9;22) translocation is the creation of a fusion protein BCR/ABL which is a con-stitutively active cytoplasmic tyrosine kinase. Interferon (IFN) � is capable of induc-ing hematological control in 80–90% of patients and a major cytogenetic responsein 30–50%. In practice, 3–6 million units of subcutaneous IFN is used. The mostcommon side effects are fever, fatigue, and appetite loss. IFN should be usedcautiously in patients with a history of serious depression because it may exacer-bate this problem. The addition of low-dose cytarabine to IFN increased the cyto-genetic response rate. Hairy-cell leukemia (HCL) is an uncommon B-cell chroniclymphoproliferative disorder. IFN, splenectomy, and purine analogues are the treat-ment options for HCL.

Key words: Chronic myeloid leukemia; Interferon; Cytogenetic response;Hairy cell leukemia



M. MASUDA

IFN in reducing Ph chromosome-positive cellsis called a cytogenetic response. Table 1 showsthe criteria for hematological and cytogeneticresponses. The disappearance of Ph chromo-some-positive cells from the bone marrow onexamination six months to one year after thestart of IFN therapy is called complete cyto-genetic response (CCR) and the reduction ofthe cells to less than 35% of the pre-treatmentlevel is called partial cytogenetic response(PCR). The combination of CCR and PCR iscalled major cytogenetic response (MCR). It isgenerally considered that 30 to 50% of chronicphase patients treated with IFN achieve MCR.Figure 1 shows the relationship between thecytogenetic effects of IFN therapy and thesurvival period of CML patients at the M.D.Anderson Cancer Center.1) It shows that 38patients achieved MCR, and only three of themdied in 60 months, indicating a significantlylonger survival period for these patients, ascompared with those who could not achieveMCR.

The Euro score is an index to predict theresponse to IFN in CML patients.2) It is basedon the analytical results of IFN therapy in atotal of 1,573 CML patients in 12 medical insti-tutions worldwide. Table 2 outlines this score.The score is calculated using the followingparameters: age, spleen size, and count of blastcells, basophils, eosinophils, and platelets. Based

prolong the chronic phase as much as possibleby preventing blast crisis.

The blood cells of CML show a reciprocaltranslocation in which a part of the 9th chromo-some is replaced with a part of the 22nd chro-mosome, which is designated the Philadelphia(Ph) chromosome. This chromosome producesan abnormal gene called BCR/ABL fusiongene, which has been considered to stimulatetyrosine kinase activity and cell growth, leadingto leukemia.

Thus, the identity of CML lies in the increasein the cells with the Ph chromosome, and thetarget of CML treatment is to reduce them.Busulfan and hydroxycarbamide have beenused to treat CML and reduce leucocytes, butthey have almost no effect on reducing cellswith Ph chromosome. The following threetherapeutic methods are available to reducethese cells: (1) hematopoietic stem cell trans-plantation, (2) interferon (IFN) therapy, and(3) therapy with imatinib mesilate, which hasrecently become available in Japan.

Interferon Therapy for ChronicMyeloid Leukemia

IFN normalizes leucocytosis and spleno-megaly in most patients with CML. This iscalled a hematological response and achievedin 80 to 90% of patients with IFN. The effect of

Table 1 Decision Criteria for IFN Effect for Chromic Myeloid Leukemia

• Hematological response • Cytogenetic effectComplete hematological response (CHR) Ph1 positive rate

Normal leukocyte count CCR 0%Elimination of juvenile granulocytes PCR�35%Platelet count�450,000 MCR 35 to 94%Elimination of clinical symptoms, such as splenomegaly NR 95 to 100%

Partial hematological response (PHR)Leukocyte count of 50% or lower of pretreatment level,

and of fewer than 20,000Normal leukocyte count, but with residual immature

granulocytesPersistent splenomegaly


INTERFERON THERAPY FOR LEUKEMIA

on this score, CML patients are classified intothree groups of low, intermediate, and highrisk: the five-year survival rate of these groupsis 76%, 55%, and 25%, respectively. This indi-cates that long-term survival cannot be expectedfrom the IFN therapy in the high-risk group.Another index to classify the risk of CML isthe Sokal score obtained by analyzing survivalresults by busulfan therapy before IFN wasintroduced. The Sokal score is the same as theEuro score except that it does not include theeosinophilic and basophilic counts. The Sokal

score has also demonstrated that the low-riskgroup would achieve prolonged survival withIFN therapy.

Practice of Interferon Therapy forChronic Myeloid Leukemia Patients

Usually, patients with chronic phase CMLare treated with self-injection of 3 to 6 millionunits of IFN. The adverse effects of therapyinclude fever, chills, headache, myalgia, generalmalaise, anorexia, nausea, vomiting, and diar-

Sur

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38292740

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16

CCR�PCRMCRCHROthersp�0.00384

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0 6 12 18 24 30 36 42 48 54 60

Number of patients

Number of deaths

(%)

Fig. 1 IFN therapy for CML: survival by cytogenetic effect(Kantarjian, H.M. et al.: J Clin Oncol 1999; 17(1): 284–292)

Table 2 Prognostic Score of IFN Therapy for Chronic Myeloid Leukemia (Euro score)

• Prognostic score�{0.6666�age*�0.0420�spleen size (cm)

�0.0584�blast (%)�0.0413�eosinophil (%)�0.2039�basophil**�1.0956�platelet count***}�1,000

*: age: less than 50 years�0, 50 years or older�1**: basophil: less than 3% of peripheral blood basophil�0, 3% or higher�1***: Platelet count: less than 1.5 million�0, 1.5 million or higher�1

Prognostic score 5-year survival

Low risk 780 or lower 76%Intermediate risk 780 to 1,480 55%High risk 1,481 or higher 25%


rhea. These adverse effects are often resolvedby continuing the IFN therapy and can often beovercome with drugs such as antipyretics.

It is considered important to continuouslyadminister the maximed tolerable dose of IFNto maximize the therapeutic effect of IFN ther-apy for CML. Higher cytogenetic effects can beexpected from therapy if one avoids reducingdoses or lengthening the intervals betweenadministration (which one might be tempted todo in the presence adverse effects such as fever,malaise, and anorexia). It is therefore essentialto inform the patients fully about CML andmake them fully understand the significance ofIFN therapy. We have used the survival curvein Figure 1 to help the patients understand thefact that the cytogenetic effect produced byIFN prolongs survival.

Clinically important adverse effects of IFNinclude psychological and nervous symptomsincluding depression. Particular attentionshould be paid to patients who have depressivetendencies before starting IFN therapy, be-cause IFN may cause severe depression leadingto a suicide attempt.

Self-injection of IFN reduces leucocytes tothe normal level, eliminates splenomegaly andother clinical symptoms, and improves hemato-logical status by bringing the platelet count tonormal. This complete hematological responseis achieved in 80 to 90% of chronic phase CMLpatients treated with IFN. It is considered thatfailure to achieve such a response indicatesdifficulty in achieving a cytogenetic response.Therefore, IFN therapy should be stopped if nocomplete hematological response is achieved6 and 12 months after IFN therapy has started.Our experience shows that no cytogeneticresponse can be expected unless the leucocytecount falls below 5,000/�l (Table 3). However,reducing the leucocyte count to less than5,000/�l may reduce platelets or hemoglobinas well, preventing patients from continuingIFN therapy. IFN therapy should be continuedfor at least one year. If bone marrow examina-tion one year after therapy was started shows a

M. MASUDA

reduction in Ph chromosome-positive cells,MCR may be achieved by continuing thetherapy even if MCR has not been achieved atthe time of examination.

Combination Therapy with Interferonand Other Agents for ChronicMyeloid Leukemia

Combination therapy of IFN with cytarabinehas been reported to increase the cytogeneticresponse of IFN by about 10%.1) However, it isdifficult to perform combination treatment inJapan because self-injected cytarabine is notavailable. An oral preparation of cytarabine,cytarabine ocfosfate, is available in Japan, butthe combination of IFN and this preparationhas been reported in a few cases of CML, andthe combined effect remains unclear.

A study from the M.D. Anderson CancerCenter has reported combination therapy withIFN and GM-CSF for CML.4)

Imatinib mesylate, a tyrosine kinase inhibi-tor active for the BCR/ABL fusion gene, hasbeen reported to provide higher efficacy forCML than IFN.5) Although it provides higherefficacy than IFN during the early stage, it isfeared that it may induce early resistancebecause of its simple structure. To overcomethe resistance, a trial on the combination ofIFN and imatinib mesylate is now underwayin the U.S. It should be noted that long-actingPEG interferon, which is approved only fortype C hepatitis in Japan, is being used in thattrial.

Table 3 Relationship between Leukocyte Count andCytogenetic Effect

Leukocyte CCR�PCR NR

5,000� 12/24 (50%) 5/24 (20%)5,000� 0 7/24 (30%)

p�0.046(Derived from results in Department of Hematology,Tokyo Women’s Medical University)


INTERFERON THERAPY FOR LEUKEMIA

Interferon Therapy for Hairy CellLeukemia

HCL is characterized by the development ofcells with many hairy cytoplasmic projections.Since it becomes chronic, it is classified as achronic leukemia. Typical hairy cells in Westerncountries are positive for tartrate-resistant acidphosphatase staining. There is a subtype called“Japanese type HCL”, and its hairy cells showonly weak tartrate-resistant acid phosphatasestaining. Both types of HCL often causesplenomegaly.

HCL is treated with IFN therapy, splenec-tomy, and purine analogues. Recently, the effi-cacy of anti-CD20 antibody, rituximab, hasbeen reported. The standard therapy for HCLshould be started with splenectomy and, if thedisease progresses, treatment with IFN or purineanalogues should be considered.

The IFN therapy for HCL is based on theadministration of 3 to 5 million units/day ofIFN-� consecutively 3 times a week. The re-sponse rate of this therapy ranges from 50 to90%.6) Treatment with IFN improves bloodcell abnormalities and reduces splenomegaly.Smaller doses of 0.2 to 0.6 million units of IFNwill reduce the adverse effects, but will alsoreduce the efficacy rate. It is generally con-sidered that the efficacy of IFN therapy for

Japanese type HCL is lower than that for theEuropean/American type.

REFERENCES

1) Kantarjian, H.M., O’Brien, S., Smith, T.L. etal.: Treatment of Philadelphia chromosome-positive early chronic phase chronic myelog-enous leukemia with daily doses of interferonalpha and low-dose cytarabine. J Clin Oncol1999; 17(1): 284–292

2) Hasford, J., Pfirrmann, M., Hehlmann, R. et al.:A new prognostic score for survival of patientswith chronic myeloid leukemia with inter-feron alfa. Writing committee for collabora-tive CML prognostic factors project group.J Nat Cancer Inst 1998; 90: 850–858.

3) Sokal, J.E., Cox, B.B., Bacarrani, M. et al.: Prog-nostic discrimination in “good risk” chronicgranulocytic leukemia. Blood 1984; 789–799.

4) Cortes, J., Kantarjian, H., O’Brien, S. et al.:GM-CSF can improve the cytogenetic responseobtained with interferon-alpha therapy inpatients with chronic myelogenous leukemia.Leukemia 1998; 12: 860–864.

5) Kantarjian, H., Sawyers, C., Hochhaus et al.:Hematologic and cytogenetic responses toimatinib mesylate in chronic myelogenousleukemia. N Engl J Med 2002; 346: 645–652.

6) Masuda, M. and Mizoguchi, H.: Interferontherapy for hairy cell leukemia. nano GIGA1994; 99: 2051–2055.


Introduction

Interferon (IFN) was discovered in the 1950’sduring research on viral interference, and itsantitumor and other effects were reported fromthe 1960’s. During the 1970’s, attention was paidto IFN as an anti-cancer drug because its anti-tumor effect was reported in clinical studies.Now, it is clinically used to treat Type C hepa-titis, multiple sclerosis, and various tumorsincluding renal tumor, malignant melanoma,and brain tumor.

IFN is classified by its properties into 3 types:


IFN-�, IFN-�, and IFN-�. IFN-� and IFN-�code common gene loci and have common cel-lular surface receptors, while IFN-� has differ-ent dynamics. Therefore, the former and latterare called Types I and II IFN, respectively. Inthe clinical application of IFN for brain tumor,IFN-� is mainly used in Western countries,while IFN-� was approved by the Ministry ofHealth, Labor, and Welfare and has been clini-cally used in Japan.

This paper describes the history of the clini-cal application of different types of IFN forbrain tumor, current issues, and prospects for

Practice of Interferon Therapy—Brain tumor—JMAJ 47(1): 18–23, 2004

Toshihiko WAKABAYASHI* and Jun YOSHIDA**

*Associate Professor, Center for Genetic and Regenerative Medicine,Nagoya University School of Medicine

**Professor and chairman, Department of Neurosurgery,Nagoya University Graduate School of Medicine

Abstract: This paper outlines the current clinical application of interferon-� fortreating brain tumor. Since approved as a therapeutic drug for brain tumor, IFN-�has been reported to be effective when it was used alone, in combination withchemo-radiation therapy (IAR therapy), and as a maintenance therapy. Recently,the regimens with IFN-� have been improved to obtain a higher efficacy rate. Forexample, liposome is used as a drug delivery system (DDS) to administer IFN-�protein or genes. Although much remains to be examined about administrationmethods for DDS, it is expected that new developments in the field of gene therapywill improve the therapeutic results of antitumor therapies by cytokines includinginterferon.

