Association of pyrazolone drug hypersensitivity with HLA-DQ and DR antigens

Association of pyrazolone drug hypersensitivity withHLA-DQ and DR antigens

M. L. KOWALSKI, G. WOSZCZEK, B. BIENKIEWICZ and M. MIS

Department of Clinical Immunology and Allergy, Medical University of Lo´dz, Poland

Summary

Background In sensitive patients pyrazolone drugs can precipitate adverse reactionsranging from urticaria and angioedema to anaphylactic shock, presumably by immunolo-gical, IgE-mediated mechanism. However, up to now no genetic factors influencing thedevelopment of allergic reaction have been reported in this type of hypersensitivity.Objective The aim of our study was the investigation whether the susceptibility todevelopment of pyrazolone drugs hypersensitivity (PDH) reactions was associated withHLA class II antigens.Methods To test this hypothesis we studied the distribution of HLA-DR and DQ antigensin 26 pyrazolone sensitive patients and control groups including unselected generalpopulation and clearly defined atopic and non-atopic groups.Results Significantly higher frequencies of DQ 7 and DR11 antigens were found in PDHgroup as compared with control unselected population (RR¼ 16.48,P<0.0001;Pcor<0.002and RR¼ 4.57,P¼ 0.0002;Pcor¼ 0.003 for DQ and DR antigen respectively). Similarly,statistically significant increased frequencies of DQ 7 and DR11 in patients with PDH wereobserved compared with atopic control group (RR¼ 18.43,P<0.0001;Pcor<0.002 andRR¼ 6.33, P¼ 0.0007;Pcor¼ 0.01, for DQ and DR antigen respectively). However, incomparison to non-atopic control group only the frequency of DQ 7 antigen wassignificantly increased (RR¼ 15.42,P¼ 0.0001;Pcor¼ 0.0015). DQ 7 antigen was presentin 46.1% of PDH patients compared with 4.9%, 4.4% and 5.3% in the general population,atopic and non-atopic groups respectively, suggesting pyrazolone hypersensitivity as a traitpositively correlated with this HLA antigen.Conclusion Our data suggest a genetic predisposition to pyrazolone hypersensitivityreactions, linked to HLA-DQ locus.

Keywords: pyrazolone, hypersensitivity, HLA class II antigens

Clinical and Experimental Allergy, Vol. 28, pp. 1153–1158. Submitted 29 September 1997;revised 9 February 1998; accepted 11 February 1998.

Introduction

Non-steroidal anti-inflammatory drugs (NSAID) are amongthe most often prescribed drugs in routine clinical practice.Adverse reactions to NSAIDs ranging from urticaria andangioedema to asthma attacks and anaphylactic reaction arequite frequently encountered [1–3]. Patients experiencingadverse reactions to NSAIDs can be divided into twogroups: patients with hypersensitivity to aspirin-like drugs

and patients with hypersensitivity to pyrazolone drugs likenoramidopyrine and aminophenazone [4,5]. Urticaria,angioedema and/or anaphylactic shock are the most oftenadverse symptoms appearing in patients with pyrazolonedrugs hypersensitivity (PDH), and these patients can safelyuse other chemically non-related non-steroidal anti-inflam-matory drugs like aspirin, indomethacin etc. In patients withPDH the reaction seems to depend on the allergic, IgE-mediated mechanism involving specific antibodies to pyr-azolone derivatives [4–7]. In contrast, aspirin intolerancemanifesting either as asthmatic attack or urticaria/angioe-dema results probably from inhibition of cyclo-oxygenases,

Clinical and Experimental Allergy,1998, Volume 28, pages 1153–1158

1153q 1998 Blackwell Science Ltd

Correspondence: M. L. Kowalski, Department of Clinical Immunology andAllergy, Medical University of Lodz, 11, Mazowiecka str., 92-215 Lo´dz,Poland.

leading to imbalance in arachidonic acid derivativesproduction [4]. It has been well established that severalgenetic factors may influence the development of allergicdiseases [8]. Although significant association between IgE-mediated immune responsiveness to specific inhalant aller-gens and MHC alleles is well documented similar data ondrug-induced allergy are sparse [9–12].

The aim of our study was the investigation whether thesusceptibility to pyrazolone drugs hypersensitivity, presum-ably mediated by IgE, was associated with HLA class IIantigens. To test this hypothesis we studied the distributionof HLA-DR and DQ antigens in patients with clearlydefined PDH and in control groups.

