Clinical associations of antiribonucleoprotein antibodies in patients with systemic lupus erythematosus

Clinical Associations of Antiribonucleoprotein Antibodies in Patients With Systemic Lupus Erythematosus

By Evert J. ter Borg, Henk Groen. Gerda How, Pieter C. Limburg.

Aaktje A. Wouda, and Cees G.M. Kallenberg

The authors undertook a cross-sectional study

to investigate the clinical associations of antiri-

bonucleoprotein (anti-RNP) antibodies in 49

patients with systemic lupus erythematosus

(SLE) without other concomitant connective

tissue disorders. The traditional counterimmu-

noelectropheresis (CIE) and the immunoblot-

ting (IB) technique were compared. Clinically,

special attention was given to the identification

of sclerodermalike features. All patients com-

pleted a detailed questionnaire, physical exami-

nation, and additional investigations including

pulmonary function tests, chest roentgeno-

gram, radionuclide transit studies of the esoph-

agus, and nailfold capillary microscopy. Pulmo-

nary function testing and radionuclide transit

studies of the esophagus were very sensitive

for the detection of (subclinical) pulmonary and

esophageal involvement, respectively. Within

the relatively homogeneous SLE population, a

subset was recognized that was characterized

clinically by the presence of sclerodermalike

features such as Raynaud’s phenomenon, scle-

rodactyly, interstitial changes on chest roent-

genogram, and decreased numbers of nailfold

capillary loops, and serologically by the pres-

ence of anti-RNP antibodies. IB was somewhat

more sensitive than CIE for the detection of

anti-RNP (anti-Sm/anti-nRNP) antibodies but

From the Department of Internal Medicine, Divisions of Rheumatology, Clinical Immunology, Pulmonologv, and Vascular Diseases, University Hospital, Groningen. The Netherlands.

Supported by grant 87/CR/64 of the Dutch Foundation Against Rheumatism.

Evert J. ter Borg, MD: Department of Internal Medicine, Divisions of Rheumatology and Clinical Immunology; Henk Groen, MD: Department of Internal Medicine, Divisions of Clinical Immunology and Pulmonology; Gerda Horst; De- partment of Internal Medicine; Division of Clinical Immunol- ogy; Pieter C. Limburg, PhD: Department of Internal Medi- cine, Division of Rheumatology; Aaktje A. Wouda, MD:

Department of Internal Medicine, Division of Vascular Diseases; Cees G.M. Kallenberg, MD, PhD: Department of Internal Medicine, Division of Clinical Immunology.

Address reprint requests to E.J. ter Borg, MD, Rheumatol- ogist, Hospital Rijnstate DH, Lawick van Pabststraat 72, 6814 HK Arnhem, The Netherlands.

o 1990 by W.B. Saunders Company. 0049-0172/90/2003-0003$5.00/0

did not identify other clinical associations. Thus,

anti-RNP antibodies in SLE are associated with

scleroderma-associated features. For clinical

practice, CIE is the technique recommended for

their detection.

@ 1990 by W. 6. Saunders Company.

INDEX WORDS: SLE; antinuclear antibodies; antiribonucleoprotein antibodies; autoantibodies.

S YSTEMIC lupus erythematosus (SLE) is characterized by the occurrence of a variety

of autoantibodies directed to cellular antigens such as DNA, RNA, and RNA-protein complexes.’ Anti-double stranded DNA (anti- dsDNA) antibodies are rather specific for SLE and are observed at a high frequency (75% to 95%) in lupus patients with active disease.’ Anti-Sm antibodies are the autoantibodies most

specific for SLE, but they are found at a relatively low frequency (20% to 40%).lW3 Antiribonu- cleoprotein (anti-nRNP) (also referred to as anti-(Ul)RNP) antibodies are associated with mixed connective tissue disease (MCTD)4 but can also, in lower titers, be detected in SLE (30% to 40%) .‘,5 Anti-Sm antibodies almost invariably are accompanied by anti-nRNP antibodies whereas anti-nRNP antibodies may occur without anti-Sm.’ Antibodies to the SSA and SSB antigens are associated with Sjbgren’s syndrome primarily, but also may occur in SLE (preva-

lence 30% and 15%, respectively).’ Anti-Sm antibodies precipitate uridine-rich

(U) small nuclear (sn)RNAs, in particular Ul, U2, and U4-6, whereas anti-nRNP sera precipitate Ul snRNA only.6 The U snRNAs are complexed with a number of polypeptides desig- nated as 70kd and A to G proteins.’ Anti-Sm, in particular, reacts with BB’ and D, while anti- nRNP reacts with 70kd, A and C polypeptides. Anti-Sm and anti-nRNP antibodies are tradition- ally detected by immunodiffusion (ID), passive hemagglutination (PHA) or counterimmunoelec- tropheresis (CIE). However, these methods do not accurately distinguish between antibodies against different snRNA associated polypep-