Key words: Brain tumor; Interferon-�; IAR therapy; Gene therapy



INTERFERON THERAPY FOR BRAIN TUMOR

combinations with other therapies or drugswere attempted. So far, the following combina-tions have been examined.

1. Combination with radiotherapyFor the combination with radiotherapy, which

has been the most effective adjuvant therapyfor malignant brain tumor, Miyoshi et al.5) andKorosue et al.6) performed basic research withIFN-� and IFN-�, respectively. The followinghypotheses were obtained: partially synchro-nized radiotherapy with IFN in relation to theDNA synthesis inhibiting effect of IFN mightbe effective; IFN might play a role by sensitiz-ing patients to radiation; and there might be aninteraction between sublethal damage by radia-tion and the direct antitumor effect of IFN.

Regarding clinical applications, Mahaley etal. reported that the combination of radio-therapy and IFN significantly prolonged themedian survival time in patients with malignantglioma, and that the combination providedbetter results than the combination of radio-therapy and BCNU (carmustine), which waspreviously the standard therapy for braintumor patients in the institution.7)

2. Combination with chemotherapyVarious combinations of IFN and anticancer

agents have been examined. The Mayo Clinicreported that the combination of BCNU andIFN-� caused a significantly higher synergisticeffect than that with other drugs in 35 patientswith recurrent glioma: the combination achievedan efficacy rate of 29% and a period of 10.1months, and blocked the progression of thedisease for 6 months or longer in 37% of thepatients. Nitrosourea anticancer drugs, such asACNU (nimustine hydrochloride) and MCNU(ranimustine), are available in Japan, but singletherapy with any of the drugs has been effec-tive for only 30 to 50% of patients with braintumor.

Examination of the combination of IFN-�and ACNU with 13 human glioma cell linesshowed the combination 5 mg of ACNU and

new therapeutic techniques.

Interferon Single Therapy

In studies of the antitumor effect of IFN-�and IFN-� using brain tumor cells, Lundblad1)

and Wakabayashi2) reported a direct inhibitoryeffect on brain tumor, and Otsuka et al.3) reportedan indirect inhibitory effect through immuno-competent cells. Nakagawa and Ueda reportedthe clinical effect of IFN-� on malignant braintumor: they achieved partial response in patientswith glioblastoma and medulloblastoma by thesystemic and local administration, respectively,of IFN-�. Subsequent phase II studies on theuse of recombinant IFN-� for malignant gli-oma showed a response rate of 10.3 to 20%.

Nagai et al., who performed the systemic andlocal administration of IFN-�, reported anoverall response rate of 22.2% in 54 evaluablepatients, and the response rates of 16.7% and42.9% in patients with glioblastoma and medul-loblastoma, respectively.4) In 10 patients withmalignant glioma, Yoshida et al. systemicallyadministered 3�105 to 3�106 units of IFN-�for 16 to 50 days continuously via an intrave-nous route or locally administered 5�104 to3�106 units into the tumors for 7 to 73 dayscontinuously via an Ommaya reservoir im-planted when a tumor was removed. The resultshowed the size of the tumor was reduced by50% or higher in 2 of 7 systemically treatedpatients and 1 of 3 locally treated patients.

However, it was reported that, in any case,the antitumor effect after the administrationperiod lasted for only a short period, and thatthe administration of IFN alone would noteventually prolong survival, although it mightprovide remission during the administrationperiod. Therefore, investigators started toattempt various regimens with IFN.

Interferon Combination Therapy

To improve the therapeutic results of theinterferon single therapies for brain tumor,


1�103 IU of IFN-� provided a tumor prolifera-tion inhibiting effect of at least 2 log cell kill,and that the effect was obtained in 9 cell lines,as compared with 2 and 1 cell line by the singletherapy with ACNU and IFN, respectively. Fur-ther, the effect was higher than that of at least2 log cell kill observed in 7 cell lines treatedwith 10 mg of ACNU alone.8) When ACNU isclinically applied at a usual dose of 2 to 3 mg/kg body weight, the concentration obtained inbrain tumors is approximately 1 to 5 mg. It ispractically impossible to increase the dosebecause of possible adverse effects, such asbone marrow suppression. Therefore, the re-sults indicating the potentiation of the antitu-mor effect more than the addition of the effectof each anticancer drug and IFN at a usual dosesuggest the effectiveness of the combinationtherapy.

3. Combination with radio-chemotherapySince the combination of IFN-� and ACNU

showed high antitumor activity in a basic ex-perimental study with a human glioma cell line,a clinical study was started in Japan by combin-ing the IFN-� and ACNU combination therapywith radiotherapy (IFN-�-ACNU-Radiation[IAR] therapy) as an adjuvant therapy formalignant glioma. Yoshida et al. reported thatthe prognosis as determined by the mean sur-vival period was significantly improved withIAR therapy (25.3 months) as compared withradiation alone (15.2 months) and radiation�

ACNU (19.7 months), and that the initial re-sponse rate by IAR therapy was higher thanthat by radiation�ACNU (60.5% vs. 35.7%).Further, Yoshida et al. also confirmed the effi-cacy of IAR therapy in 175 malignant gliomapatients followed for a long time.9) Hatano et al.reported that increasing the administrationfrequency of IFN-� to twice daily increasedits antitumor effect.10) A U.S. study on thecombination of IFN-�, BCNU, and radiationfor malignant brain tumor reported a mediansurvival time of 12.7 months and a mean sur-vival time of 16.1 months for Grade IV astro-

Fig. 1 54-year-old male patient: An enhanced lesion on CTscan indicating a tumor was observed in the rightfrontal lobe (a). It was diagnosed as glioblastoma.Since the postoperative image showed a residualtumor (b), IMR therapy was performed. A markedreduction of the tumor was observed at the end of theinitial induction therapy (c). This patient received3-month maintenance therapy, with no tumor recur-rence for the subsequent 2 years.

a

b

c

T. WAKABAYASHI and J. YOSHIDA


therapeutic effect could be expected from themaintenance therapy in patients who devel-oped the disease for the first time at 47 years oryounger, or who achieved a partial response ora better response with the initial inductiontherapy. These results suggest that both initialinduction and maintenance therapies may beimportant for the treatment of malignantglioma.12)

New Developments in InterferonTherapy

1. Drug delivery system (DDS)-combinedinterferon (liposome)

Although IFN-� has been clinically appliedfor treating brain tumor, the clinical efficacy ofIFN-� alone is less than expected when it wasintroduced in an uncombined form. It seemsnecessary to combine it with other therapies ordrugs to fully realize its potential. In fact, IFN-� shows a marked antitumor effect at as low as100 units in vitro, while it has been reported toproduce tumor reduction by 50% or higheronly in 15% of clinical cases, even at 10 millionunits. This difference in the efficacy of IFN maybe explained by the pharmacokinetics of IFN,its stability in blood or tissue, or the blood brainbarrier.

In an effort to overcome the problem of the

cytoma, and 46.3 and 61.3 months for Grade IIIastrocytoma.

These results indicate that the inter-disciplin-ary combination of IFN-�, nitrosourea drug,and radiotherapy should be the first-line initialadjuvant therapy for inducing remission afteran operation for malignant brain tumor (Figs.1-a, b, and c). However, since recurrence wasobserved in most of the cases who responded tothe combination, it is necessary to establish anappropriate maintenance therapy at an earlystage after the induction of initial remission.11)

Interferon Maintenance Therapy

Although up to 60% of patients with malig-nant brain tumor could achieve remission byinitial induction therapy, most of them experi-enced recurrence. For example, the remissionand mean survival periods of patients withglioblastoma were reported to be as short as11.2 and 13.9 months, respectively. Therefore,various maintenance therapies following initialinduction therapy are being examined.

Wakabayashi et al. performed IFN-�-MCNU-Radiation (IMR) therapy as an initial induc-tion therapy in patients who developed malig-nant glioma for the first time, and comparedthe remission period between those treatedwith a maintenance therapy consisting of1�106 units of IFN-� every 2 weeks and80 mg/m2 of MCNU every 6 weeks for at least3 months after the end of the induction therapyand those not treated with it. The patientsregistered into the initial induction therapywere randomly divided into 2 groups with andwithout the maintenance therapy, and theywere compared for time to tumor progression(TTP) and total survival period. The resultsshowed a significantly prolonged survival pe-riod in the maintenance therapy group (Fig. 2).Particularly, the patients who achieved com-plete remission by the initial induction therapyappeared to achieve a significantly prolongedremission period by receiving the maintenancetherapy. It was also suggested that a certain

Fig. 2 Comparison between groups treated with andwithout IMR maintenance therapy

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low in vivo effect of IFN, liposome has beenexamined as a drug delivery system (DDS).Epstein et al. examined the embedding of IFNin liposome and successfully changed the bio-logical activities and pharmacokinetics of IFN.Kato et al. added sulfatide to liposome as acomponent to deliver IFN through the bloodbrain barrier into the cerebral parenchyma,and compared the stability, pharmacokinetics,intraorgan distribution, and antitumor effectbetween the embedded and free IFN. Theresult showed the blood titer of the free IFNbecame undetectable as early as 2 hours afterintravenous administration, while the lipo-some-embedded IFN was detected at as high as103IU/ml or higher even 8 hours after admin-istration. Further, an IFN titer of 100 IU/gtissue or higher was confirmed in the brain andsubcutaneously implanted brain tumor tissuewhere no IFN was detected after the intrave-nous administration of the free IFN. It is ex-pected that the clinical application of DDS willprogress to increase the effectiveness of IFNfor brain tumor.13)

2. Interferon gene therapyLarsson et al. reported that endogenous

IFN-� was produced from glioma cells using asuper-induction technique. This glioma-derivedendogenous IFN-� has an antitumor effect onhuman glioma cells. We have been developingIFN gene therapy in which human IFN-� genesare embedded in the liposome with an affinityfor glioma cells to selectively introduce theliposome into glioma cells and locally generatea large amount of endogenous IFN-�, therebycausing an antitumor effect on glioma. Sincethis technique ensures the secretion and main-tenance of a much higher local concentrationof IFN than administration from outside, theso-called paracrine effect can be expected.Further, the technique has been reported tocause phenomena that have not been observedwith exogenous IFN, such as the induction ofapoptosis of transgenic glioma cells. Finally, weexpect an association with the immune system

to indirectly enhance the antitumor effect.14)

A clinical study on the gene therapy for braintumor (malignant glioma) using this positively-charged liposome embedded-human IFN-�gene (local injection of the IFN-� gene-embed-ding liposome into brain tumor) was started onApril 3, 2000 at the Nagoya University Hospi-tal. So far, 5 patients have been registered andexamined for the safety and efficacy of the ther-apy. The results of the study will be reportedsoon.

Conclusions

This paper outlines the current clinical appli-cation of interferon to brain tumor. Thereremains much to be examined about the use ofIFN, such as appropriate administration regi-mens and the importance of maintenance ther-apy. However, together with the new develop-ments in IFN therapy including the use of DDSand gene therapy, it is expected that the thera-peutic results of antitumor therapies with cyto-kines including IFN will be improved.

REFERENCES

1) Lundblad, D. and Lundgren, E.: Block of aglioma cell line in S by interferon. Int J Cancer1981; 27: 749–754.

2) Wakabayashi, T., Yoshida, J., Kobayashi, T. etal.: Effect of interferon on malignant braintumor. Cancer and Chemotherapy 1982; 9:1400–1406. (in Japanese)

3) Otsuka, S., Handa, H., Yamashita, J. et al.:Single agebt therapy of interferon for braintumors, correlation between natural killeractivity and clinical course. Acta Neurochir1984; 73: 13–23.

4) Nagai, M. and Arai, T.: Clinical effect of inter-feron in malignant brain tumors. NeurosurgRev 1984; 7: 55–64.

5) Miyoshi, T., Ogawa, S., Kanamori, T. et al.:Interferon potentiates cytotoxic effects of5-fluorouracil on cell proliferation of estab-lished human cell lines originating from neo-plastic tissues. Cancer lett 1983; 17: 239–247.

6) Korosue, K., Tamaki, N. and Matsumoto, S.:

T. WAKABAYASHI and J. YOSHIDA


Basic study on interferon and irradiationcombination therapy in treatment of braintumor. Neuro Med Chir 1984; 24: 233–239. (inJapanese)

7) Mahaley, M.S. Jr., Urso, M.B., Whalay, R.A.et al.: Interferon as adjuvant therapy with ini-tial radiotherapy of patients with anaplasticgliomas. J Neurosurg 1984; 61: 1069–1071.

8) Yoshida, J., Wakabayashi, T., Inoue, T. et al.:Efficacy of HuIFN-� and ACNU combinationtherapy for malignant brain tumor: first report;in vitro basic examination. Cancer and Che-motherapy 1984; 12: 99–104. (in Japanese)

9) Yoshida, J.. Kajita, Y., Wakabayashi, T. et al.:Long-term follow-up results of 175 patientswith malignant glioma: Importance of radicaltumor resection and postoperative adjuvanttherapy with Interferon, ACNU and radiation.Acta Neurochir (Wien) 1994; 127: 55–59.

10) Hatano, N., Wakabayashi, T., Kajita, Y. et al.:Efficacy of postoperative adjuvant therapywith human Interferon beta, MCNU, andradiation (IMR) for malignant glioma: com-

parison among three protocols. Acta Neuro-chir (Wien) 2000; 142: 633–639.