Patients and methods

Patients with pyrazolone drug hypersensitivity

Twenty-six patients (21 women, five men, mean age 32.4,range 18–58 years) with documented history of immediatesystemic reactions after pyrazolone derivatives ingestionwere included into the study (urticaria and angioedemaoccurred in 26 patients, laryngeal angioedema in 15 casesand anaphylactic shock in five cases). Twenty-three patientshad more than one pyrazolone-induced adverse reactions.Skin testing with noraminophenazon was performed in 23PDH patients as described in previous study [13]: first skin-prick tests (SPT) and then, if negative, intradermal tests(IDT) were done. For SPT 0.001%, and (if negative) after15 min 0.01% noraminophenazon solution were used. If theskin-prick tests were negative, intradermal tests with0.001% and 0.01% solution of noraminophenazon wereperformed. Both skin-prick and intradermal tests werecompared to histamine and solvent as a positive andnegative control, respectively. For IDT the weal of at least5 mm in diameter with flare was considered as a positivereaction. During the skin testing procedure blood pressure,heart rate and peak expiratory flow were measured at 30 minintervals and patients remained under the observation for atleast 1 h after the skin testing was completed. In all 23patients skin-prick tests (SPT) with 0.001%, and then 0.01%solution of noraminofenazon were negative. Positiveintradermal skin tests were observed in 11 patients (48%).

Skin-prick tests with common inhaled allergens wereperformed in all patients. The following allergens wereused for skin-prick testing: mixed grass pollens, mixedtree pollens, cat dander, dog dander,Alternaria species,Dermatophagoides pteronyssinusand Dermatophagoidesfarinae (Allergopharma, Germany). The positive controlwas histamine and the diluent was used as a negativecontrol. A positive skin-prick test was defined as a meanweal diameter of at least 3 mm or larger than that of thenegative control, accompanied by flare reaction. Seventeen

patients (65%) had positive skin-prick test to at least oneallergen of the tested panel, compatible with positive historyof allergic symptoms. All patients had clear history of goodtolerance of aspirin.

Population control subjects

Control group consisted of 182 unrelated individuals of bothsexes from the central area of Poland referred to ourTransplantation Immunology Unit for HLA tissue typing.The group included organ donors and recipients, mothersand putative fathers examined for disputed paternity, familymembers (only one member from a family) examined aspotential bone marrow donors and members of theUniversity staff.

Atopic patients

The group comprised 45 atopic patients different fromunselected control population (28 women, 17 men, meanage 32.9; range 20–65 years) with positive history ofatopic diseases (asthma, rhinitis, dermatitis) and withpositive skin-prick tests to at least one allergen from apanel tested.

Non-atopic patients

The group consisted of 38 healthy unrelated persons (27women, 11 men, mean age 29.3, range 20–48 years) withnegative personal and family history of atopy and negativeskin-prick tests with a panel of allergens.

HLA antigens typing

HLA-DR and DQ typing was performed in all studiedsubjects at the Transplantation Immunology Unit of theDepartment of Clinical Immunology and Allergy usingconventional microcytotoxicity assay [14].

The lymphocytes for the test were obtained from periph-eral blood by centrifugation on Ficollpaque (Gibco, Ger-many) gradient and B-cell enriched by passage throughnylon wool columns. The following antisera (Biotest, Behr-ing; Germany) were used: for locus DR: 1, 1þ 10, 2, 3, 4, 5,4þ 9, 7, 7þ 9, 8, 10, 11, 12, 14, 52, 53, 53þ 7; for locusDQ: 1, 2, 7.

Statistical analysis

The frequencies of HLA antigens in patients and controlswere compared with chi-square analysis with Yeates correc-tion for number of subjects. TheP-values of less than 0.05were considered significant. To correct for incidental sig-nificance, theP-value was multiplied by the number of

1154 M. L. Kowalskiet al.

q 1998 Blackwell Science Ltd,Clinical and Experimental Allergy, 28, 1153–1158

antigens compared (Pcor). Relative risk (RR) was calculatedas the cross product in a 2× 2 table.

