1540 LETTERS

The distinction between vasculitis coincidental with and one that is causally related to the antiphospholipid syndrome

To the Editor: I read with interest the case report by Goldberger et

al, entitled “Vasculitis in the Antiphospholipid Syndrome” ( I ) . If I read the case report correctly, the authors described the occurrence of inflammatory vasculitis (incidentally, all vasculitides are, by definition, “inflammatory”) of large (anterior tibialis artery) and small (arterioles in muscle) arteries which (the vasculitis) they (the authors) attributed to the antiphospholipid (aPL) syndrome.

Judging by the photomicrographic illustrations shown in the case report, the small-vessel vasculitis (au- thors’ Figure 3) is convincing, but the purported large-vessel vasculitis (authors’ Figure 1) is not. Not all blood vessels with pcrivascular lymphocytic infiltrates signify vasculitis (2,3), especially when the patient was an elderly diabetic “with atherosclerotic peripheral vascular disease” ( I ) . More important is the authors’ implication that the vasculitis observed was causally related to the aPL syndrome, which remains unproven. On the other hand, the patient, as de- scribed, appeared to have systemic lupus erythematosus (SLE), and large- and small-vessel vasculitis associated with SLE is well known (4-6).

To avoid confusion and to avoid creating or perpe- trating a misconception, one should scrupulously recognize the distinction between vasculitis coincidental with and one that is causally related to the aPL syndrome. There may have been SLE or non-SLE patients who exhibited vasculi- tis coincidental with serologic evidence of aPL syndrome, but to date, there has been no convincing and documented evidence (patients in whom histopathologic features of vas- cular lesions were described and illustrated with sufficient clarity) that true vasculitis is a manifestation of aPL syn- drome. On the contrary, all available evidence still points to arterial and venous thrombosis as the pathologic basis of vasculopathy in primary and secondary aPL syndromes (4,7,8). The’latest case report by Goldberger et al (I), despite its implication, has not changed that premise.

J. T. Lie, MD, FACR University of California

Davis Medical Center Sacramento, CA

1. Goldberger E, Elder RC, Schwartz RA, Phillips PE: Vasculitis in the antiphospholipid syndrome: a cause of ischemia responding to corticosteroids. Arthritis Rheum 35569-572, 1992

2. Schwartz CJ, Mitchell JRA: Cellular infiltration of the human arterial adventitia associated with atheromatous plaques. Circu- lation 26:73-78, 1962

3. Lie JT: Inflammatory aneurysm of the aorta or chronic periaor- titis: a nosologic quandary. Cardiovasc Pathol 1:75-79, 1992

4. Lie JT: Vasculopathy in the antiphospholipid syndrome: throm- bosis or vasculitis, or both? J Rheumatol 16:713-715, 1989

5. Lie JT: Pathology of vascular lesions in systemic lupus erythe- matosus. Lupus 1 (suppl 1):35, 1992

6. Igarashi T, Nagaoka S, Matsunaga K, Katoh K, Ishigatsubo Y, Tani K, Okubo T, Lie JT: Aortitis syndrome (Takayasu’s arteri- tis) associated with SLE. J Rheumatol 16:1579-1583, 1989

7. Grob JJ, Bonerandi JJ: Cutaneous manifestations associated with the presence of lupus anticoagulant: a report of two cases and a review of the literature. J Am Acad Dermatol 15:211-219, 1986

8. March-Segovia D, Cardiel MH, Reyes E: Antiphospholipid arterial vasculopathy. J Rheumatol 16:762-767, 1989

Reply To the Editor:

We agree with Dr. Lie that care must be taken in ascribing clinical events to serologic abnormalities. The large-vessel vasculitis shown in our case report (Figures 1 and 2) consists of transmural inflammation and internal elastic lamina disruption. This is unlikely to be due to atherosclerotic disease in which inflammation is confined to the adventitia of large blood vessels.

While our patient had antinuclear antibodies and a false-positive VDRL, she exhibited no other clinical or laboratory criteria for the diagnosis of SLE.

More important than the nosologic distinction of whether this patient did or did not have SLE is that histo- logic and laboratory evidence of vasculitis was demonstrated in this patient with the aPL syndrome. This is the likely reason that high-dose corticosteroid therapy was followed by wound healing, while previous attempts at anticoagula- tion had led to progressive amputations.

Edward Goldberger, MD Rachel C. Elder, MD Robert A. Schwartz, MD Paul E. Phillips, MD, FACP, FACR State University of New York

Syracuse, NY Health Science Center

Synovial vascularity is increased in rheumatoid arthritis: comment on the article by Stevens et al

To the Editor: We read with interest the recent paper by Stevens et

al, in which a detailed morphometric comparison is made of the synovial microvasculature in normal subjects and in patients with chronic rheumatoid arthritis (RA) (1). Contrary to standard rheumatology teaching, the authors report that capillaries were distributed more deeply in rheumatoid syn- ovium and were significantly less densely arranged. We have recently published the results of a similar morphometric study, the conclusions of which are quite different (2). Using anti-Factor VIII-related antigen-stained synovial mem- brane biopsy specimens from patients with RA (n = 9) within 3 years of disease onset who were not taking any disease- modifying drugs, the number of blood vessels per square millimeter was significantly increased compared with control samples obtained postmortem (n = 13). Similar results were also obtained in patients with advanced disease requiring knee arthroplasty (3).