11) Wakabayashi, T., Yoshida, J., Mizuno, M. et al.:Effectiveness of interferon-�, ACNU andradiation therapy in pediatric patients withbrainstem glioma. Neurol Med Chir (Tokyo)1992; 32: 942–946.

12) Wakabayashi, T., Kajita, Y., Hatano, N. et al.:Initial and maintenance combination treat-ment with lnterferon-�, MCNU (Ranimustine),and radiotherapy for patients with previouslyuntreated malignant glioma. J Neurooncol2000; 49: 57–62.

13) Kato, K., Yoshida, J., Kageyama, N. et al.:Liposome-entrapped human interferon-�; Itspharmacokinetics and antitumor activity againsthuman brain tumor cells. J Clin Biochem Nutr1998; 4: 139–147.

14) Mizuno, M., Yoshida, J., Sugita, K. et al.:Growth inhibition of glioma cells transfectedwith the human �-interferon gene by liposomecoupled with a monoclonal antibody. CancerRes 1990; 50: 7826–7829.



Introduction

Interferon (IFN) is used in treating variousdermatological diseases. This paper focuseson the IFN therapy for malignant melanomaand cutaneous malignant lymphoma becausemany patients suffer from them and Japanesemedical insurance covers the IFN therapyfor them. The paper goes on to summarize theIFN therapies clinically studied for other dis-eases in Japan and foreign countries. Cutane-ous adverse reactions to IFN therapies are alsodiscussed.

Treatment for Malignant Melanomaand IFN

Malignant melanoma (Fig. 1) is a malignanttumor of melanocytes. The annual develop-ment rate of malignant melanoma in Japan is


about 1.5 to 2 per 100,000 persons,1) and therate tends to increase.2) Malignant melanoma isknown to easily metastasize and be resistant tochemotherapy. It is also known to regress spon-taneously. Therefore, investigators have con-sidered it as a tumor with antigenicity to betreated with immune therapy. Although vari-ous therapies have been examined, includingthe use of BCG (Bacille bilié de Calmette-Guérin), adoptive immune therapy, vaccinetherapy, and gene therapy, most of themremain at the level of basic research. IFN-�was found effective for cutaneous metastaticfoci of melanoma3) and has been widely used asa postoperative adjuvant therapy for malignantmelanoma in Japan.

Malignant melanoma is classified into severaldisease stages by the thickness of the tumor,presence/absence of lymph node metastasis,and presence/absence of distant metastasis,

Interferon Therapy in the Field ofDermatologyJMAJ 47(1): 24–31, 2004

Kazuko MATSUMURA* and Hiroshi SHIMIZU**

*Assistant, **Professor, Department of Dermatology,Hokkaido University Graduate School of Medicine

Abstract: Interferon therapies for dermatological diseases were clinically reviewed.This article will mainly focus on interferon therapy for malignant melanoma andcutaneous lymphoma in Japan. The cutaneous adverse symptoms that accompanyinterferon therapies are also discussed in this review.

Key words: Interferon; Malignant melanoma;Cutaneous malignant lymphoma; Adverse reactions



and is treated according to the stage of thedisease. The American Joint Committee onCancer (AJCC) revised the disease stageclassification of malignant melanoma in 2001(Tables 1 and 2).4) Malignant melanoma ismainly treated with surgical excision. IFN-� isused alone or in combination with chemo-therapy as a postoperative adjuvant or mainte-nance therapy for the disease in the IIB to IIIstages.5,6) Unfortunately, no prospective studywith an adequate population has been per-formed due to associated ethical problems andthe small number of patients. However, IFN-�has been widely used as a postoperative adju-vant therapy in Japan because a basic study

Fig. 1 Malignant melanoma

Table 1 Melanoma TNM Classification4)

T classification Thickness Ulceration Status

T1 �1.0mm a: without ulceration and level II/IIIb: with ulceration or level IV/V

T2 1.01�2.0mm a: without ulcerationb: with ulceration

T3 2.01�4.0mm a: without ulcerationb: with ulceration

T4 �4.0mm a: without ulcerationb: with ulceration

N classification No. of Metastatic Nodes Nodal Metastatic Mass

N1 1 node a: micrometastasis*

b: macrometastasis†

N2 2�3 nodes a: micrometastasis*

b: macrometastasis†

c: in transit met(s)/satellite(s)without metastatic nodes

N3 4 or more metastatic nodes,or matted nodes, or intransit met(s)/satellite(s)with metastatic node(s)

M classification Site Serum LactateDehydrogenase

M1a Distant skin, subcutaneous, or nodal mets NormalM1b Lung metastases NormalM1c All other visceral metastases Normal

Any distant metastasis Elevated

*: Micrometastases are diagnosed after sentinel or elective lymphadenectomy.†: Macrometastases are defined as clinically detectable nodal metastases confirmed by thera-

peutic lymphadenectomy or when nodal metastasis exhibits gross extracapsular extension.

IFN IN DERMATOLOGY


K. MATSUMURA and H. SHIMIZU

showed IFN-� locally administered to a tumormigrated through lymph ducts into the tumor-affected lymph nodes at a high concentration7)

and because a retrospective study showed a sig-nificantly higher 5-year survival rate with DAV(DTIC [dacarbazine], ACNU [nimustine], andVCR [vincristine]) therapy plus IFN-� thanwith DAV therapy alone in patients with StageIII malignant melanoma.8)

DAV plus IFN-� therapy has been per-formed with the following protocol.9,10) DTIC isadministered by intravenous drip infusion at adose of 80 to 140 mg/m2 for 5 days continu-ously. ACNU at 50 to 80 mg/m2 and VCR at 0.5to 0.8 mg/m2 are intravenously administered

with a side tube on Day 1. In parallel with thesetreatments, IFN-� is locally injected for 5 to10 days at several intracutaneous sites aroundthe primary surgical site at a total dose of3,000,000 IU/body. This is considered as asingle course, and repeated after withdrawalintervals of 4 to 6 weeks. This therapy isrepeated for 2 to 3 courses for the IIA and IIBstages, and for 5 to 6 courses for the IIC and IIIstages. The maintenance therapy with IFN-�is performed, if possible, by locally injectingit to several intracutaneous sites around theprimary surgical site at a total dose of3,000,000 IU/body every 2 to 4 weeks for 2 to 3years. Although the local injection of IFN-�

Table 2 Proposed Stage Groupings for Cutaneous Melanoma4)

Clinical Staging* Pathologic Staging†

T N M T N M

O Tis N0 M0 Tis N0 M0IA T1a N0 M0 T1a N0 M0IB T1b N0 M0 T1b N0 M0

T2a N0 M0 T2a N0 M0IIA T2b N0 M0 T2b N0 M0

T3a N0 M0 T3a N0 M0IIB T3b N0 M0 T3b N0 M0

T4a N0 M0 T4a N0 M0IIC T4b N0 M0 T4b N0 M0III‡ Any T N1 M0

N2N3

IIIA T1-4a N1a M0T1-4a N2a M0

IIIB T1-4b N1a M0T1-4b N2a M0T1-4a N1b M0T1-4a N2b M0

T1-4a/b N2c M0IIIC T1-4b N1b M0

T1-4b N2b M0Any T N3 M0

IV Any T Any N Any M1 Any T Any N Any M1

*: Clinical staging includes microstaging of the primary melanoma and clinical/radiologic evaluation formetastases. By convention, if should be used after complete excision of the primary melanoma withclinical assessment for regional and distant metastases.

†: Pathologic staging includes microstaging of the primary melanoma and pathologic information aboutthe regional lymph nodes after partial or complete lymphadenectomy. Pathologic stage 0 or stage 1Apatients are the exception; they do not require pathologic evaluation of their lymph nodes.

‡: There are no stage III subgroups for clinical staging.


CDDP�VBL�IFN-��IL-2 therapy.14) Althoughsome investigators have reported high responserates for these regimens, the regimen mosteffective for life prognosis (chemotherapyalone, chemotherapy�BRM therapy, or BRMtherapy alone) has not been determined. Sincenone of the above regimens are covered byJapanese medical insurance, the VI stage dis-ease is often treated with DAC-TAM therapy.15)

IFN Therapy for Cutaneous MalignantLymphoma

Several types of lymphoma cause cutaneouslesions; among these, IFN therapy is used formycosis fungoides and adult T cell lymphoma.IFN therapy is known to be effective for skinlesions to some degree. However, IFN therapyhas not been strictly evaluated for life progno-sis in relation to any type of cutaneous malig-nant lymphoma.

1. Mycosis fungoidesMycosis fungoides (Fig. 2) is the most fre-

quent type of cutaneous malignant lymphoma.It is T cell lymphoma in which erythematousstage and plaque stages last for a long time, and

is painful, the pain can be relieved by dissolvingit in 1 to 3 ml of a 1% procaine injection solu-tion. No lidocaine injection solution can beused because IFN-� changes its formulation tocause clouding. Fever that may occur after thelocal injection of IFN-� can be relieved byadministering an anti-inflammatory analgesic.

It should be noted that several cases withsecondary cancer suspected to derive fromDTIC or ACNU (acute myeloid leukemia andmyelodysplastic syndrome) were recentlyreported in patients treated with the postop-erative adjuvant therapy.11) It is necessary todecide whether the DAV plus IFN-� therapyshould be performed or not for patients in theII stage, and if applicable in the III stageas well, by carefully considering the patient’sage, physical status, complications, and tumorthickness. Patients choose their therapy underthe informed consent. Postoperative adjuvanttherapy with only a local injection of IFN-� hasalso been examined.9) That is, IFN-� is intracu-taneously injected once daily at several sitesaround the surgical site at a total dose of3,000,000 IU/body, and a course consisting of10 injections is repeated after withdrawalintervals of 4 to 6 weeks. It is considered appro-priate to perform 2 to 3 courses for the II stagedisease and 5 to 6 courses for the III stagedisease. The decision to choose an optimalpostoperative adjuvant therapy should bemade carefully, in accordance with the patient’scondition.

The IV stage disease should be treated bya combination of surgical excision of localizedmetastatic foci, chemotherapy, BRM therapy,radiotherapy, immunotherapy, and thermo-therapy. Known regimens of the BRM therapyinclude the CDDP�IFN-��IL-2 therapy inwhich chemotherapy, IFN-�, and interleukin-2(IL-2) are combined,12) DTIC�BCNU�CDDP�TAM�IFN-��IL-2 therapy,13) and DTIC�

Fig. 2 Mycosis fungoides

List of abbreviationsDTIC: dacarbazine, ACNU: nimustine, VCR: vincristine, DAV: DTIC/ACNU/VCR combination therapy,CDDP: cisplatin, BCNU: carmustine, TAM: tamoxifen, VBL: vinblastine

IFN IN DERMATOLOGY


occasionally progress to a tumor stage. Patientswith mycosis fungoides often die when the dis-ease progresses to the tumor stage. It does notrespond well to treatments. However, the dis-ease progresses slowly before the tumor stagewithout causing visceral erosion. Therefore,during the erythematous stage and plaquestage, treatment is performed to prevent thedisease from progressing to the tumor stage.The disease is managed by reducing tumor cellsand minimizing the demerits associated withadverse reactions. So far, the disease during theerythematous stage and plaque stages has beentreated with phototherapy (psoraren ultravio-let A therapy: PUVA).16) Although actino-therapy remains important, the use of IFNalone or in combination with phototherapy hasbeen increased since the early 1990’s.16) Whenthe lesions of the disease extend to the wholeskin, recombinant IFN-� (rIFN-�) is adminis-tered by intravenous drip infusion at 2,000,000to 4,000,000 IU once daily, 3 to 5 times a week.When it is locally administered, it is adminis-tered to several sites in and around the lesion ata total dose of 200,000 to 2,000,000 IU/lesion,or 1,000,000 to 2,000,000 IU/cm2. Natural IFN-� (nIFN-�) is intramuscularly injected oncedaily 2 to 3 times a week at a dose of1,000,000 IU. In any case, the effectiveness ofthe therapy is determined at 4 weeks from thestart.17) However, there was a patient in whomskin lesions of cutaneous malignant lymphomawere successfully relieved with nIFN-�, but sub-sequently extended to other organs, leading todeath.18) Although it is unknown whether thepatient experienced exacerbation of the dis-ease through its natural course or nIFN-�changed the characteristics of tumor cells,extreme care should be exercised in using IFN,as with other therapeutic techniques. There is aprotocol of IFN-� in which 3,000,000 IU/m2 ofIFN-� is subcutaneously injected 3 times weeklyin combination with the oral administration ofetretinate,19) although it is not covered by Japa-nese medical insurance.

2. Adult T cell leukemia/lymphomaAdult T cell leukemia/lymphoma is leuke-

mia and lymphoma caused by HTLV-1. It isclassified into 4 types, namely, acute, lym-phoma, chronic, and smoldering types,20) andthe smoldering type is further divided intocutaneous and narrow sense smoldering sub-types.21,22) It has been reported that the intra-muscular injection of 1,000,000 IU of nIFN-�once daily was effective for eruptions in pa-tients with the cutaneous type characterized bythe cutaneous infiltration of tumor cells with-out leukemia, tumor-induced lymph node swell-ing, or tumor cell infiltration to other organs.17,23)

nIFN-� has been reported effective to somedegree even in patients with cutaneous tumoror leukemia,24) while there have been manypatients including patients during acute exacer-bation or with acutely progressing disease,who have not responded to IFN-�.17) Therefore,one should refrain from using IFN-� in suchpatients.