Results

The distribution of HLA class II antigens in all studiedgroups is shown in Table 1. Comparison of HLA DR andDQ antigens between patients with PDH and control popu-lation showed increase in the incidence of DQ 7, DR 5 andDR 11(a split of DR 5) antigens in PDH patients. Thefrequency of DQ 7 antigen in PDH group was significantly

higher (P<0.0001;Pcor<0.002) with RR¼ 16.48 comparedwith the population control group, to atopic group(P<0.0001; Pcor< 0.002; RR¼ 18.43) and to non-atopicgroup (P¼ 0.0001;Pcor¼ 0.0015; RR¼ 15.42) (Table 2).There was a significant difference in the frequency of DR 5antigen (P¼ 0.0002; Pcor¼ 0.003; RR¼ 4.59) whenpatients with PDH were compared with control population,with atopic group (P¼ 0.0004; Pcor¼ 0.006; RR¼ 6.40)and higher frequency of DR 5 when compared with thenon-atopic group (P¼ 0.018;Pcor¼ NS.; RR¼ 3.47). Simi-larly, DR 11 antigen, which is a split of DR 5 was found with

Association of pyrazolone drug hypersensitivity with HLA-DQ and DR antigens1155


Table 1. The frequency of HLA-DR and DQ antigens in studied groups

HLA class II PDH patients Population group Atopic group Non-atopic groupantigens n ¼ 26 n ¼ 182 n ¼ 45 n ¼ 38

n % n % n % n %

DR 1 9 34.6 45 24.7 12 26.7 7 18.4DR 2 7 26.9 61 33.5 12 26.7 12 31.6DR 3 3 11.5 41 22.5 13 28.9 6 15.8DR 4 6 23.1 34 18.9 8 17.8 10 26.3DR 5 16 61.5 47 25.8 9 20.0 12 31.5DR 7 2 7.6 56 30.7 9 20.0 9 23.7DR 8 1 3.8 13 7.1 1 2.2 1 2.6DR 9 0 – 2 1.0 1 2.2 0 –DR 10 0 – 8 4.4 1 2.2 2 2.6DR 11 14 53.8 37 20.3 7 15.5 10 26.3DR 12 0 – 10 5.5 2 4.4 2 5.3DR 14 0 – 13 7.0 1 2.2 1 2.6

DQ 1 15 57.7 95 52.2 21 46.7 17 44.7DQ 2 4 15.4 45 24.7 8 17.8 10 26.3DQ 7 12 46.1 9 4.9 2 4.4 2 5.3

Table 2. Comparison of differences between studied groups

PDH vs population group PDH vs atopic group PDH vs non-atopic groupHLA antigens RR P RR P RR P

DQ 7 16.48 < 0.0001 18.43 <0.0001 15.42 <0.0001Pcor<0.002 Pcor< 0.002 Pcor<0.0015

DR 11 4.57 ¼ 0.0002 6.33 ¼ 0.0007 3.27 ¼ 0.025Pcor<0.003 Pcor¼ 0.01 Pcor¼ NS

DR 5 4.59 ¼ 0.002 6.40 ¼ 0.0004 3.47 ¼ 0.018Pcor<0.003 Pcor¼ 0.006 Pcor¼ NS

DR 7 0.18 ¼ 0.014 0.33 ¼ NS 0.27 ¼ NSPcor¼ NS Pcor¼ NS Pcor¼ NS

RR, relative risk;P, Chi square analysis with Yeates correction when adequate;Pcor, P multiplied by number of antigens tested;NS, not statistically significant.

higher frequency in PDH group in comparison to the controlgroup (P¼ 0.0002;Pcor¼ 0.003; RR¼ 4.57), atopic group(P¼ 0.0007; Pcor¼ 0.01; RR¼ 6.33) and to non-atopicindividuals as well (P¼ 0.025; Pcor¼ NS; RR¼ 3.27).Comparison of DR 7 frequencies in studied groups showeda decrease of the DR 7 frequency in patients with PDH

compared with the control population (P¼ 0.014;Pcor¼ NS; RR¼ 0.18), but it was not significant whencompared with the atopic group (P> 0.05; RR¼ 0.33) andnon-atopic group (P> 0.05; RR¼ 0.27).

When frequencies of HLA DR and DQ antigens wereanalysed in PDH group divided according to the atopy status(17 atopics and nine non-atopics), the HLA DR and DQdistribution pattern was similar (Table 3) in both atopic andnon-atopic groups of PDH patients compared with the PDHgroup as a whole. Significantly higher frequency of DQ 7antigen was observed in both subgroups in comparison witha population control and with atopic and non-atopic groups(Table 4). There was also no difference in the distribution ofDQ 7 and DR 11(5) antigens in PDH patients dividedaccording to the results of skin tests with noraminophenazon(11 positive patients and 12 negative). There were nosignificant differences in HLA antigens distributionbetween atopic group, non-atopic group and populationcontrol group.

