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846 LETTERS 5. 6. 7. 8. 9. 10. 11 Williams B: Immunogenetic heterogeneity in rheumatoid dis- ease as illustrated by different MHC associations (DQ, Dw and C4) in articular and extra-articular subsets. Br J Rheumatol 305-9, 1991 Lanchbury JSS, Jaeger EEM, Sansom DM, Hall MA, Words- worth P, Stedeford J, Bell JI, Panayi GS: Strong primary selection for the Dw4 subtype of DR4 accounts for the HLA- DQw7 association with Felty’s syndrome. Hum Immunol 32: 56-64,1991 Miiller CA, Voss C, Ning E, Pawelec G, Samson D, Schmidt H: Reevaluation of the HLA-class I1 association of Felty’s syn- drome (abstract), The Eleventh International Histocompatibil- ity Conference. Yokohama, Japan, November 6-13, 1991 Sansom DM, Bidwell JL, Maddison PJ, Campion G, Klouda PT, Bradley BA: HLA DQa and DQP restriction fragment length polymorphisms associated with Felty’s syndrome and DRCpositive rheumatoid arthritis. Hum Immunol 19:269-278, 1987 So AKL, Warner CA, Sansom D, Walport MJ: DQP polymor- phism and genetic susceptibility to Felty’s syndrome. Arthritis Rheum 31:-994, 1988 Clarkson R, Bate AS, Grennan DM, Chattophadhyay C, Sand- ers P, Davis M, Kelly C: DQw7 and the C4B null allele in rheumatoid arthritis and Felty’s syndrome. Ann Rheum Dis 49:976-979, 1990 Olerup 0, Troye-Blomberg M, Schreuder GMT, Riley EM: HLA-DR and -DQ gene polymorphism in West Africans is twice as extensive as in North European Caucasians: evolutionary implications. Roc Natl Acad Sci USA W3480-8484, 1991 Tiwari JL, Terasaki PI, editors: HLA and Disease Associations. New York, Springer-Verlag. 1985 Entry criteria influence conclusions about rates of flare in lupus pregnancy: comment on the article by Petri et al To the Editor: Petri et a1 are to be congratulated for their thoughtful study on the frequency of lupus flare during pregnancy (1). Their conclusions differ from those reported by myself and my colleagues (2,3). Although Petri and co-authors have identifed some design differences between our studies and theirs, I would like to suggest additional aspects that are also important. First, Petri’s study included patients who were first diagnosed with systemic lupus erythematosus (SLE) during pregnancy, whereas ours did not. This is important because women who have inactive disease are unlikely to be diag- nosed during pregnancy. Including newly diagnosed patients biases the study toward the identification of flare. In Petri’s study, minor changes in disease status, even if untreated, were counted as flares. In our studies, changes in disease activity resulting in treatment changes of <lo mg prednisonelday were not counted as flares. (This point is mentioned in the text, but not in the Patients and Methods section, of ref. 3.) Our choice emphasizes clinically meaningful changes; Petri’s emphasizes the biologic impli- cations of small variations. Petri included more than one pregnancy per patient and more than one flare per pregnancy. We counted only one pregnancy and one flare per patient, in the belief that counting patients twice leads to bias favoring overestimation of flare. As noted by Petri et al, we knew almost all of our patients prior to pregnancy, whereas they knew only 4 of the 37 patients in their study. Neither Petri et a1 nor we separately discussed the subset of antiphospholipid antibody-positive patients. It is likely, because of referral patterns, that our series included proportionately more of this subgroup: evidence for this is the 85% fetal survival rate in Petri’s series, compared with 72% in our series. (In our patients, almost all fetal deaths were associated with antiphospholipid antibody.) The impli- cation of this difference is that Petri and coworkers’ patients were referred because of concerns related to the mother (prior or present disease activity) and ours because of concerns related to the fetus (prior fetal losses), a point which would favor identification of flare in their series. It is also likely that the average duration of pregnancy in our series was shorter, though calculating flares per month at risk should control for this. As Petri and colleagues noted, more than 40% of their patients were black, whereas - 10% of our patients were black. They conclude that this difference is unimpor- tant, but I am less certain. Finally, Petri et a1 identified proteinuria (with micro- hematuria) with normal complement and anti-DNA antibody levels as renal flare rather than as toxemia, and third- trimester thrombocytopenia as hematologic flare. These specific decisions are judgment calls, a fact that led us to calculate flare rates both including and excluding late pro- teinuria and late thrombocytopenia. It is not my intent to suggest that the truth lies either with Petri’s conclusions or with ours, but rather to indicate that, in SLE, variations in the definition of flare and in patient acquisition are sufficiently broad and important that they can lead to diametrically opposed conclusions from apparently similar studies. Writers and readers of reports of clinical studies must understand this before they infer a biologic principle from the observations described. Michael D. Lockshin, MD NIH Bethesda, MD 1. Petri M, Howard D, Repke J: Frequency of lupus flare in pregnancy: the Hopkins Lupus Pregnancy Center experience. Arthritis Rheum 34:1538-1545, 1991 2. Lockshin MD, Reinitz E, Druzin ML, Munman M, Estes D: Lupus pregnancy: case-control prospective study demonstrating absence of lupus exacerbation during or after pregnancy. Am J Med 77:893-898. 1984 3. Lockshin MD: Pregnancy does not cause systemic lupus erythe- matosus to worsen. Arthritis Rheum 32:665470, 1989 Reply To the Editor: We agree with Dr. Lockshin that differences in patient selection and definitions may partly explain the differing conclusions of our study on SLE flare rates during pregnancy and of his studies (1-3). We also agree that the appropriate exercise in comparing our study with his is not to decide which is correct and which is wrong, but to dissect

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846 LETTERS

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6.