Attempts at IFN Therapy for OtherDiseases

Other diseases for which the therapeuticeffect of IFN has been reported include viralverruca,25,26) porphyria cutanea tarda,27) cry-oglobulinemia associated with type C hepati-tis,28) Kaposi’s sarcoma associated with AIDS,29)

intraepidermal carcinoma, such as Bowen’sdisease, actinic keratosis, and Paget’s disease.30)

Cutaneous Lesions Associated withIFN Therapy

As the use of therapies involving variouscytokines has advanced, it has become knownthat such therapies may cause cutaneouslesions.31) The cutaneous lesions that can becaused by IFN are summarized below.

1) Erythema and skin itching: Urticaria,edematous erythema, and erythematouspapula may occur in the initial stage of IFNtherapy, often in a few weeks. However, IFN



therapy can often be continued with symptom-atic therapy or by adjusting the dose or admin-istration intervals.

2) Psoriasis: IFN may exacerbate concur-rent psoriasis vulgaris or induce psoriasis.32–34)

Psoriasis may worsen so severely that thetreatment of the primary disease has to bediscontinued.

3) Alopecia: Alopecia frequently occurswith IFN therapy.35) The incidence of alopeciaranges from 10 to 30%, depending on reports.It has been particularly frequently reportedwith the use of IFN-�. It often occurs 2 to 3months after the start of IFN therapy andresolves in several months even when thetherapy is continued.

4) Pigmentation and depigmentation: Sev-eral cases with pigmentation or depigmenta-tion have been reported.36–37)

5) Pemphigus: Pemphigus is an autoim-mune disease characterized by blisters on thewhole body surface. A small number of caseswith the disease have been reported with theuse of IFN-� or �.38,39) The disease requiresimmediate treatment because it can be lethal.

6) Skin ulcers at injection site: The subcuta-neous or intramuscular injection of IFN-� or �may cause ulcers at the injection site.40–43) Theymay occur a while after the start of the IFNtherapy, often after 6 months or later. It isinferred that IFN may exacerbate the skinulcers. It is desirable to inject IFN intramuscu-larly, instead of subcutaneously, to preventthem. It is necessary to change injection sitesregularly to avoid injecting IFN at the same sitecontinuously. Although the ulcers may resolvewith conservative external therapy, they mayrequire surgical treatment when they are asso-ciated with extensive skin necrosis.

7) Others: The use of IFN has been reportedto cause contact dermatitis,44) sarcoidosis,45) anderythema nodosum.46)

Conclusions

IFN therapy in the field of dermatology is

mainly performed for treating malignant mela-noma and cutaneous malignant lymphoma.The former is treated with IFN-� used for post-operative adjuvant therapy, while the latter istreated with IFN-� in patients in whom lesionsremain at the cutaneous level and progressslowly. The DAV�IFN-� regimen is includedin the standard therapies for malignant mela-noma. However, IFN therapy causes variouscutaneous adverse reactions. Since IFNtherapy is generally used for intractable ormalignant primary diseases, efforts should bemade to continue it as long as skin symptomscan be controlled with symptomatic therapiesor by adjusting the dose of IFN. However,extreme care should be exercised regardingcutaneous symptoms during IFN therapy,because they may threaten the patient’s life.

REFERENCES

1) Ishihara, K., Ikeda, S. and Hirone, T.: Prognos-tic factors of melanoma. Skin Cancer 1989; 4:349–361. (in Japanese)

2) Ishihara, K., Saida, T. and Yamamoto, A.:National questionnaire survey about inci-dence of malignant melanoma. Skin Cancer2000; 15: 7–14. (in Japanese)

3) Ishihara, K., Hayasaka, K. and Yamazaki, N.:Current status of melanoma treatment withinterferon, cytokines and other biologic re-sponse modifiers in Japan. J Invest Dermatol1989; 92: 326S–328S.

4) Balch, C.M., Buzaid, A.C., Soong, S.J. et al.:Final version of the American Joint Commit-tee on Cancer staging system for cutaneousmelanoma. J Clin Oncol 2001; 19: 3635–3648.

5) Saida, T. and Yamamoto, A.: Melanoma—Guides for Diagnosis and Treatments. The 96thannual meeting of the Japanese Society ofDermatology (Okayama), 1997. (in Japanese)

6) Japanese Society of Malignant Tumors (ed.):Handling Codes of Malignant Melanoma andSkin Malignant Tumors. Kanehara & Co.,Ltd., Tokyo, 2002; pp.16–37. (in Japanese)

7) Yamamoto, A., Washimi, T. and Kato, M. et al.:Lymphatic migration of locally injected IFN-�in patients with malignant melanoma. SkinCancer 1986; 1: 47–53. (in Japanese)

IFN IN DERMATOLOGY


8) Yamamoto, A. and Ishihara, K.: Clinical studyof DAV�IFN-beta therapy (combinationadjuvant therapy with intravenous DTICACNU and VCR, and local injection of IFN-beta) for malignant melanoma. Int J Immuno-therapy 1996; 12: 73–78.

9) Yamamoto, A.: Current status of treatmentsfor melanoma. Ohtsuka Yakuho 2000; 564: 42–47. (in Japanese)

10) Yamamoto, A.: Basis and clinical practice ofFeron and DAV-combination therapy. SkinCancer 1996; 11: 358–366. (in Japanese)

11) Uhara, H., Saida, T. and Takada, M. et al.:Investigational results on double cancers inpatients with malignant melanoma. Journal ofJapanese Society of Dermatology 2000; 110:2123–2126. (in Japanese)

12) Khayat, D., Borel, C., Tourani, J.M. et al.:Sequential chemoimmunotherapy with cis-platin, interleukin-2, and interferon alfa-2a formetastatic melanoma. J Clin Oncol 1993; 11:2173–2180.

13) Richards, J.M., Gale, D., Mehta, N. et al.: Com-bination of chemotherapy with interleukin-2and interferon alfa for the treatment of meta-static melanoma. J Clin Oncol 1999; 17: 651–657.

14) Legha, S.S., Ring, S., Eton, O. et al.: Develop-ment of a biochemotherapy regimen withconcurrent administration of cisplatin, vin-blastine, dacarbazine, interferon alfa, andinterleukin-2 for patients with metastaticmelanoma. J Clin Oncol 1998; 16: 1752–1759.

15) Yamazaki, N., Yamamoto, A., Wada, T. et al.:Dacarbazine, nimustine hydrochloride, cis-platin and tamoxifen combination chemo-therapy for advanced malignant melanoma. JDermatol 1999; 26: 489–493.

16) Japanese Society of Malignant Tumors (ed.):Handling Codes of Mycosis Fungoides, SezarySyndrome, and Cutaneous Malignant Tumors.Kanehara & Co., Ltd., Tokyo, 2002; pp.110–116. (in Japanese)

17) Nakayama, J., Rikihisa, W. and Hamada, M.:Clinical evaluation of gene recombinant humanIFN-� (biogamma) therapy for mycosis fun-goides: Therapeutic Experience from Depart-ment of Dermatology, Kyushu UniversityMedical School. Journal of Society of Derma-tology in Western Japan 1997; 59: 773–779. (inJapanese)

18) Sawamura, D., Harada, K., Aizu, T. et al.:Sezary syndrome with acute progressive pul-monary infiltration after improvement of skineruption. Dermatology 2001; 202: 273–274.

19) Zachariae, H. and Thestrup-Pedersen, K.:Interferon alpha and etretinate combinationtreatment of cutaneous T-cell lymphoma. JInvest Dermatol 1990; 95: 206S–208S.

20) Shimoyama, M.: Diagnostic criteria and clas-sification of clinical subtypes of adult T-cellleukaemia-lymphoma. A report from theLymphoma Study Group (1984–87). Br JHaematol 1991; 79: 428–437.

21) Shirono, M.: Adult T Cell Leukemia andLymphoma (ATLL): Nature of various erup-tions. Teishin Medicine 1993; 45: 369–376. (inJapanese)

22) Japanese Society of Malignant Tumors (ed.):Handling Codes of Adult T Cell Leukemia,Lymphoma, and Cutaneous Malignant Tumors.Kanehara & Co., Ltd., Tokyo, 2002; pp.117–121. (in Japanese)

23) Ishihara, K.: Late phase II clinical study ofOH-6000 for mycosis fungoides. Skin Cancer1993; 8: 352–367. (in Japanese)

24) Uchiyama, N. and Kurokawa, I.: Case withchronic adult T cell leukemia with long-termremission with gene recombinant humaninterferon-�. Clinical Dermatology 2000; 42:913–915. (in Japanese)

25) Weck, P.K., Buddin, D.A. and Whisnant, J.K.:Interferons in the treatment of genital humanpapillomavirus infections. Am J Med 1988; 85:159–164.

26) Shirahama, S.: Treatment of verruca withinterferon-�. Clinical Dermatology 1998; 52:141–144. (in Japanese)

27) Horie, H.: Treatment of porphyria cutaneatarda with interferon. Progress in Medicine2000; 2359: 181–183. (in Japanese)

28) Sasaki, H., Urushibara, K., Otoyama, K. et al.:Case with cryoglomulinemic purpura relievedwith interferon therapy for type C hepatitis.Journal of Japanese Society of Dermatology2000; 110: 2141–2146. (in Japanese)

29) Krown, S.E.: Management of Kaposi sarcoma:The role of interferon and thalidomide. CurrOpin Oncol 2001; 13: 374–381.

30) Ishihara, K., Ikeda, S., Mori, S. et al.: Latephase II clinical study of SUN4800 in cutane-ous malignant tumors. Journal of Society of



Dermatology in Western Japan 1989; 51: 776–795. (in Japanese)

31) Asnis, L.A. and Gaspari, A.A.: Cutaneousreactions to recombinant cytokine therapy. JAm Acad Dermatol 1995; 33: 393–410.

32) Quesada, J.R. and Gutterman, J.U.: Psoriasisand alpha-interferon. Lancet 1986; 1(8496):1466–1468.

33) Endo, M., Koizumi, Y., Matsumura, K. et al.:Psoriasis vulgaris with exacerbated eruptionsduring IFN-�2b therapy for type C hepatitis.Clinical Dermatology 1993; 35: 771–777. (inJapanese)

34) Sakamoto, Y., Maruyama, Y., Watanabe, F. etal.: Exacerbation and induction of psoriasiswith interferon-�. Clinical Dermatology 1997;51: 325–327. (in Japanese)

35) Iino, S.: Adverse reactions of interferon. Re-search Report of Intractable Hepatitis Investiga-tion Group Specified by the Ministry of Healthand Welfare. 1993; pp.7–11. (in Japanese)

36) Elgart, G.W., Sheremata, W. and Ahn, Y.S.:Cutaneous reactions to recombinant humaninterferon beta-1b: the clinical and histologicspectrum. J Am Acad Dermatol 1997; 37: 553–558.

37) Simsek, H., Savas, C., Akkiz, H. et al.: Inter-feron-induced vitiligo in a patient with chronicviral hepatitis C infection. Dermatology 1996;193: 65–66.

38) Ramseur, W.L., Richards, F. II and Duggan,D.B.: A case of fatal pemphigus vulgaris in as-sociation with beta interferon and interleukin-2 therapy. Cancer 1989; 63: 2005–2007.

39) Kirsner, R.S. and Federman, D.G.: Interpre-

tation of cutaneous biopsy specimens: Choiceof pathologist by primary care practitioners.South Med J 2001; 94: 461–463.

40) Konohana, A., Hasegawa, Y. and Kobayashi,T.: Cutaneous ulcerations resulting from intra-muscular injections of interferon alfa. J AmAcad Dermatol 1996; 35: 788–789.

41) Weinberg, J.M., Wolfe, J.T., Sood, S. et al.:Cutaneous necrosis associated with recombi-nant interferon injection. Report of threecases with interferon beta-1b and review ofthe literature. Acta Dermato-Venereol 1997;77: 146–148.

42) Kontochristopoulos, G., Stavrinos, C., Aroni,K. et al.: Cutaneous necrosis by subcutaneousinjection of �-interferon in a patient withchronic type B hepatitis. J Hepatol 1996; 25:271.

43) Albani, C. and Albani, G.: A case of cutaneousnecrosis during interferon-beta 1b (B-IFN)therapy in multiple sclerosis. J Neurol Neuro-surg & Psychiat 1997; 62: 418.

44) Pigatto, P.D., Bigardi, A., Legori, A. et al.: Al-lergic contact dermatitis from beta-interferonin eyedrops. Contact Dermatitis 1991; 25: 199–200.

45) Komori, K., Namiki, T. and Matsunaga, T.:Sarcoidosis after interferon-� therapy. Der-matological Practice 1999; 21: 129–132. (inJapanese)

46) Sampaio, E.P., Moreira, A.L., Sarno, E.N. etal.: Prolonged treatment with recombinantinterferon gamma induces erythema nodosumleprosum in lepromatous leprosy patients. JExp Med 1992; 175: 1729–1737.