Discussion

This is the first study reporting strong association of parti-cular HLA class II antigens with immediate, presumablyIgE-mediated hypersensitivity reactions to pyrazolonederivatives, although previous studies have also linkedsome non-IgE-mediated adverse reactions to NSAIDs tospecific HLA phenotypes. Mullarkeyet al. [15] demon-strated that there is a significant association between aspirin-sensitive asthma and HLA- DQ 2 antigen, Pellicanoet al.[16] observed higher frequency of B22 and Cw1 antigens in



Table 3. The frequency of HLA-DR and DQ antigens in PDHpatients divided according to atopy status

HLA class II PDH atopics PDH non-atopicsantigens n¼ 17 n¼9

n % n %

DR 1 6 35.3 3 33.3DR 2 5 29.4 2 22.2DR 3 3 17.6 – –DR 4 3 17.6 3 33.3DR 5 10 58.8 6 66.7DR 7 1 5.9 1 11.1DR 8 1 5.9 – –DR 9 – – – –DR 10 – – – –DR 11 8 47.1 6 66.7DR 12 – – – –DR 14 – – – –

DQ 1 10 58.8 5 55.5DQ 2 3 17.6 1 11.1DQ 7 8 47.1 4 44.4

Table 4. Comparison of differences between PDH subgroups and control groups

PDH vs population group PDH vs atopic group PDH vs non-atopic groupHLA antigens RR P RR P RR P

DQ 7 PDH atopic 17.1 <0.0001 19.11 ¼ 0.0002 16.0 ¼ 0.0009Pcor¼ 0.002 Pcor¼ 0.003 Pcor¼ 0.013

PDH non-atopic 15.38 ¼ 0.001 17.2 ¼ 0.003 14.4 ¼ 0.009Pcor¼ 0.0015 Pcor¼ 0.05 Pcor¼ NS

DR 11 PDH atopic 3.48 ¼ 0.0002 4.82 ¼ 0.0004 2.49 ¼ 0.018Pcor¼ 0.003 Pcor¼ 0.006 Pcor¼ NS

PDH non-atopic 7.84 ¼ 0.027 10.86 ¼ 0.025 5.6 NSPcor¼ NS Pcor¼ NS

DR 5 PDH atopic 4.1 ¼ 0.004 5.7 ¼ 0.003 3.1 NSPcor¼ NS Pcor¼ 0.005

PDH non-atopic 5.74 ¼ 0.02 8.0 ¼ 0.015 4.3 NSPcor¼ NS Pcor¼ NS

RR, relative risk;P, Chi square analysis with Yeates correction when adequate;Pcor, P multiplied by number of antigens tested;NS, not statistically significant.

patients with fixed drug eruption caused by pyrazolones andRoujeauet al. [17] found small and not significant increasein B35 and DR 5 phenotypes in patients with cutaneousadverse reaction to pyrazolone derivatives. However, allthese reactions are non-IgE-mediated, representing eithernon-immunological mechanisms (aspirin sensitive asthma)or delayed-type hypersensitivity. In contrast, high incidenceof atopy, an immediate type of reactions and presence ofspecific IgE to pyrazolone derivatives in the skin of sensi-tive patients suggest an immunological, IgE-mediatedmechanism of pyrazolone drug hypersensitivity reactionsobserved in our patients. However, the diagnosis of PDH isstill based mainly on clinical history, and no reliablein vitrodiagnostic method has been used in clinical practice up tonow. We evaluated [13] the reliability of different methodsto confirm PDH diagnosis and we found that the carefulhistory of pyrazolone adverse reactions is still the mostimportant in the PDH diagnosis and may only be confirmedby intradermal skin testing in some patients. In vitro testsmeasuring pyrazolone specific IgE in serum (e.g. RAST orELISA) do not seem to be sensitive enough and have to becarefully evaluated in well defined populations of sensitivepatients before they can be recommended for routinediagnostic use [13].