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8.

9.

10.

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Williams B: Immunogenetic heterogeneity in rheumatoid dis- ease as illustrated by different MHC associations (DQ, Dw and C4) in articular and extra-articular subsets. Br J Rheumatol 305-9, 1991 Lanchbury JSS, Jaeger EEM, Sansom DM, Hall MA, Words- worth P, Stedeford J, Bell JI, Panayi GS: Strong primary selection for the Dw4 subtype of DR4 accounts for the HLA- DQw7 association with Felty’s syndrome. Hum Immunol 32: 56-64,1991 Miiller CA, Voss C, Ning E, Pawelec G, Samson D, Schmidt H: Reevaluation of the HLA-class I1 association of Felty’s syn- drome (abstract), The Eleventh International Histocompatibil- ity Conference. Yokohama, Japan, November 6-13, 1991 Sansom DM, Bidwell JL, Maddison PJ, Campion G, Klouda PT, Bradley BA: HLA DQa and DQP restriction fragment length polymorphisms associated with Felty’s syndrome and DRCpositive rheumatoid arthritis. Hum Immunol 19:269-278, 1987 So AKL, Warner CA, Sansom D, Walport MJ: DQP polymor- phism and genetic susceptibility to Felty’s syndrome. Arthritis Rheum 31:-994, 1988 Clarkson R, Bate AS, Grennan DM, Chattophadhyay C, Sand- ers P, Davis M, Kelly C: DQw7 and the C4B null allele in rheumatoid arthritis and Felty’s syndrome. Ann Rheum Dis 49:976-979, 1990 Olerup 0, Troye-Blomberg M, Schreuder GMT, Riley EM: HLA-DR and -DQ gene polymorphism in West Africans is twice as extensive as in North European Caucasians: evolutionary implications. Roc Natl Acad Sci USA W3480-8484, 1991 Tiwari JL, Terasaki PI, editors: HLA and Disease Associations. New York, Springer-Verlag. 1985

Entry criteria influence conclusions about rates of flare in lupus pregnancy: comment on the article by Petri et al To the Editor:

Petri et a1 are to be congratulated for their thoughtful study on the frequency of lupus flare during pregnancy (1). Their conclusions differ from those reported by myself and my colleagues (2,3). Although Petri and co-authors have identifed some design differences between our studies and theirs, I would like to suggest additional aspects that are also important.

First, Petri’s study included patients who were first diagnosed with systemic lupus erythematosus (SLE) during pregnancy, whereas ours did not. This is important because women who have inactive disease are unlikely to be diag- nosed during pregnancy. Including newly diagnosed patients biases the study toward the identification of flare.

In Petri’s study, minor changes in disease status, even if untreated, were counted as flares. In our studies, changes in disease activity resulting in treatment changes of <lo mg prednisonelday were not counted as flares. (This point is mentioned in the text, but not in the Patients and Methods section, of ref. 3.) Our choice emphasizes clinically meaningful changes; Petri’s emphasizes the biologic impli- cations of small variations.

Petri included more than one pregnancy per patient and more than one flare per pregnancy. We counted only one pregnancy and one flare per patient, in the belief that counting patients twice leads to bias favoring overestimation of flare. As noted by Petri et al, we knew almost all of our

patients prior to pregnancy, whereas they knew only 4 of the 37 patients in their study.

Neither Petri et a1 nor we separately discussed the subset of antiphospholipid antibody-positive patients. It is likely, because of referral patterns, that our series included proportionately more of this subgroup: evidence for this is the 85% fetal survival rate in Petri’s series, compared with 72% in our series. (In our patients, almost all fetal deaths were associated with antiphospholipid antibody.) The impli- cation of this difference is that Petri and coworkers’ patients were referred because of concerns related to the mother (prior or present disease activity) and ours because of concerns related to the fetus (prior fetal losses), a point which would favor identification of flare in their series. It is also likely that the average duration of pregnancy in our series was shorter, though calculating flares per month at risk should control for this.

As Petri and colleagues noted, more than 40% of their patients were black, whereas - 10% of our patients were black. They conclude that this difference is unimpor- tant, but I am less certain.

Finally, Petri et a1 identified proteinuria (with micro- hematuria) with normal complement and anti-DNA antibody levels as renal flare rather than as toxemia, and third- trimester thrombocytopenia as hematologic flare. These specific decisions are judgment calls, a fact that led us to calculate flare rates both including and excluding late pro- teinuria and late thrombocytopenia.

It is not my intent to suggest that the truth lies either with Petri’s conclusions or with ours, but rather to indicate that, in SLE, variations in the definition of flare and in patient acquisition are sufficiently broad and important that they can lead to diametrically opposed conclusions from apparently similar studies. Writers and readers of reports of clinical studies must understand this before they infer a biologic principle from the observations described.

Michael D. Lockshin, MD NIH Bethesda, MD

1. Petri M, Howard D, Repke J: Frequency of lupus flare in pregnancy: the Hopkins Lupus Pregnancy Center experience. Arthritis Rheum 34:1538-1545, 1991

2. Lockshin MD, Reinitz E, Druzin ML, Munman M, Estes D: Lupus pregnancy: case-control prospective study demonstrating absence of lupus exacerbation during or after pregnancy. Am J Med 77:893-898. 1984

3. Lockshin MD: Pregnancy does not cause systemic lupus erythe- matosus to worsen. Arthritis Rheum 32:665470, 1989

Reply To the Editor:

We agree with Dr. Lockshin that differences in patient selection and definitions may partly explain the differing conclusions of our study on SLE flare rates during pregnancy and of his studies (1-3). We also agree that the appropriate exercise in comparing our study with his is not to decide which is correct and which is wrong, but to dissect