IFN IN DERMATOLOGY


Introduction

Twenty years have passed since interferonwas clinically applied to treat multiple mye-loma. Only IFN-� has been used and evaluatedfor its efficacy when used alone or in combina-


tion with chemotherapy and for its significancewhen used in the induction or maintenancetherapy. Although not definitely determined,the positioning of IFN-� in the therapeuticstrategy of multiple myeloma is described herewith recent therapeutic results. The therapeutic

Practice of Interferon Therapy—Multiple myeloma and other related

hematological malignancies—JMAJ 47(1): 32–37, 2004

Akihisa KANAMARU* and Takashi ASHIDA**

*Professor, **Lecturer, Department of Hematology,Nephrology and Rheumatology, Kinki University School of Medicine

Abstract: Practical aspects of the interfron (IFN) therapy for multiple myelomaand other neoplasms of hematopoietic organs are reviewed. While there has beenno established evaluation of therapeutic responses to IFN for myeloma, recentECOG randomized trials of multiple-drug chemotherapy with versus without IFNhave reportedly demonstrated greater efficacy of the therapy combined with IFN.A multicenter collaborative study of ROAD-IN (MCNU, VCR, melphalan, dexa-methasone, and IFN-�) conducted in Japan has shown favorable results. Meta-analyses of clinical trial data covering a large patient population also evidenced anincrease in response rates and prolongation of responsive duration. From thesestudies, one can conclude that the significance of IFN in the therapeutic strategyfor myeloma lies in its efficacy as a maintenance therapy regimen rather than asa single-drug induction therapy and that, if used for remission induction, IFN maymore effectively be administered some way behind other chemotherapeutic regi-men. IFN is used also in the treatment of such neoplasms as hairy cell leukemiaor lymphoma, besides myeloma. A prospective role of IFN has been proposed inmini-transplantation.

Key words: Multiple myeloma; Interferon � (IFN-�); ROAD-IN therapy;Hairy cell leukemia



2. Induction therapy with IFN-�Although randomized comparative studies

initially failed to demonstrate the superiority ofIFN-�, results indicating its effectiveness haverecently become available.(1) ECOG study

The Eastern Cooperative Oncology Group(ECOG) performed a phase III clinical studyin untreated patients to compare complete re-sponse and survival rates between the VBMCP(vincristine, BCNU, melphalan, cyclophospha-mide, and prednisolone) regimen and the regi-men plus either IFN-�, or high-dose cyclo-phosphamide.3) IFN-� was administered at adose of 5�106 units/m2 thrice weekly fromDay 22. The results obtained from 628 subjectsshowed a significantly higher CR rate in theVBMCP�IFN-� group than the VBMCPgroup (18% vs. 10%). Although no significantdifference was noted for survival rate, theresponse duration was significantly longer inthe VBMCP�IFN-� group. Further, theVBMCP�IFN-� group fared better than theVBMCP�high-dose cyclophosphamide groupin relation to complications from serious infec-tions. ECOG concluded that the VBMCP�

IFN-� regimen was especially effective in elderlypatients and for IgA-type myeloma.(2) Japanese multi-center joint study

Similar results have been reported in Japan.

role of IFN-� for other related hematologicaldiseases is also mentioned.

IFN-� Therapy for Multiple Myeloma

There have been many reports on the thera-peutic results of IFN-� for multiple myeloma.Positive and negative reports have beenrepeatedly published. IFN-� regimens that hadproven effective in pilot studies have oftenfailed to show any significant effect in random-ized comparative studies. The utility of IFN hasalso been discussed in terms of medical eco-nomics. IFN is now generally considered animportant option for treating multiple mye-loma probably because the disease remainslethal in spite of the advance of hematopoieticstem cell transplantation, i.e. it is often difficultto meet the eligibility for the transplantationsince the disease frequently develops in elderlypopulation, and because an acceptable thera-peutic strategy has not been established yet.Before describing the practice of the treat-ment, let us consider the biological activitiesof IFN-�.

1. Action mechanism of IFN-� formyeloma cells

The use of IFN-� as a therapeutic drug formyeloma is justified from the following find-ings1,2): (1) IFN-� stimulates the cytotoxic activ-ity of NK cells; (2) it stimulates macrophages toexpress major histocompatibility antigens andtumor-specific antigens associated with antigenpresentation; (3) it inhibits colony formationfrom myeloma cells in culture; (4) it inhibits theproduction of M protein from myeloma cells;(5) it reduces the expression of IL-6 receptorassociated with myeloid cell proliferation; and(6) it down-regulates the expression of onco-genes, such as c-myc and N-ras. Based on thesefindings, IFN-� has been clinically applied.However, it has also been reported that IFN-�stimulated the proliferation of myeloma cellswhen it was used at a low concentration.

Fig. 1 Induction therapy for multiple myeloma(ROAD-IN regimen)

MCNU (ranimustine): 40mg/m2, i.v., day 1, VCR(vincristine [Oncovin]): 1.2mg/m2, i.v., day 1, L-PAM(melphalan [Alkeran]): 8mg/m2 p.o., days 1 to 6,DEXA (dexamethasone): 40mg/body p.o. (i.v.), days1 to 4, 9 to 12, 17 to 20, IFN-� (interferon-�):2,000,000 units/m2 (max: 3,000,000 units/body) sc,days 20 to 42 (thrice/weekly)

MCNU

VCR

L-PAM

DEXA

IFN-�

1 2 3 4 5 6 week

INTERFERON FOR MYELOMA


A. KANAMARU and T. ASHIDA

A study on induction/maintenance therapywith IFN-� was started in 1991 as being fundedby the Foundation of Inter-disciplinary Thera-pies Studies.4) Figure 1 shows the regimen usedin the study. IFN-� was administered thriceweekly from Days 22 to 42 after MCNU(ranimustine), vincristine (Oncovin®), mel-phalan (Alkeran®), and dexamethasone wereadministered. Maintenance therapy with 2�

106 units/m2 (up to 3�106 units/m2) of IFN-�was performed until the disease recurred. Thestudy was undertaken as a single-arm pilotstudy including 161 patients, and resulted in aCR rate of 24%, PR rate of 51%, and mediansurvival period of 3.6 years. The survival periodwas 4.3 years in patients with CR or PR.

However, the study concluded that no sig-nificance could be offered for the maintenancetherapy with IFN-�. The regimen used wasnamed the “ROAD-IN” regimen (ROAD-INbeing an acronym formed from the initials ofthe drugs used). The protocol was based onthe DMVM-IFN-� therapy which had beenoriginally developed by Kitani, T. et al.5) inthe Hanshin Myeloma Study Group. AlthoughIFN-� was initially administered for 20 days

from the day when the drugs were started, theduration was subsequently reduced to 12 days.A CR rate of more than 25% was obtained.

Our Kinki University group took part inthese studies from the start. The results wereexcellent, with 46.4% (13 patients each) ofCR and PR rates in 28 patients treated withthe DMVM-IFN-� or ROAD-IN therapies.The overall survival rate in the CR patients(as determined by the Kaplan-Meier method)reached a plateau of about 60% at 5 years.Figure 2 shows a representative case: althoughthe M protein was 7,000 mg/dl at hospitaliza-tion, it returned to the normal range in about2 months.(3) Other multi-drug combination regimens

Other multi-drug combination regimenswith IFN-� include the VAD-IFN-� regimenincluding vincristine, adriamycin, and dexa-methasone, VMCP-IFN-� regimen includingvincristine, melphalan, cyclophosphamide, andprednisolone, and PACB-IFN-� regimen includ-ing prednisolone, adriamycin, cyclophospha-mide, and BCNU. The regimens resulted in CRrates ranging from 1 to 30%, median remissionperiods from 12 to 26 months, and median sur-

Fig. 2 Clinical case of a 72-year-old male patient with multiple myeloma

DMVM

IFN-�

IgG(mg/dl)

8,000

6,000

4,000

2,000

Myeloma cell0%

Myeloma cell0%

NCC 40.1�104

Mgk. 92NCC 17.3�104

Mgk. 139

WBC Hb Plt (/ml) (g/dll)(�104)

8,000

6,000

4,000

2,000

14

12

10

8

30

20

10

1992 Nov. 1993 Jan. Feb. Mar. Apr.

NCC 22.8X104

Mgk. 116Myeloma cell 44.8%

NCC 22.8�104

Mgk. 116Myeloma cell 44.8%


4. Meta-analysis of IFN-� therapy formultiple myeloma

The efficacy of IFN-� has been analyzedaccording to evidence-based medicine. Whatis most valuable in the analysis is the meta-analysis that compares the results of severallarge-scale prospective randomized compara-tive studies. Ludwid et al., who examined 3,948patients from 30 randomized comparativestudies,9) showed that significantly higher CR,PR, and overall survival rates could be achievedin the IFN-��chemotherapy group than thechemotherapy group, although the differenceswere marginal.

An Oxford joint study group of myelomatrialists also performed a meta-analysis in 4,012patients from 24 randomized studies. The resultdemonstrated that IFN-� moderately improvedrecurrence-free and overall survival rates.10) Itis therefore considered that individual studiesfailed to show any significant difference possi-bly due to the small number of patients exam-ined. Table 1 shows the results of the meta-analyses.

5. Adverse effects of IFN-� therapyIn the treatment of multiple myeloma,

IFN-� causes adverse effects similar to thoseobserved in other clinical fields. The ROAD-IN regimen caused leucopenia in 72% of thecases, thrombocytopenia in 15%, fever in 26%,and malaise in 49%.4) None of these adverse

vival periods from 32 to 52 months.6)

3. Maintenance therapy with IFN-�Contradictory results have been reported for

the efficacy of the maintenance therapy withIFN-�. Many investigators claim that IFN-�should be used for maintenance therapy ratherthan induction therapy because myeloma cellsstop the proliferation and reach a plateau phaseafter remission is achieved and IFN-� is alsoeffective for the cells in the G0 stage that havenot entered the cell cycle. The SouthwestOncology Group (SWOG) compared therecurrence-free survival period between IFN-�alone and IFN-� plus prednisolone in patientswho achieved remission with the VAD regi-men, and reported that the latter regimen wassuperior.7) The median progression-free sur-vival period was 9 and 19 months in the IFN-�and IFN-�� prednisolone groups, respectively(p�0.008). They made the comparison underthe idea that the maintenance therapy withIFN-� was significantly effective. The medianoverall survival period was not significantly dif-ferent (46 vs. 57 months).

Futhermore, a study reported that remissionwas clearly more prolonged in a group treatedwith the induction and maintenance therapiesusing IFN-� than in a group not treated withthe IFN-�-containing regimen (median remis-sion period: 21.2 vs. 6.4 months).8)

Table 1 Meta-Analyses of the Effect of IFN on Multiple Myeloma9)

Significant effects in groups treated with IFN

Ludwig & Fritz Oxford group

Induction therapyResponse rate Increased by 6.6% Increased by 4.4%Response period Prolonged by 4.8 months Prolonged by about 6 monthsSurvival period Prolonged by 3.1 months Prolonged by about 2 months

Maintenance therapyResponse period Prolonged by 4.4 months Prolonged by about 6 monthsSurvival period Prolonged by 7.0 months Prolonged by about 7 months

(Acta Oncol 2000; 39: 815–821)



induction therapy only when it is combinedwith multi-drug chemotherapy regimens, andis more effective when its administration isdelayed. Although the meta-analyses indicatethat IFN-� is an important and useful drug inthe treatment of multiple myeloma, evalua-tions of its usefulness will be modified.

Stem cell transplantation conditioned withnon-myeloablative regimen has been rapidlyprogressing in various fields. This kind of trans-plantation targets patients for whom the con-ventional transplants have not been indicateddue to the higher age and the complicationsaffecting performance status, and the majorityof patients with multiple myeloma could be in-cluded in the target for this mini-transplantation.It is expected to become a promising therapyfor relatively elderly patients of 50 or older.IFN-� may play a role in the new therapeuticmodality.

REFERENCES

1) Ludwig, H., Fritz, E., Zulian, G.B. et al.:Should alpha-interferon be included as stan-dard treatment in multiple myeloma? Eur JCancer 1998; 34: 12–24.

2) Blade, J. and Esteve, J.: Viewpoint on theimpact of interferon in the treatment of mul-tiple myeloma: benefit for a small proportionof patients? Med Oncol 2000; 17: 77–84.

3) Oken, M.M., Leong, T., Lenhard, R.E. Jr. etal.: The addition of interferon or high dosecyclophosphamide to standard chemotherapyin the treatment of patients with multiplemyeloma, Phase III Eastern CooperativeOncology Group clinical trail EST 9486.Cancer 1999; 86: 957–968.

4) Wada, M., Mizoguchi, H., Kuriya, S. et al.:Induction therapy consisting of alternatingcycles of ranimustine, vincristine, melphalan,dexamethasone and interferon alpha (ROAD-IN) and a randomized comparison of inter-feron alpha maintenance in multiple myeloma:a co-operative study in Japan. Br J Haematol2000; 109: 805–814.

5) Kitani, T.: New combination chemotherapiesincluding IFN. Clinical Hematology 1993; 34:

effects was serious. The type and frequency ofadverse effects are similar in other reports.Since IFN-� dose-dependency causes adverseeffects, some patients refused to receive it ata dose of 3�106 units or higher: the secondcourse of IFN-� had to be discontinued in asmall number of patients.