There are a number of features which may explain these differing results. First, Stevens et a1 examined 7

LETTERS 1541

synovial membrane specimens, all obtained from patients undergoing knee arthroplasty. While it is stated that all specimens showed active disease, granulation tissue was not an obvious feature, and plasma cells and occasional poly- morphonuclear neutrophil infiltrations only were observed. These histopathologic features are not typical of the synovial membrane at arthroplasty, which shows focal mononuclear cell infiltrates, predominantly CD4+, CD45RO+ T cells, in >80% (4).

Second, while the use of the biotinylated lectin, Ulex europaeus agglutinin I (UEA-I), an accepted marker for endothelial cells, is mentioned in the methodology section, it is not clear whether UEA-I was used in calculating the capillary density. We believe that the use of an endothelial cell marker is of importance in trying to estimate membrane vascularity. As is shown by Figure 2 in our article ( 2 ) , in inflamed synovial tissues it is often difficult to identify blood vessels when they are surrounded by a cellular infiltrate. Thus, the failure to use a specific marker could lead to an underestimation of capillary density.

Finally, Stevens et a1 counted only capillaries from the joint space to the subsynovial margin. In the control specimens, the subsynovial margin was taken to be the region in which cellularity declined sharply and connective tissue predominated. In rheumatoid specimens, this bound- ary was less clearly defined, and capillaries within an arbi- trary 350 pm were counted. In contrast, all vessels within 150 pm of the joint surface were counted in our study, both in the rheumatoid and control specimens. We believe that this method results in a more accurate comparison, and that inclusion of vessels other than capillaries reflects vascular proliferation as a whole, and not just what is happening in the exchange capillary bed.

Rheumatoid synovial membrane obtained from pa- tients with untreated or with advanced disease is signifi- cantly more vascular than that of normal subjects. An anatomic basis for chronic hypoxia in end-stage rheumatoid synovium is not supported.

Oliver FitzGerald, MD Barry Bresnihan, MD St. Vincent’s Hospital Dublin. Ireland

1. Stevens CR, Blake DR, Merry P, Revell PA, Levick JR: A comparative study by morphometry of the microvasculature in normal and rheumatoid synovium. Arthritis Rheum 34: 1508- 1513, 1991

2. FitzGerald 0, Soden M, Yanni G , Robinson R, Bresnihan B: Morphometric analysis of blood vessels in synovial membranes obtained from clinically affected and unaffected knee joints of patients with rheumatoid arthritis. Ann Rheum Dis 50:792-796, 1991

3. Yanni G, Whelan A, Feighery C, FitzGerald 0, Bresnihan B: Examination of synovial vascular endothelium in untreated and advanced rheumatoid arthritis (abstract). Br J Rheumatol 30 (suppl 1):7, 1991

4. Yanni G, Whelan A, Feighery C, Bresnihan B: Analysis of cell populations in rheumatoid arthritis synovial tissue. Semin Arthri- tis Rheum 21:393-399, 1992

Synovial vascularity is decreased in rheumatoid arthritis: reply

To the Editor: As Drs. FitzGerald and Bresnihan quite rightly point

out, their study is very different from our study. First, the specimens they used for the assessment of vascularity were from arthroscopic biopsies of early RA, whereas the speci- mens we used were from synovium removed at joint replace- ment surgery. That the specimens used in our study were not typical of the synovial membrane at arthroplasty is, I as- sume, based on our brief description of the histopathologic features. Since it was not the purpose of that study to describe the rheumatoid synovium, our histopathologic de- scription was not comprehensive. We are certainly not suggesting that plasma cell and polymorphonuclear infil- trates were the only features observed; in fact, focal mono- nuclear cell infiltrates were among the many other charac- teristic features of the rheumatoid synovium specimens at arthroplasty .

As for their second point, endothelial cell staining was used in calculating the capillary density. As stated in the methodology section, under “Preparation of synovial tissue,” “Paraffin-embedded sections were used with endothelial cell staining to obtain data on capillary spatial distribution. ”

As can be seen from Figure 2 of our study, the frequency distribution histogram of capillary depths, all capillaries within an arbitrary 350 pm from the surface in both normal and rheumatoid synovial specimens were cata- loged. This was done irrespective of whether the capillaries occurred within the synovium or the deeper subsynovial tissue. Capillary density was calculated only within what for each group was considered to be synovium (by the criteria described). In the control group, the mean thickness of the synovium was less than 60 pm, and the capillary density for normal specimens includes only those capillaries observed in this functionally important region. The capillary density for rheumatoid specimens was likewise calculated, but the thickness of the area evaluated varied considerably.

It is important to note, however, that vascularity declines sharply between the synovium and the subsyn- ovium (i.e., deeper than 60 pm) in normal tissues. Capillaries occurring outside this region will have negligible effect on the perfusion of the synovial fluid or peripheral regions of the synovium. Thus, FitzGerald et al’s having counted all vessels to a depth of 150 pm (including venules) in their density assessment of both normal and rheumatoid vasculature results in flawed data. No doubt in this selected depth band, rheumatoid synovium does appear more vascular than nor- mal; however, this only reflects the effect of including a large amount of relatively poorly vascularized subsynovial tissue in the density measurement of normal synovium.

To reiterate, it is clear from our study that the region of inflamed synovium which approximates the functionally important normal synovial membrane region (i.e., to a depth of 60 pm) is poorly vascularized. This, I still maintain, supplies an anatomic basis for chronic hypoxia in end-stage rheumatoid synovium.

Cliff Stevens, PhD London Hospital Medical College Whitechapel, London, UK