Annals of the Rheumatic Diseases 1994; 53: 450-454

Immunohistochemical markers for arthritis inpsoriasis

D J Veale, L Barnes, S Rogers, 0 FitzGerald

AbstractObjectives-To examine the immuno-histological features in the involved skin ofpatients with psoriatic arthritis (PA)(n = 15), compared with those in involvedskin from patients with psoriasis but noarthritis (n = 5), and with a group withnormal skin (n = 4), to identify markersfor arthritis in psoriasis.Methods-Skin was obtained frompatients by 6 mm punch biopsy andnormal skin was provided by the depart-ment of plastic surgery. Samples werestained with monoclonal antibodiesagainst T cells (CD3, CD8, CD4,CD45Ro), B cells (CD20), macrophages(mac387), vascular endothelium (FVIII-related antigen) and a Langerhan's cellmarker (pl55). The number of cells/vessels staining with each monoclonalantibody was calculated and serialsections ofskin were examined to estimatethe presence ofDR +keratinocytes.Results-There were significantly moreCD45Ro T-cells and blood vessels inpatients with psoriatic arthritis comparedwith both psoriasis alone, and with normalcontrols (p<002). While B-cells were notseen in psoriasis without arthritis or innormal skin, a small but significantnumber were observed in PA (p<002).Furthermore, while DR + keratinocyteswere present in both psoriatic arthritisand psoriasis skin, there were significantlymore DR + cells in the psoriatic arthritisepidermis compared with psoriasis alone(p<002).Conclusions-This study suggests thatincreased numbers of CD45Ro T-cells,greater vascularity, the presence ofB-cells, and increased numbers of DR +epidermal cells are markers for arthritisin patients with sporiasis.

(Ann Rheum Dis 1994; 53: 450-454)

Psoriasis (Ps) is a common, chronic,inflammatory skin disorder which affects 2-3%of the population in Northern Europe.' A sub-group of between 5-7%/o of these patients willhave an associated inflammatory arthritis.23The reasons for this are not clear and indeedit is not possible to predict which patients willdevelop an arthritis.

Immunohistological studies in Ps havedemonstrated a number of characteristicfindings: inflammatory cells, predominantly T

lymphocytes, accumulate in the skin,4-6 thereare prominent microvascular changes7 8 andkeratinocytes (KCs) become highly acti-vated.9'-" The activated T lymphocyte expres-ses the antigen CD45Ro+, the class II MHCantigen HIA-DR+ and receptors all of whichare important molecules in the recognition andbinding of antigen peptide.'2 Cell surfacemarkers, including adhesion molecules such asintercellular *adhesion molecule (ICAM-1),play important roles in cell-cell recognition,binding and communication necessary in theimmune response.'3 In contrast to thepreviously perceived role of KCs as beinguninvolved in the inflammatory process, it isnow known that they produce a number ofpro-inflammatory cytokines and that they mayexpress both MHC class II HLA-DR antigensas well as ICAM-1.1° " Furthermore, it hasbeen suggested that the presence ofHIA-DR+keratinocytes may be a marker for arthritis inpsoriasis. 14

In this study, a quantitative immuno-histological examination of the involved skinfrom patients with psoriatic arthritis (PA) wasundertaken. Results were compared with skinobtained from patients with psoriasis but noarthritis (Ps) and with normal control skin toidentify markers for arthritis in psoriasis.

Materials and methodsPATIENT POPULATIONPatients with Ps and PA were recruited fromoutpatient clinics and as inpatients from thewards of the dermatology and the rheuma-tology services of the City of Dublin Skin andCancer Hospital, Beaumont Hospital and StVincent's Hospital, Dublin. This ensured thatpatients with a spectrum of mild to severe skinand joint disease were included in the study.Patients were required to satisfy the criteria ofMoll and Wright for the diagnosis of PA;'5however, patients with a rheumatoid factortitre greater than 1:80 were excluded from thestudy. Patients who had taken disease-modifying antirheumatic drugs or undergonepsoriasis therapy within the three monthsbefore assessment were excluded. All patientsgave their informed consent, and the study hadthe approval of the Ethics Committees of allthree hospitals.

Skin biopsies were obtained from 15 patientswith PA. There were eight females and themean (range) age was 50 years (21-75). Themean (range) disease duration of psoriasis was15 years (0-25-50) and of arthritis was sevenyears (0-25-24). All patients had psoriasis

St Vincent's Hospital,Dublin, Department ofRheumatologyD J Veale0 FitzGeraldDepartment ofDermatologyS Rogers*The City ofDublinSkin Cancer Hospital,*Dublin, IrelandL BarnesCorrespondence to:Dr 0 FitzGerald,St Vincent's Hospital, ElmPark, Dublin 4, Ireland.