IFN-� Therapy forOther Hematopoietic Diseases

IFN-� has been used to treat not only mul-tiple myeloma, but also low-grade malignantlymphoma such as follicular lymphoma, hairycell leukemia, and chronic lymphocytic leuke-mia. IFN-� has also been reported for thetreatment of pre-leukemic myelodysplasticsyndrome. However, IFN-� has not been sofrequently used as for myeloma, and the effi-cacy for those diseases has not been estab-lished. The use of IFN-� for only hairy cellleukemia is covered by Japanese medical insur-ance. IFN-� is not considered as the first linetherapy for these hematological diseases inmost medical institutions. It is not highly ratedeven in the few institutions where it does comeinto consideration as the first line therapy.However, it is possible that IFN-� will play asignificant role in combination with other drugs.

Conclusions

The efficacy of therapeutic regimens formultiple myeloma has been systematicallyevaluated since the MP regimen (melphalanand prednisolone) was clinically applied. Sincethen, many multi-drug chemotherapy regimenshave been attempted, but none has becomestandard for the disease. Chemotherapy regi-mens including IFN-� have been unsatisfactoryas well. At the present, IFN-� is evaluated as atherapeutic drug for multiple myeloma as fol-lows: (1) IFN-� is not useful when used alone;(2) many investigators think that it should beused for maintenance therapy rather thaninduction therapy; and (3) it is effective in

A. KANAMARU and T. ASHIDA


455–459. (in Japanese)6) Wada, M.: Multiple myeloma and interferon:

Antitumor effect of interferon after remission.Daily Medical Practice and Blood 1997; 7:1277–1284. (in Japanese)

7) Salmon, S.E., Crowley, J.J., Balcerzak, S.P. etal.: Interferon versus interferon plus predni-sone remission maintenance therapy for mul-tiple myeloma: A Southwest Oncology Groupstudy. J Clin Oncol 1998; 16: 890–896.

8) Ludwig, H., Cohen, A.M., Polliack, A. et al.:Interferon-alpha for induction and mainte-

nance in multiple myeloma: results of twomulticenter randomized trial and summary ofother studies. Ann Oncol 1995; 6: 467–476.

9) Ludwig, H. and Fritz, E.: Interferon in mul-tiple myeloma-summary of treatment resultsand clinical implications. Acta Oncol 2000; 39:815–821.

10) Wheatley, K. (on behalf of the MyelomaTrialists’ Collaborative Group). Which mye-loma patients benefit from interferon ther-apy? An overview of 24 randomized trials with4000 patients. Br J Haematol 1998; 102: 140.



Introduction

The research on gustatory and olfactory senseshave not been fully developed as compared tothose on visual and auditory functions. Yet thesesenses contribute significantly to one’s QOL in


everyday life. Due to hearing difficulty, agedpeople tend to be isolated from their commu-nities and also from participating in socialactivities. Considering these aspects, gustatoryand olfactory disturbances among them mayinterfere with their desire to live and enjoy

Olfactory Disturbances—Pathophysiological findings and

the development of new therapeutic procedures—JMAJ 47(1): 38–43, 2004

Mitsuru FURUKAWA

Professor, Department of Otorhinolaryngology,Graduate School of Medicine and School of Medicine, Kanazawa University

Abstract: Chronic rhinosinusitis is the most frequent cause of hyposmia. Weestablished a new experimental animal model to investigate pathological findingsin the olfactory epithelium and olfactory bulb of rats and describe the possibleetiology of hyposmia due to rhinosinusitis. Not only dysfunction of the olfactoryepithelium but a central type of hyposmia caused by disorders of the olfactory bulbwas demonstrated by immunohistochemistry. The possible etiology of hyposmiaafter common colds and dysosmia after traumatic olfactory disorders is alsodescribed based on recent studies. Hyposmia after common colds is stronglyassociated with nasal obstruction, swelling of the nasal mucosa, and edema of themucosa of the olfactory cleft observed by nasal fiberscopy. Viral infection is consid-ered one of the etiologies of anosmia after common colds, especially in womenfrom 40 to 60 years old, and results in a poor outcome. One possible explanationof olfactory dysosmia is misdirected connections during reinnervation of the olfac-tory bulb by olfactory nerve fibers after apoptotic change of olfactory receptorneurons and traumatic amputations of olfactory filla at the level of ethmoid laminacribrosa. These findings suggested new ideas for the treatment of patients withdifferent types of olfactory disturbances.

Key words: Pathophysiology; Olfactory disturbances; Paranasal sinusitis;Common cold; Parosmia

� Sensory Organ Disorders


(PCNA) antibody, anti-single-stranded DNA(ssDNA) antibody, and anti-inducible nitricoxide synthase (iNOS) antibody. To ascertainthe presence (or absence) of changes to thecentral olfactory system, an immunohistologi-cal study was conducted on the olfactory bulbsamples of the rats affected by paranasal sinus-itis by using an anti-tyrosine hydroxylase (TH)antibody.

The results of these observations may besummarized as follows: The onset of paranasalsinusitis was confirmed in 6 animals after 3days, 7 animals after 7 days, 6 animals after 14days, 6 animals after 21 days, and 7 animalsafter 28 days following exposure to Staphylo-coccus aureus. Inflammation developed in theolfactory epithelium that was affected by para-nasal sinusitis within 3 days and the inflamma-tory condition persisted even after 28 days. Thethickness of the olfactory epithelium, the num-ber of olfactory cell layers, and the count ofthe olfactory cells per 100�m2 of the olfactoryepithelium continued to be markedly reduceduntil after 21 days. The olfactory neurofibrilbundles became elongated and scarce in pro-portion to the time (i.e., number of days) thatthe foreign body was retained in the nasalcavity. The olfactory cell regenerating activitywas markedly reduced for the initial 7 days andhardly recognized on the 21st or 28th day.Apoptosis of the olfactory cells was most pro-nounced on the 3rd and 7th days, after whichthe activity was reduced and became barelyrecognizable on the 21st or 28th day. TheiNOS expression in the olfactory epitheliumwas hardly noted in the normal olfactory epi-thelium. The enzyme expression was abundantaround the basal cells of the samples obtainedfrom the animals with paranasal sinusitis; but itwas somewhat reduced where the olfactoryepithelium had undergone marked degenera-tion. In the olfactory bulb, the TH expression ofthe juxtaglomerular cells began to be reducedon the 7th day and became much reduced onthe 21st and 28th days.

It has been shown for the first time that in

their lives.At the beginning of the 21st century, our

aging society continues to be complex and facesfurther problems to be solved. The patho-physiological elucidation of various olfactorydisturbances and the development of new ther-apeutic methodology are much desired. Thecurrent situation is presented in this literature.

Chronic Paranasal Sinusitis

Paranasal sinusitis is the most frequent causeof olfactory disturbances in Japan.1) It is truethat sequential changes that occur at the olfac-tory mucosa caused by paranasal sinusitis havenot been investigated sufficiently. Nor haveappropriate animal models been found that aresuitable for such studies. Therefore, we pre-pared a model for experimental paranasalsinusitis by using rats to elucidate the mecha-nism by which olfactory disturbances developand to conduct histological observations of theolfactory epithelium and olfactory bulb.2)

1. Pathophysiology(1) Olfactory disturbance

(direct effects of sinusitis)A foreign material (polyvinyl acetal) coated

with Staphylococcus aureus was inserted intoone of the nasal cavities of rats and 3, 7, 14, 21,and 28 days later, samples from the nasal cavityand olfactory bulb were collected (from 10 ani-mals at each experiment) to prepare coronalsections. HE stain was applied to the samplesfrom the nasal cavity to examine the maxillarysinus and ascertain the onset of paranasalsinusitis.

The HE-stained nasal sinus section obtainedfrom the rats affected by paranasal sinusitiswas used to measure the thickness of the olfac-tory epithelium. The sections from the nasalcavity of the rats with paranasal sinusitis wereused for immunohistological observation of theolfactory epithelium by using the following anti-bodies: anti-protein gene product 9.5 (PGP9.5)antibody, anti-proliferating cell nuclear antigen

OLFACTORY DISTURBANCES AND TREATMENT


addition to the olfactory epithelium, histologi-cal changes develop in the olfactory bulb andcentral olfactory disturbances may occur inchronic paranasal sinusitis.(2) Olfactory disturbance

(indirect effects of sinusitis)Inflammatory changes in the olfactory cleft,

nasal polyps, especially those of the olfactorycleft, and excessive secretion that are causedby sinusitis have been pointed out. It is wellknown that these conditions are also accompa-nied by morphological deviations of the nasalcavity, such as accentuated curved nasal sep-tum and nodules of the nasal septum. The patho-physiology of olfactory disturbances caused bychronic paranasal sinusitis may therefore besummed up as the so-called mixed olfactorydysfunctions, where the aforementioned olfac-tory epithelial changes and respiratory olfac-tory dysfunction — due to deviations in air flowwithin the nasal cavity — are involved.

2. TreatmentNeedless to add, the treatment of chronic

paranasal sinusitis, the cause of olfactory dis-turbances, also constitutes the basis of treat-ment of the latter.(1) Surgical treatment

Surgical correction of morphological devia-tions of the nasal cavity — e.g., modification ofthe nasal septum, excision of the turbinate, andelimination of nasal polyps — and endoscopicsurgery of the paranasal sinus are effective inimproving respiratory or mixed olfactory dis-turbances. However, complete recovery fromextensive and multiple polyps is difficult. It hasbeen reported that the recovery rate is about50%.3)

(2) Drug therapy(i) Nasal instillation, nasal spraying, or local

injection of adrenal cortex hormonesWith the patient in the head-down (chin-up)

position, 1 to 2 drops of a 0.1% solution ofbetamethasone sodium (Rinderon®) are instilledin the nasal cavity 3 to 4 times a day, duringwhich time the patient is instructed to hold the

position for about 5 minutes. If no improve-ment is seen within one month, the medicationis discontinued. When the patient is unable tohold his head in the specified position or he haschronic sinusitis or has recently undergonesurgery, the same preparation is sprayed froman atomizer twice a day. Topical application of2mg/0.5mlV of dexamethasone or 40 mg/1mlVof methylprednisolone to the olfactory mucosais also recommended. Both are applied onceevery 2 weeks and repeated 4 to 6 times.(ii) Oral medication

Recently, long-term application of a smallamount of macrolide antibiotics has been re-commended as a conservative or postoperativeadjuvant therapy for chronic paranasal sinus-itis. This medication is usually combined withethyl L-cysteine hydrochloride (Cystanin®) orL-carbocysteine (Mucodyne®).(iii) Therapeutic modalities projected in

the near futureFor the etiology of chronic paranasal sinus-

itis, it has been proven that inflammatory cyto-kines (e.g., IL-1�, TNF-�, GM-CSF, and IL-6)are involved. Therefore, much is expected fromgene therapy to control the genes responsiblefor the expression of these cytokines at thegenetic level or chemotherapy targeted at thesegenes.

Olfactory Disturbances Following aCommon Cold

It is understood that olfactory disturbancescomplicating upper respiratory inflammationare caused by nasal occlusion, swelling of thenasal mucosa, or edema of the mucosa of theolfactory cleft. Most of these symptoms aretransient, being eliminated in 2 to 3 days. How-ever, in some instances they may develop aftera cold and their prognosis is considered to bepoor. The condition frequently affects womenbetween 40 to 69 years of age.4) The questionof the exaggerated susceptibility to infectionby viruses from the olfactory nerve and theresistance to recovery from disturbances in this

M. FURUKAWA


age range, as well as the higher frequency ofoccurrence among women, have not been fullyelucidated.

1. PathophysiologyExcessive secretion or dryness of the olfac-

tory mucosa and ciliary dysfunctions of theolfactory cells due to acute inflammation andsubsequent secondary infection following viraldiseases may explain the development of olfac-tory disturbances. Histopathological findingsfrom the material obtained by a biopsy of theolfactory mucosa were presented by Tomlinson,5)

who cited central nervous dysfunction via theolfactory nerve, and by Yamagishi,6) who calledattention to a reduction in the number of olfac-tory cells.

2. TreatmentFor peripheral or central olfactory distur-

bances, vitamin B12, vitamin A, and adenosinetriphosphate (ATP®) are commonly used. Thereis a report that extols the favorable effect ofOriental medicine (e.g., Toki-Shakuyaku-Sanand Keishi-Bukuryo-Gan).7) Sometimes theserum zinc content is reduced, with rapid lossof the gustatory and olfactory sensations and aresultant acute loss of taste for food. Whetherthe state is acute or chronic, it has been pointedout that reductions in the serum zinc levelresults in anorexia and gustatory and olfactorydisturbances. It is not certain why a drop in theserum zinc level triggers these symptoms. Inthe brain, the zinc content is at the highest inthe hippocampus, followed by the cortex, stria,and cerebellum. It is also known that zinc existsat a high concentration at the terminals of themossy fibers of the cerebellum and hippocam-pus, suggesting that zinc is involved in the func-tioning of the central nervous system.8)

Parosmia

If a loss or reduction in the olfactory functionrepresents quantitative deviations of olfactoryfunctions, parosmia is typical of qualitative

disturbances of the same function. In clinicalpatients, parosmia may be found in olfactorydysfunctions following a cold (mentioned ear-lier) and following trauma suggestive of dis-ruption of the olfactory fibers. Characteristi-cally, parosmia develops after some time haselapsed, instead of immediately after olfactorydysfunctions.9)

1. PathophysiologyInstead of remaining viable throughout one’s

life, the olfactory cells die after a certain time,repeating regeneration through division andproliferative processes.10) Specifically, the oldcells are replaced by new olfactory cells thatare generated by division of the stem cells ofthe basal layer so that the axons of new olfac-tory cells may constantly project to the olfac-tory bulb.11)

According to a recent finding, the site of theolfactory bulb to which the axons of olfactorycells project is well preserved in individualsand remains constant throughout one’s life. Inother words, the axons that have newly devel-oped accurately recognize the sites on theglomeruli: by projecting toward these sites, the“olfactory map” on the olfactory bulb is con-tinually being recreated and maintained.