Recent studies have emphasized the importance ofgenetic factors including HLA genes for the developmentof atopy and allergic diseases [8]. We found significantlyhigher incidence of HLA DQ 7 and DR 11(5) antigens in thegroup of PDH patients comparing to unselected controlgroup as well as atopic and non-atopic groups and lowerfrequency of DR 7 antigen in PDH group in comparison topopulation control group. The strongest and highly signifi-cant (after correction) association of pyrazolone hypersen-sitivity was seen with DQ 7 antigen in comparison to allcontrol groups. Having in mind relatively low frequency ofDQ 7 antigen in general population (below 5%) the presenceof this antigen in 46.1% of PDH patients may be consideredas a significant risk factor for development of PDH. BothDR 5 and DR 11 (a split of DR 5) antigens typed separatelyshowed very similar distribution pattern and significantlyhigher frequency in PDH patients compared with populationand atopic groups, although the correctedP was not sig-nificant when compared with non-atopic group. The dis-tribution of HLA antigens in our control unselectedpopulation was similar to other population studies inPoland [19,20] and comparable with values found in theCaucasoid European population [19]. Similarly, a distribu-tion of HLA antigens in our atopic and non-atopic groupswas comparable to other studies in the Polish population[21]. Because of high incidence of atopy found amongpatients with PDH, we also selected atopic and non-atopicgroups for comparison to exclude HLA antigens associationwith atopy rather than PDH. When the distribution of HLA

antigens in PDH group was analysed according to patientsatopy status, the similar frequencies pattern was observed inatopic and non-atopic patients with PDH. Statistically sig-nificant increase in DQ 7 antigen was also observed in bothatopic and non-atopic PDH patients in comparison to allcontrol groups, suggesting that pyrazolone hypersensitivityis the trait positively correlated with DQ 7, regardless of thepresence or absence of sensitivity to typical atopic allergens.The increased incidence of these particular antigens (DQ 7and DR11(5)) in PDH patients together can be explained byoccurrence of linkage disequilibrium phenomenon betweenthe HLA -DQ and HLA -DR loci [22,23], resulting in thefact that both antigens can be frequently found together inCaucasoid population. Thus, it could not be definitelyconcluded whether DQ 7 or DR11(5) or both, were involvedin the pathogenesis of PDH. The lower frequency of DR 7antigen in PDH patients can be explained probably byincreased frequency of HLA DR 11(5) antigens in thisgroup.

In previous studies concerning correlation of specific IgEresponsiveness and MHC loci, the strongest associationswere observed when small, clearly defined allergens werestudied in monosensitized subjects [24–26]. That could bepartially the case in our study. Pyrazolones are smallmolecules, thus they are probably unable to generate spe-cific immune response by themselves, but can precipitatesuch response in a hapten driven mechanisms like penicillindrugs [27,28] or can directly modify MHC molecules. Theexact nature of the antigen related to pyrazolone inducedhypersensitivity is unknown. Pyrazolone drugs are less andless frequently prescribed in clinical practice, thus mainlypatients with strong genetically driven predisposition toadverse reaction to this kind of drugs may develop specificIgE and clinical symptoms after exposition to the drug.HLA-DQ 7, DR11 haplotype may represent such geneticpredisposition to pyrazolone hypersensitivity. We are notaware of any other antigen or hypersensitivity reactionassociated with HLA-DQ 7 antigen.

The significance of HLA antigens associations withspecific sensitization is not fully understood. HLA class IImolecules are coded on the chromosome 6p and areexpressed as highly polymorphic molecules on the cellsurfaces. They play crucial role in antigen presentation toCD4þ T cells, and more generally in regulating the immuneresponse. Positive association between HLA antigens andspecific IgE responses may reflect more efficient presenta-tion of particular antigen to T helper cells, thus promotingthe process of T cell switching to TH2 lymphocytes andspecific IgE response. On the other hand a linkage disequi-librium of DQ 7 with an unknown gene related to PDHcannot be ruled out.

Taken together, our data suggest a possible geneticsusceptibility to pyrazolone drug hypersensitivity linked

Association of pyrazolone drug hypersensitivity with HLA-DQ and DR antigens1157


with HLA antigens. It remains to be established with DNAtyping techniques which particular alleles at HLA class IIloci are associated with PDH, and whether these HLAalleles or some unknown genes in linkage disequilibriumwith them are involved in PDH pathogenesis.

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Association of pyrazolone drug hypersensitivity with HLA-DQ and DR antigens