Accepted for publication7 March 1994

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Immunohistochemical markers for arthritis in psoriasis

vulgaris, eight had an asymmetric oligoarthritisand seven had a symmetrical polyarthritis. Skinbiopsies were also obtained from five patientswith psoriasis but no arthritis (Ps) and fromfour normal control subjects. Extent andseverity of psoriasis was evaluated in thepercentage of skin involved using the rule of 9s.The median (range) in the PA group was 18%(9-72) and in the Ps group was 18% (9-63)demonstrating that no significant differenceexisted in the skin disease between the twogroups. Skin biopsies were obtained before thestart of treatment of the skin disease.

CLINICAL ASSESSMENT

All patients were assessed by the samephysician (DV). A full history was takenincluding previous therapy as an outpatient orinpatient. The distribution and percentage ofskin involved by psoriasis was recorded and thepresence of nail dystrophy and pattern of jointinvolvement was noted.

TECHNIQUE OF SKIN BIOPSY

Punch biopsy specimens, 6 mm in diameter,were obtained from the edge of a psoriaticplaque using local anaesthesia with 2%lignocaine. Normal control skin was providedby the department of plastic surgery frompatients undergoing split skin grafts.

TISSUE PREPARATIONThe biopsies were divided into two pieces, oneof which was placed on sephadex and snapfrozen in liquid nitrogen. Sections 5 ,um thickwere then cut from the frozen specimens andplaced on glass slides. Several sections fromeach biopsy were placed on each slide to obtaina representative assessment. They were driedat room temperature overnight, wrapped intin-foil and then stored at -70°C untilprocessed. The remaining biopsy tissue wasfixed in formalin and embedded in paraffin forhaematoxylin and eosin, plasma cell and mastcell staining. Plasma cells were demonstratedusing methyl green pyronin (MGP) stain andmast cells with a uronitrate metachromaticstaining method.

IMMUNOHISTOCHEMICAL STAINING TECHNIQUETissue sections stored at -70°C were allowedto thaw at room temperature before beingunwrapped. The sections were then fixed inacetone for 10 minutes before staining. Themonoclonal antibodies used are showntogether with their respective antigens andspecificities in table 1.A standard three-stage immunoperoxidase

labelling technique utilising avidin-biotin-immunoperoxidase complex (ABC)'6 wasemployed. Colour was developed byimmersing the slides in a solution of 0.05%/o(weight/volume) 3,3'-diaminobenzidine tetra-hydrochloride (Sigma, St Louis, MO) and0.0030/o hydrogen peroxide in 0-05 M Tris-0-15 M NaCl buffer, pH 7-4. Staining of serial

Table 1 Monoclonal antibodies: source, antigen recognisedand respective specificity

Monoclonal Source Antigen SpecificityAntibody

T3 DAKO CD3 All T cellsT4 DAKO CD4 Helper T cellsT8 DAKO CD8 Suppressor/

cytotoxic T cellsUCHLI DAKO CD45Ro Memory T cellsMac 387 DAKO Li MonocytesLeu-M3 BD CDl4 MonocytesL26 DAKO CD20 B cellsHLA-DR DAKO Class II B cells/

Activated T cellsFVIII-Rag DAKO FVIII-Rag Endothelial cellsp155 * Unknown Monocytes/

Langerhans cells

Dako = Dakopatts (Cophenhagen, DK), BD = Becton-Dickinson (Sunnyvale, CA, USA), *gift from Dr Alex Whelan.

sections of skin was undertaken using anti-HLA-DR, anti-CD3 and the monoclonal p155which recognises monocyte-derived phagocyticcells'7 such as dendritic Langerhan's cells. Apatient was considered to have HLA-DR+keratinocytes if cells were HLA-DR+ andCD3/p l 55 negative.

Tonsillar tissue was used for immuno-histological controls; the positive controls wereprocessed in exactly the same way as the skinand the primary antibody was replaced by PBSfor the negative controls.

MICROSCOPIC EVALUATION

All sections of tissue were examined under400 x magnification using a Leitz Dialux 20microscope by DV. The total number of cellswas counted for each monoclonal using a 1mm Indx graticule (Graticules Ltd, Tonbridge,Kent, UK) and the number of blood vesselswas counted per high power field. The numberof cells and blood vessels per mm2 of tissue wasthen calculated. Only sections in which boththe epidermis and the dermis were identifiedwere assessed. A coefficient of variation of lessthan 8&80% was obtained for the quantificationof cell types and blood vessels.

STATISTICAL ANALYSIS

Differences between the mean number of cellsand vessels in the tissues were assessed usingthe Wilcoxon signed rank test. Correlationswere calculated using Spearman rankcoefficient of correlation.