In parosmia, however, it is understood thataxonal projection occurs at different sites onthe olfactory bulb following regeneration.12) Anolfactory stimulus may be detected by repro-jection through neural regeneration but projec-tion to a different site results in the perceptionof a different type of olfactory stimulus.

2. TreatmentThe current therapeutic modalities are gen-

erally similar to those applied to the peripheraland central olfactory disturbances describedabove. In addition, administration of vitaminA, which is known to affect differentiation andproliferation of the olfactory epithelium, hasbeen reported. Leopold, et al. ruled out theefficacy of vitamin A: instead they cited a caseof parosmia in which unilateral excision of the



olfactory mucosa was found to be effective.13)

They attributed the improvement of the symp-tom to appropriate nerve projection pathwaybut this case is somewhat unique and follow-upstudies are needed to prove the validity of theprocedure.

3. Therapeutic procedures for the near futureApoptotic death of the olfactory cells has

been observed in the early stage following dis-ruption of the olfactory fibers in experimentsusing mice and rats. It was proven that thenumber of olfactory cells and the thickness ofthe layer of these cells are reduced; but within3 to 4 weeks, regeneration of these cells iscompleted, thus restoring the olfactory activi-ties and functions. It is readily conceivable thatsimilar processes take place in man. Prognosisis poor in those clinical patients who suggestdisruption of their olfactory fibers: the olfac-tory function cannot be restored in most ofthese patients.

For the cause of parosmia, incomplete con-nection between olfactory fibers and the olfac-tory bulb — in spite of the regeneration of theolfactory cells — is considered. It is believedthat the formation of granulation tissue aroundthe lamina cribriform is the most significantdisturbance. Therefore preventing the forma-tion of granulation tissue at the site notedabove or enabling the neural connection inspite of the presence of the granulation tissuewill lead to the development of new therapeu-tic approaches.

In Closing

Recent pathophysiological findings on chronicparanasal sinusitis (a condition most often citedas the cause of olfactory disturbances in Japan),olfactory disorders consequent to the commoncold, and parosmia were presented. Trends inthe therapeutic modalities projected in thenear future (including gene therapy) were alsointroduced.

REFERENCES

1) Zusyo, H.: Chronic paranasal sinusitis andolfactory disturbances. JOHNS 1987; 3: 275–280. (in Japanese)

2) Tatsutomi, S.: Histological study of the olfac-tory epithelium and olfactory bulb in an experi-mental paranasal sinusitis model using rats.Journal of the Juzen Medical Society 2000;109(4,5): 318–329. (in Japanese)

3) Downey, L.L., Jacobs, J.B. and Lebowitz,R.A.: Anosmia and chronic sinus disease.Otolaryngol Head Neck Surg 1996; 115: 24–28.

4) Leopold, D.A.: Physiology of Olfaction. edCummings, C.W., In Otolaryngology/Head andNeck Surgery, vol.1, Mosby CV, St Louis, 1986;pp.640–664.

5) Tomlinson, A.H. and Esiri, M.M.: Herpessimplex encephalitis immunohistological dem-onstration of spread of virus via olfactorypathways in mice. J Neurol Sci 1983; 60(3):473–484.

6) Yamagishi, M., Hasegawa, S. and Nakano, Y.:Examination and classification of human olfac-tory mucosa in patients with clinical olfactorydisturbances. Arch Otorhinolaryngol 1988;1245(5): 316–320.

7) Shimada, K., Ogino, H. and Takemoto, I.:Effect of Toki-Shakuyaku-San on central olfac-tory disturbances. The Japanese Journal ofTaste and Smell Research 1997; 4(3): 339–340.(in Japanese)

8) Henkin, R.I. et al.: A syndrome of acute zincloss. Arch Neurol 1975 ; 132(11): 745–751.

9) Kimura, K., Miwa, T., Sakashita, H. et al.:Clinical observations on parosmia. Journal ofOtolaryngology of Japan 1992; 95(1): 51–57.(in Japanese)

10) Kimura, K., Kamide, M., Furukawa, M. et al.:Evaluation of turnover of olfactory epithe-lium in mice by using anti-BrdU monoclonalantibody. Journal of Otolaryngology of Japan1990; 93: 165–170. (in Japanese)

11) Graziadei, P.P. and Monti Graziadei, G.A.:Neurogenesis and neuron regeneration in theolfactory system of mammals. III. Deafferent-ation and reinnervation of the olfactory bulbfollowing section of the fila olfactoria in rat.J Neurocytol 1980; 9(2): 145–162.

12) Costanzo, R.M.: Rewiring the olfactory bulb:changes in odor maps following recovery from

M. FURUKAWA


nerve transection. Chem Senses 2000; 25(2):199–205.

13) Leopold, D.A., Schwob, J.E., Youngentob, S.L.

et al.: Successful treatment of phantosmia withpreservation of olfaction. Arch OtolaryngolHead Neck Surg 1991; 117: 1402–1406.



This article is a revised English version of a paper originally published inthe Journal of the Japan Medical Association (Vol. 128, No. 5, 2002, pages 772–777).The Japanese text is a transcript of a lecture originally aired on March 14, 2002, by the Nihon ShortwaveBroadcasting Co., Ltd., in its regular program “Special Course in Medicine”.

Treatment of Housewives’ Hand Eczema—Touching on recent topics—JMAJ 47(1): 44–51, 2004

Hiroko NANKO

Director, Department of Dermatology, Tokyo Kosei-Nenkin Hospital

Abstract: The clinical features of housewives’ (hand) eczema are described,distinguishing between dry and moist forms and the pathogenic factors andmechanism of each form, based on the past three years of patient data frompractice at Tokyo Kosei Nenkin Hospital. I will also introduce the recent understand-ing of characteristics of the hands and the barrier function of the stratum corneum,and describe their relevance to the treatment, prevention, and education in skincare of this condition, touching on recent topics.

Key words: Housewives’ eczema; Hand eczema; Stratum corneum barrier;Moisture-retentive agent; Topical steroid

What is Housewives’ Eczema?

In current usage, the term “housewives’eczema” is synonymous with “hand eczema,”which is popularly called “sore hands” or“chapped hands”. This skin disease is a type ofeczema or dermatitis. Among all parts of thehuman body, the hands are most frequentlyexposed to challenging chemicals and environ-mental conditions. Therefore they are the areamost susceptible to skin problems. This termhas been used at home and abroad because itsincidence is so high among housewives, whohave to use their hands frequently duringdomestic tasks, and in this group it is commonlychronic, recurrent and uncontrollable. In addi-

tion to housewives, others who develop occu-pational hand eczema include barbers, hair-dressers, healthcare personnel, cooks andother food/drink-related service providers,cleaners, and office workers who deal withpapers or bills. This disease is commonly seenin dermatology clinics.

In this paper, I will focus on non-occupa-tional housewives’ hand eczema and refer tosome recent topics relevant to this disease.

1. Statistical aspectAlthough the overall clinical incidence of

hand eczema, including housewives’ handeczema, has been reported in some Japaneseand foreign literature, the actual incidence is

� Housewives’ Eczema


unknown. Over 30 years ago (1965), the LundUniversity (Sweden) department of dermatol-ogy conducted a study involving 4,633 patients.The researchers found that the hands wereaffected in 34% of all patients seen at thedepartment of dermatology, that more thanhalf of these patients had hand eczema, andthat women outnumbered men by a ratio of2 to 1.1) In Japan, the statistics on patientswho visited the Shimane Medical University(Department of Dermatology) for the past 15years were reported by Jidoi five years ago.According to his report, consistently about 8%of all outpatients had hand eczema, and womenoutnumbered men by approximately 4 to 1.2) Inthe department of dermatology of our hospitallocated in the center of Tokyo, about 5% of allnew outpatients seen in the past three years(from 1999 to 2001) had the disease, with amale/female ratio of 1 : 2.3. The incidence washighest in women in their 20s and 30s, and wasalso high in patients in their 50s and 60s, fol-lowed by patients in their 70s (Fig. 1).

Figure 2 shows the number of patients whovisited our department by month. More patientsvisited in the seasons from spring to autumn(April to October) except September and inDecember, suggesting a trend similar to thereport by Jidoi indicating that the lowestnumber of patients visited in January andSeptember. Focusing on the number of female

patients, a similar trend was observed: the totalnumber was not higher in winter, except for thedry form of the disease described later. Also,16% of all patients with eczema and dermatitis(other than atopic dermatitis and seborrheicdermatitis) presented with hand eczema. One-fourth (24%) of these patients were female.

Although simple comparisons cannot bedrawn among these results, I have formed thefollowing broad impressions: that the largeproportion of outpatients presenting with handeczema in the past has recently decreased byhalf although the absolute number of patientswith hand eczema has not decreased, thatthe incidence is more than 2 times higher infemales than males in all ages, that women wholive in rural areas are likely to develop the con-dition at nearly twice the rate of those who livein urban areas, and that a higher number ofpatients visit hospitals in the months or seasonswith high levels of activity compared to winter.In conclusion, the onset of hand eczema maybe related to two factors, gender and life habits.

2. Clinical featuresIn practice, both dry and moist forms of the

disease are mixed in a given patient. The dis-ease alternately exacerbates and remits and, inquite a few cases, may become chronic. Roughcategorization into dry and moist forms facili-tates understanding the clinical features of

Fig. 1 Number of patients presenting with hand eczemafor the past three years by age

Fig. 2 Number of patients presenting with hand eczemafor the past three years by month

200(Number of patients)

180160140120100

80604020

0

Male Female

0 10 20 30 40

Age

50 60 70 80 90(Age period)

100(Number of patients)

80

60

40

20

0

Male Female

1 2 3 4 5 6 7 8 9 10 11 12(Month)

TREATMENT OF HOUSEWIVES’ HAND ECZEMA


H. NANKO

housewives’ eczema.a. Dry form (Fig. 3)

In Japan, this form of housewives’ eczemahas been referred to as keratodermia tylodespalmaris progressiva (KTPP),1) and originatesfrom the tips of the first, second and thirdfingers (thumb, index and middle fingers) ofthe dominant hand and progresses centrip-etally. Left untreated, the disease involvesother fingers, and finally all fingers of bothhands. Hyperkeratosis or exfoliation with glossand redness in the fingertips appears, fre-quently accompanied by the disappearance offingerprint patterns. In this case, fissures andpain are apt to occur. Coverage with an adhe-sive bandage such as a Band Aid as first aidcauses inflammation, leading to further exacer-bation. This is the stage when many patientsvisit hospitals for the first time. Deformationsof the nails, such as vertical and horizontallines and roughness are commonly observedbecause the entire fingertip is affected, suggest-ing that the condition has become chronic.

Itching is mild and rarely involves the backof the finger other than the end phalanx. Once

developed, the disease frequently relapses andbecomes chronic. It tends to occur and exacer-bate particularly in winter. According to thestatistics presented by Jidoi, 98% of the patientswith KTPP were female and the disease occursin winter at higher incidence.2)

b. Moist form (Fig. 4)In the moist form of housewives’ eczema,

severe itching and redness/inflammation aswell as the appearance of small vesicles andeffusion are observed. The backs of hands andfingers are frequently affected, in addition tothe palms. Since this disease develops acutely,many patients presenting with this disease visithospitals at an earlier stage. Some patients visithospitals because the skin under a ring isaffected and the resultant inflammation doesnot allow the ring to be removed. Some combi-nation of irritative dermatitis due to detergentsand other agents and delayed allergy to nickelor rubber gloves is indicated. Unlike the dry-form eczema KTPP described in the previoussection, the moist form is observed throughoutthe year.

3. Pathogenic factors and mechanismPathogenic factors of housewives’ eczema

appear to include both endogenous and exog-

Fig. 3 Dry-form (KTPP) housewives’ eczemaKeratotic inflammation presents as disappearance of finger-prints and gloss. Such inflammation frequently involves theentire area around the distal phalanx, often associated withabnormal nail growth (79-year-old patient).