164 Seminars in Arthritis and Rheumatism, Vol20, No 3 (December), 1990: pp 164- 173

ANTI-RNP ANTIBODIES IN SLE 165

tides. Reactivities with the individual RNAs and

polypeptides can be demonstrated by the RNA- immunoprecipitation (RNA-IP)6 and immunoblotting (IB)’ techniques, respectively. IB has been found to be more sensitive than the conventional methods for the detection of anti-SmgV9 and

anti-nRNP.’ While disease activity in SLE frequently corre-

lates with levels of distinct antinuclear antibodies

(ANAs), in particular anti-dsDNA”*” reports associating ANA specificities with particular disease characteristics are less conclusive.3”2-15 It is uncertain, for example, whether SLE patients with anti-Sm antibodies have higher or lower

incidences of central nervous system disease and renal disease.2*3~‘2,‘3 Anti-nNRP antibodies in

SLE have been associated with a relatively be- nign disease and a low incidence of renal disease.83’3,‘6 SLE patients with anti-dsDNA antibodies only were found to have a lower prevalence of pleuropericardial disease, myositis, and Raynaud’s phenomenon than those with anti-

nRNP antibodies only.‘6 The occurrence of anti- SSB antibodies in SLE has been associated with both increased’ and decreased” prevalences of

nephritis and with an increased frequency of rheumatoid factor (RF) positivity.18 In the pres-

ence of anti-SSA antibodies, an increased frequency of photosensitive skin disease, renal involvement, and RF positivity has been reported.” However, most of the aforementioned reports used conventional methods for detecting antibodies to ribonucleoproteins (anti-RNP antibodies) or have been performed in retrospect.

We initiated a cross-sectional study to investi-

gate whether the presence of anti-RNP antibodies in SLE is associated with particular clinical features, and compared the traditional CIE technique with the supposedly more sensitive IB technique. Special attention was given to the recognition of sclerodermalike features. All patients completed a detailed questionnaire, physical examination, and additional investigations including pulmonary function tests, radionuclide transit studies of the esophagus, and nailfold capillary microscopy.

MATERIALS AND METHODS

Patients

Fifty-eight unselected patients (44 women and 14 men), who agreed to participate in the study

and who fulfilled the revised ARA criteria for the diagnosis of SLE,*’ were included. At the time of study patients had no evidence of clinical disease activity or only minor (but stable) disease activ-

ity.

Diagnostic Criteria

Diagnosis of Raynaud’s phenomenon was based on a typical history of triphasic or biphasic symmetrical attacks of discoloration of the fin-

gers and/or toes on cold or emotional stimuli.*’ Systemic sclerosis, rheumatoid arthritis and

dermato/polymyositis were diagnosed according to previously published and well-accepted criteria.22-24 Definite MCTD was defined by the

criteria recently proposed by Sharp.25 CREST syndrome (subcutaneous calcinosis, Raynaud’s phenomenon, esophageal hypomotility, sclerodactyly, and teleangiectasia) was diagnosed when four out of the five characterizing criteria were present; all patients had subcutaneous calcinosis.*”

Study Design

Previous historical data, in particular the presence of the 1982 revised SLE ARA criteria,*’

were noted from the chart. All patients completed a detailed questionnaire and physical ex-

amination using a protocol emphasizing the symp- toms and features of connective tissue disorders. Clinical evaluation was performed without know-

ledge of the laboratory findings. All patients had roentgenograms of chest, hands, and feet, radionuclide transit studies of the esophagus, nailfold capillary microscopy, and pulmonary function testing. Laboratory investigations included: complete blood count, urinanalysis, serum creatinine,

serum creatine phosphokinase (CPK), immuno- globulin M-RF (IgM-RF), C3 and C4 levels. ANAs (titer and fluorescence pattern), anti-

dsDNA antibodies, and anti-RNP antibodies as assessed by CIE and IB.