ResultsINCREASED B-CELLS IN THE INFILTRATE OF

PATIENTS WITH PA

There was a B-cell infiltrate demonstrated inthe dermis of 14 of the 15 patients with PA. Inone patient, B-cells were identified infiltratingthe epidermis from a dermal papillae (fig 1).No B-cells were present in the dermis in fourout of five controls with Ps or in any of thecontrols with normal skin. A small number ofB-cells was present in the skin biopsy of onepatient with Ps. The mean (SE) number ofcells per mm2 of B-cells in the dermal infiltratewas significantly greater in PA compared withPs and with normal controls [15-9 (4 3) v 1 5

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Table 2 Relationship between the presence ofdermalB-cells and arthritis

Patients (n) B-cell infiltrate in involved skinpresent absent

PA(15) 14t 1Ps (5) 1 4Normal (4) 0 4

tp=0-02.

r am*- 'O X.

Figure 1 Section ofinvolved skin from a patient with psoriatic arthritis showing CD20 Bcells infiltrating the epidermis from the dermal papillae. (Original magnification X 400).

Figure 2 Section of involved skinfrom a patient with psoriatic arthritis showing CD4 + Tcells infiltrating the epidermis and dermis. (Original magnification x 250).

(1.4); p = 002]. The relationship between thepresence of B-cells in the dermal infiltrate andarthritis is shown in table 2. Finally, using theplasma cell marker MGP, an occasional plasmacell was demonstrated in the dermal infiltratein patients with PA while no plasma cells werenoted in Ps or in the normal controlspecimens.

INCREASED CD45Ro T-CELLS IN PA

T-cells, as demonstrated by the CD3 marker,were the most abundant inflammatory cells inthe dermal infiltrate of both Ps and PA. Mostof these cells were also CD4+ (fig 2) andCD45Ro+ indicating that they were memoryT-cells. In comparison to Ps, the patients withPA had significantly more CD45Ro T cells/mm2 [mean (SE), 396-6 (176-4) v 161-5(37-6); p =0O02]. Most of the remainingmononuclear cells were monocyte/macrophagein origin as they stained positive with the

Table 3 Epidermal HLA-DR+ cells in PA, Ps andnormal controls

Patients (total No) Epidermal HLA-DR+ cellsCelWmm2 (SE)

PA(15) 161-7 (25.7)*Ps (5) 90 9 (18)Normal (4) 149-2 (41-8)

*p= 0-02 PA vs Ps.

Mac387, p155 and CD14 monoclonal anti-bodies. There was no significant difference inthe number of monocytes between psoriaticpatients with and without arthritis.

HLA-DR+ KERATINOCYTES OCCUR BOTH IN PAAND IN PS

While there were significantly more HLA-DR + cells/mm2 in PA epidermis comparedwith Ps [161.7 (25.7) v 909 (18); p = 002),there was no significant difference in thenumber of HLA-DR+ cells/mm2 in PAepidermis compared with the normal controls(table 3). To assess which epidermal cells wereHLA-DR+, serial sections of skin from threepatients with PA and three controls with Pswere examined using a marker for HLA-DR,CD3 and the Langerhan's cell marker p 155.HLA-DR+ cells which were negative for CD3and p155 and thus consistent with kera-tinocytes were demonstrated in the epidermisfrom involved skin in patients with PA (fig 3)as well as in patients with Ps (fig 4).

VASCULARITY IN PA AND PS

The number of blood vessels was assessed inall sections of skin and the mean number ofvessels per mm2 of tissue calculated. Therewere significantly more blood vessels in PA andPs skin compared with normal controls [PA:112 (17), Ps: 77 (18), Controls: 51 (7);p=0 02]. The number of vessels in thepatients with PA tended to be greater than inPs although the difference did not reachstatistical significance.

DiscussionIn this study, a small but significant number ofB cells was demonstrated in the involved skinof 14/15 patients with PA. In contrast, no Bcells were found in 4/5 patients with Ps or in4/4 normal control skin specimens. WhileCD4 + CD45Ro+ T-cells accounted for themajority of cells in the dermal infiltrate in bothPA and Ps, there were significantly greaternumbers of activated T cells in PA skincompared to Ps and to normal controls.

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Figure 3 Serial sections of involved skin from a patientwith psoriatic arthritis stained with monoclonal antibodiesto show (A) HLA-DR+ cells, (B) Langerhan's cells and(C) CD3 T cells. In (A) there are numerous cells in theepidermis staining positive for HLA-DR (arrows), whichare p15S5 and CD3 negative (B and C). The staining ofLangerhan 's cells in (B) is concentrated at the dermo-epidermaljunction. TceUls stained with CD3 in (C) arescattered throughout the dermis and epidermis. Epidermalcells staining DR+ and negative with p155 and CD3 areDR+ keratinocytes. (Original magnification x 400).