Fig. 4 Moist-form housewives’ eczemaThe eczema occurs acutely and is associated with severeitching and inflammation. The forearms and dorsal hands arealso affected. In many cases, an allergic mechanism is sug-gested (43-year-old patient exacerbated by rubber gloves).


enous factors. Endogenous factors includeatopic predisposition, and local hyperidrosis.Patients who have these predispositions arethought to have a higher incidence of handeczema.3) According to a questionnaire investi-gation of 6,666 twins two years ago by Bryld etal. (Denmark), hand eczema occurs in identicaltwins with nearly double the incidence seen inpairs of fraternal twins; however, any predis-position is related to the onset, though whetherit is atopy or contact allergy is unknown.4)

However, this hypothesis is debatable and wecannot know whether either of these factors isessential.a. Dry form

The dry form of hand eczema (KTPP) is anirritative and nonallergic contact dermatitis.The disease is initiated in two steps. The firststep is the removal of skin surface lipid(delipidation) in the course of domestic choresthat may involve frequent hand washing withsoap, detergent and hot water, repeated use ofalcohol cottons or organic solvents such asacetone and benzene, and frequent contactwith newspapers or other papers. The secondstep is exposure of the skin to different chemi-cals involved in these domestic tasks. Thereforethis type of eczema can occur in anyone whoencounters these conditions. Chemicals such assurfactants can denature protein.1)

b. Moist formThe moist form of eczema may occur prima-

rily due to allergic contact dermatitis. The dis-ease develops only in individuals who are sen-sitive to certain substances, and each patientseems to respond to a specific sensitizing sub-stance. The variety of sensitizing substances iswide. Commonly encountered sensitizing sub-stances for housewives’ eczema include metalssuch as nickel, chromium, and cobalt, perfume,hair-dye, permanent wave liquid (especiallytype 1), and rubber or synthetic gloves. Therange of known causative agents is nowexpanding to foods, including spices, andgardening-related substances. Also, contacturticaria (immediate allergy) has been caused

by fresh seafood and the latex protein in natu-ral rubber gloves, which can exacerbate house-wives’ eczema. When there is a suggestion thatthese allergic mechanisms may be involved, anaggressive search for the causative agents isnecessary, using patch or prick tests.

Understanding the Characteristics ofthe Hands and the Barrier Function ofthe Stratum Corneum

1. Characteristics of the handsThe palms have a peculiar skin structure,

which is related to the fact that the hands arethe body part most frequently exposed toexternal stimuli. The stratum corneum of thepalms consists of approximately 50 layers, andis much thicker than the skin on other parts ofthe hands (about 15–20 layers). Also unlike thefacial skin, the stratum corneum has no hairfollicles and sebaceous glands. In areas wherehair follicles are present, the super surface lipidmembrane overlying the stratum corneum ispredominantly produced by the sebaceousglands associated with hair follicles, while inthe palms and soles the membrane is composedexclusively of lipid produced by metabolism ofepidermal cells. The super surface lipid mem-brane is well developed in the face, whereasthe membrane in the palm is thinner, which iscompensated for by a thick stratum corneum.Additionally we should understand that theback of the finger’s distal phalanx has no hairfollicles and that the nail margins and fingertipshave the same properties as the palms andfinger-pulps.

2. Barrier function of the stratum corneumIt has been shown that homeostasis of bar-

rier function of the stratum corneum is main-tained primarily by three factors; 1) surfacelipid, 2) intrinsic hydrophobic lipid of the stra-tum corneum such as ceramide, and 3) naturalmoisture-retentive factors. Among these factors,ceramide has recently emerged as an importantcontributor to the moisture-retentive barrier.



Ceramide is the hydrophobic lipid that bridgesthe gap between the horny cells and forms thebarrier that keeps water from passing through.5)

The substance is supplied by a structure of theepidermal cell called a lamellar granule (orOdland body), and the process of its metabo-lism and production is under investigation.6)

The so-called natural moisturizing factors arethought to bind with water within the hornycells and play a role in enhancing the flexibilityof the keratin. The factor originates from thekeratohyaline granules of the epidermal cells,which are the soluble amino acids producedby degeneration of fillagrin. In the cosmeticsindustry, great importance is placed on thisfactor.

When the super surface lipid membraneand lipids such as ceramide between the hornycells are removed by artificial causes, internalwater is lost from the stratum corneum (trans-epidermal water loss [TEWL]) and the way isleft open for chemical stimuli or external sub-stances including allergens and microorgan-isms to invade the body, leading to susceptibil-ity to inflammation and allergic sensitization. Ifscratching also occurs (itch-scratch cycle), suchentry and inflammation are promoted, causingthe chronic disease picture involving the twoclinical forms of eczema described previously.The body part most vulnerable to the influ-ences that permit this sequential process is thehands.

Treatment and Prevention ofHousewives’ Eczema (Table 1)

1. TreatmentDry-form (KTPP) eczema is treated prima-

rily with topical moisture-retentive agents andeducation in skin care. Although topical ste-roids (ointment or tapes) may be concomi-tantly used for a short time (about a week) dur-ing the inflammation phase, moisture-retentionand education are very important. Emollientsand moisturizers are known as moisture-retentive agents; the emollient softens the stra-tum corneum and the moisturizer, in additionto its softening effect, aggressively binds towater and thereby inhibits evaporation ofwater over a long period. Typical emollientsand moisturizers are petrolatum and topicalagents containing urea or heparin, respectively.Physicians should advise patients not to applyBand-Aids or other adhesive bandages to pain-ful fissures. Instead, medical dressings can beused to cover the fissures for a short period.

Severe inflammation and itching is associ-ated with moist-form hand eczema. Thereforemedium or high potency topical steroids shouldbe used aggressively. Additionally, a short-termcoating with zinc ointment should be used forprotection. Oral antihistamine should be usedconcomitantly to suppress itching and scratch-ing. After the lesions have improved, theseagents are replaced with moisture-retentive

Table 1 Housewives’ Hand Eczema: Main Points of Treatment and Prevention

Prevention (daily life education)

• Protection of handsLimit the frequency of hand washing: 2 to 3 times per dayWear two different gloves (or skin protective cream)

Adjust domestic tasks (sharing among family membersand automatic dishwasher)Wear gloves to protect against low temperatures

• Avoid factors* leading to exacerbation* Detergent and soap, organic solvents, paper, hair-dyeing

at home, metal rings, covering fissures with Band Aids

Treatment

Dry (KTTP) moisture-retentive agents(urea and heparin preparation)

Moist topical steroids(medium or high potency)and oral antipruritic drugsmoisture-retentive agents after improvement

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agent and skin care education is started.Some reports have shown that oral disodium

cromoglycate (Intal®) is effective in patientswhose nickel allergy is confirmed and wors-ened by dietary intake of nickel. Therefore thistherapy may merit a trial.7)

A recent study on long-term intermittenttherapy with topical steroids in patients withrefractory eczema in Denmark has been re-ported.8) In this study, 120 such patients wereassigned to one of three treatments: 1) topicalsteroid on alternate days for 3 weeks, 2) topicalsteroid on Saturday and Sunday, or 3) moisture-retentive agent and a non-steroid. Treatmentwith topical steroid on alternate days for 3weeks showed the highest effectiveness (83%).In this study, mometasone furoate cream (re-leased as Flumeta cream® in Japan) was used asthe topical steroid.

A study conducted in Germany achieved areported efficacy rate of approximately 90% in28 patients using local warm bath therapy andPUVA (psoralen ultraviolet A) administered 4times per week up to a maximum of 25 times.This therapy was recommended for refractoryeczema due to a lower incidence of side effects,including phototoxic reactions, compared withconventional topical PUVA therapy.9)

2. Prevention and daily life educationIn treating and avoiding both dry and moist

eczema, patients must receive education onthe need to modifying their daily lives so as toreduce the frequency of hand washing and toavoid lipid-removing irritants and allergens.

We often find a considerable reduction of thefrequency of hand washing results when thepatient can achieve some distance from domes-tic tasks, for example with travel. It is a wellknown fact that turnover of the stratumcorneum takes two weeks. The authoritative“Fisher’s Contact Dermatitis” states that thepreferred frequency of hand washing is 2 to 3times per day,10) which is, however, impractical.It has also been reported that switching fromsynthetic detergent to liquid soap does not

modify the degree and incidence of sorehands.11) Therefore the use of double gloves,where cotton gloves are worn under rubber,vinyl or plastic gloves has conventionally beenrecommended.

Rubber gloves are known to cause delayedallergy due to the different vulcanization accel-erators used in the manufacturing processes.Natural rubber gloves are reported to causethis type of allergy as well as contact urticariadue to latex protein, which can initiate ananaphylactic reaction potentially leading todeath.12) The powder used to lubricate the inte-rior of gloves has been suggested as a causeof rash, and there is a potential additional riskof contact allergy from powders that haveabsorbed latex protein, and risk of anaphylac-tic shock resulting from inhaling the powder.12)

Recently a variety of gloves for medical use,including gloves with antigen removed, hypo-allergenic gloves, powder-free gloves, and ure-thane gloves, have become commercially avail-able.13) Patients with housewives’ eczema whoare sensitive to rubber gloves need to selectgloves based on their skin test results. For thepatients who develop immediate allergy inresponse to latex, caution should be exerciseddue to possible cross-reaction in response tobanana, avocado, kiwi fruit, and melon.14)

On the other hand, skin-protective creamsdesigned in consideration of the inconvenienceof wearing two different gloves are available,and should be tried. Patients should be instructedto devise daily life plans that are easy on thehands and use the conveniences of modernsociety. These would include, for example, theuse of a dishwasher, sharing of domestic tasksamong family members, eating out and utiliza-tion of fast food. When going out in winter,gloves should be worn for protection againstlow temperatures.

The market is flooded with many non-prescription moisture-retentive agents. Theseagents use mixtures of different ingredients toachieve moisture-retention. Commercial prod-ucts containing urea have recently appeared,



and these provide a long-lasting moisture-retentive effect and appear to be superior tosimilar products prescribed in hospitals.15)

These products’ moisture-retentive effect canpersist for as long as 2 weeks, even after dis-continuation of use, and by themselves theycan restore the barrier function of the stratumcorneum.

With respect to allergens, there is concernthat the new European coins in use beginningthis year may cause nickel allergy, dependingon the alloy used. Recent experiments suggestthe possibility that nickel leaches from thesecoins and invades the skin of the palms whenthe coins are grasped strongly for as little as 2minutes.16) Patients with housewives’ eczemashould be alert to such possibilities.

The recent boom in nail art has made nailshops common in Japan. Attention should begiven to the delipidization of the fingertipscaused by polish removers containing tolueneand other organic solvents.

Wearing cotton gloves is recommendedwhen touching newspapers and magazines.Although environmentally friendly pulps haverecently been manufactured, some literaturesuggests that there is a risk that these pulpscontain sensitizers such as oxides of the resincalled rhodine, unlike conventional chemicalpulps.17) This example indicates that environ-mentally friendly goods are not necessarilyhuman-friendly.

Conclusion

I conclude that housewives’ hand eczema istypically a lifestyle-related skin disease. Irre-spective of any predisposition, its developmentand exacerbation depend on a patient’s aware-ness of causative and preventative factors. Aswomen are increasingly assimilated into soci-ety beyond the household, the proportion ofwomen with housewives’ eczema may becomelower than that of men presenting with thiseczema. Clinicians should continue to payattention to changes in society and the environ-

ment and should include daily life education inpatient interviews.

REFERENCES

1) Ueda, H.: Housewives’ eczema. Modern Der-matology Methodology 13. Nakayama-Shoten,Tokyo, 1980; pp.81–88. (in Japanese)

2) Jidoi, J.: Statistical observation on contactdermatitis and hand eczema encountered for15 years. Clinical Dermatology 1997; 39: 889–893. (in Japanese)

3) Ichikawa, E.: Hand eczema. Clinical Derma-tology 2000; 42 (Extra edition Ver.10): 1451–1455. (in Japanese)

4) Bryld, L.E., Agner, T., Kwik, K.O. et al.: Handeczema in twins: a questionnaire investigation.Br J Dermatol 2000; 142: 298–305.

5) Tagami, H.: Stratum corneum as skin barrier.Journal of the Japanese Society of Dermatol-ogy 1998; 108: 713–727. (in Japanese)

6) Hamanaka, S.: Skin glycolipics and their func-tions. Journal of the Japanese Society of Der-matology 2002; 112: 107–115. (in Japanese)

7) Ikezawa, Z.: Hand (housewives) eczema.Current Therapy in Dermatological Diseases’97–’98. Nankodo, 1997; p.15. (in Japanese)

8) Velen, N.K., Larsen, P.O., Pedersen, K.T. et al.:Long-term, intermittent treatment of chronichand eczema with mometasone furoate. Br JDermatol 1999; 140(5): 882–886.

9) Schempp, C.M., Muller, H., Czech, W. et al.:Treatment of chronic palmoplantar eczemawith local bath-PUVA therapy. J Am AcadDermatol 1997; 36: 733–737.

10) Rietchel, R.L. and Flowler, J.F.: Hand der-matitis due to contactants. ed. by Rletchel,R.L. & Flowler, J.F.. In Fisher’s Contact Der-matitis, 4th ed, Williams & Wilkins, 1995; p.343.

11) Ukei, T., Hayakawa, R., Oiwa, K. et al.: Syn-thetic detergent and liquid soap. Dermatology1984; 26: 291–302. (in Japanese)

12) Kaniwa, M.: Hypoallergenic gloves. Dermato-logical Practice 1993; 15: 478–482. (in Japanese)

13) Kaniwa, M.: Rubber gloves: Anti-allergicgoods. Dermatological Practice 1999; 21(Sup-plement): 110–113. (in Japanese)

14) Hayakawa, R.: Latex allergy. DermatologicalPractice 1999; 21: 493–497. (in Japanese)

15) Tagami, H.: Physiology of the stratumcorneum. The 65th Annual Meeting of the

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Tokyo Division of JDA, Feb. 16, 2002. Tokyo.(in Japanese)

16) Liden, C. and Carter, S.: Nickel release fromcoins. Contact Dermatitis 2001; 44: 160–165.

17) Karlberg, A.T., Gafvert, E. and Liden, C.:Environmentally friendly paper may increaserisk of hand eczema in rosin-sensitive persons.J Am Acad Dermatol 1995; 33: 427–432.


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