Furthermore, in a subgroup of patients inwhich serial sections of skin were examined,HLA-DR+ keratinocytes were identified in theepidermis of psoriasis patients with or withoutarthritis. Finally, the number of dermal bloodvessels was significantly increased in both PAand Ps patients compared with controls.The finding of a sparse B cell infiltrate with

some plasma cells in PA skin is interesting.Psoriasis is not generally associated with B cellhyperactivity although autoantibody pro-duction has been reported.'8 19 Indeed, PA ischaracterised by the absence of rheumatoidfactor in the serum helping to distinguish thecondition from rheumatoid arthritis (RA).However, B cells with plasma cells areabundant in PA synovium where they mayform focal infiltrates similar to those seen inRA.20 Thus B cells do appear to play a role inPA and further studies of B cell function couldprove rewarding.

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Figure 4 Serial sections of involved skinfrom a patientwith psoriasis but no arthritis stained with monoclonalantibodies to show (A) HLA-DR+ cels, (B) Langerhan'scells and (C) CD3 T cells. In (A) there are numerous cellsin the epidermis staining positiveforHLA-DR (arrows),which are p155 and CD3 negative (B and C). AgainLangerhan 's cels are staining predominantly at the dermo-epidermaljunction and T cels are scattered throughout thedermis and epidermis. (Original magnification x 250).

T cells, predominantly T helper (CD4+)cells, have previously been described torepresent the majority of the cells in the dermalinfiltrate in pS4 14 and may persist in thechronic psoriatic plaque.6 Many T cells inpsoriatic skin express the class II HIA-DRantigen and these cells have been shown toincrease in the dermis and infiltrate theepidermis during early development of apsoriatic lesion.5 Further evidence for T cellinvolvement in the pathogenesis of psoriasis issuggested by the observations that cyclosporinA, a drug which inhibits T cell activation, maylead to remission of the skin disease2' andclearance of severe psoriasis has been describedafter allogenic bone marrow transplantation.22In the present study, the findings confirmprevious reports of a predominant T cellinfiltrate, these cells expressing the HLA-DRand CD45Ro antigens indicating that they arememory T cells in a post-activation state.Greater numbers of CD4 + CD45Ro+ T cellsare seen in PA skin compared with Ps and this

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44eale, Barnes, Rogers, FitzGerald

may reflect the intensity of adhesion moleculeexpression as both vascular cell adhesionmolecule (VCAM)- 1 and endothelial leucocyteadhesion molecule (ELAM)-1 appear to bindmemory T cells preferentially23 and the latteris known to be up-regulated in psoriatic skin.24

Langerhan's cells are found in normal skinforming a close network of interdigitating cellsin the stratum Malpighii. It was initiallysuggested that the number of Langerhan's cellswas increased in psoriasis.5 4 However, a

number of studies have now shown a reductionin overall number and an altered distributionpattern of epidermal Langerhan's cells inpsoriasis. It has been suggested that thesecells now migrate to the dermo-epidermaljunction.-6 More recently, it has been sug-

gested that there is a marked increase in thefrequency of PA in psoriasis patients whosekeratinocytes express HLA-DR antigen,identified as epidermal cells staining with a

monoclonal for HLA-DR but not for OKT6.14

The possibility that some of these cells mightrepresent activated T cells or B cells was notconsidered. Previous studies have demon-strated that the presence of HLA-DR+ kera-tinocytes is by no means specific topsoriasis11 14 ' being found in a number ofother dermatoses including lymphocytic vascu-

litis, lupus erythematosus, morphea and many

more. In this study, HLA-DR+ keratinocytesare seen in patients both with PA and Psalthough more abundant in those with PA.Thus the association of DR+ keratinocyteswith PA is quantitative and not absolute as

previously suggested.Vascular abnormalities have been described

in both the skin and synovium in psoriasis.Braverman extensively examined the micro-circulation in psoriatic skin and describedprolongation and dilatation of the dermalcapillary loops.7 In addition, ultrastructuralabnormalities in the blood vessels were seen on

electron microscopy with the development ofvenous-like capillaries with bridged fenes-trations.' Similar changes in vascularity havebeen described in the synovial membrane inPA.28 These studies, however have not beenquantitative and a comparison of thevascularity of PA and Ps skin has not beenpreviously undertaken. In this study, psoriaticskin is shown to be more vascular comparedwith control specimens with a trend towardsmore blood vessels in the skin from PA subjectscompared with those with psoriasis alone.

In conclusion, the present study has iden-tified quantitative immunohistochemicaldifferences in the skin from patients with PAcompared with skin from patients withpsoriasis alone. It is suggested that thepresence of a B-lymphocytic infiltrate,increased CD45Ro T-lymphocytes andincreased HLA-DR + keratinocytes are indi-cators of a more active inflammatory process

and act as markers for arthritis in psoriasis.

This study was funded by a grant from The CharitableInfirmary Charitable Trust.

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