Roentgenograms of chest, hands, and feet were performed according to routine procedures and judged by three observers without prior knowledge of clinical data. Chest roentgeno-

grams were examined for the presence of interstitial lung disease (reticular, nodular, or reticulo- nodular patterns). Roentgenograms of hands and feet were evaluated, in particular, for the presence of erosive changes, narrowing of joint spaces,

166 TER BORG ET AL

acroosteolysis, subcutaneous calcifications, and soft tissue loss of the finger tips.

Radionuclide transit studies of the esophagus

were performed according to routine procedures.

Hypomotility of the esophagus was considered when at least two of three swallowing actions were prolonged.

Nailfold capillary microscopy was performed as described previously.*’ For this study, the total

number of capillaries and the number of enlarged

loops per 5 mm (representative area), as well as the number of giant loops, bushy patterns, and

pearl necklaces of extravasates for the whole distal row of the nailfold capillary wall were

scored. Average values of the left and right

fourth finger (or the third finger if the photo- graph of the fourth finger was missing or could

not be evaluated) were used for statistical analy-

sis. Pulmonary function testing included slow in-

spiratory vital capacity (IVC), forced expiratory

volume in one second (FEV,), total lung capacity

(TLC), and diffusion capacity for carbon monox-

ide (DLCO). Pulmonary function tests were performed after acute pulmonary events had

subsided. IVC and FEV, were measured by a standard water sealed spirometer. TLC was ob- tained by helium dilution according to standard-

ized techniques. IVC, FEV,, and TLC were expressed in liters BTPS (body temperature,

pressure, saturation). FEV, was then expressed

as a percentage of IVC (FEV,/IVC) to adjust for restrictive pulmonary function loss. DLCO

was measured using the single breath technique of Krogh, as modified by Ogilvie and Cotes.”

DLCO was corrected for hemoglobin concentra-

tions to obtain DLCO values under standard conditions and was expressed in mmol/kPa/min. Pulmonary function test results were given as percentages of the predicted value. A pulmonary function test was considered abnormal when below 80% of the predicted value.

Complete blood count, urinanalysis, serum creatinine (normal value ~110 pmol/L) and serum CPK (normal value ~100 U/L) were measured according to routine procedures. IgM-RF (normal value t10 IU/mL) was measured by enzyme-linked immunosorbent assay (ELISA).29 C3 (normal value 0.64 to 1.20 g/L) and C4 (normal value 0.11 to 0.40 g/L) were measured by nephelometry.

ANAs and anti-ds DNA antibodies were deter-

mined by indirect immunofluorescence using hu-

man fetal fibroblasts3’ and Crithidia luciliae,3’ respectively, as a substrate. Serum was consid-

ered ANA positive when a serum dilution of 1:40

was positive. Fluorescence pattern was scored as

homogeneous, speckled (finely or coarsely), rim

or nucleolar. Serum was considered anti-dsDNA

positive when a serum dilution of 1:lO or more

was positive.

Antibodies to extractable nuclear antigens

(anti-ENA) were detected by CIE according to

Kurata and Tan3* using a crude extract from

rabbit thymus acetone powder (RTP; Pel Freeze,

Rogers, AR) as substrate and reference sera

showing identity with the corresponding Center

for Disease Control (CDC; Atlanta, GA) refer-

ences. Three reference sera were used: anti-Sm,

anti-(Ul)RNP and anti-SSB. Anti-SSA was

detected by CIE using human spleen extract as a

substrate. IB was performed with extracts from Hela cell

nuclei as a substrate. Hela cells were harvested at

400 g, washed with phosphate buffered saline

and resuspended in hypotonic buffer (10 mmol/L

Tris-HCl, pH 7.4, 10 mmol/L NaCl, 1.5 mmol/L MgCl,) at a concentration of 1 x 10’ cells/ml.

After swelling, cells were lysed using a Dounce

homogenizer. Nuclei were pelleted at 500 g,

resuspended in a second buffer (lOmmol/L Tris-

HCl, pH 7.4, 400 mmol/L NaCl, 1.5 mmol/L

MgCl,), sonificated four times for 15 seconds,

and centrifuged. The supernatant was put on gel

(extract of 4 x lo6 cells per cm of gel). All steps

were performed at 4°C and a mixture of protease

inhibitors was added throughout the procedure.

Proteins in the extract were separated according to their molecular weights on 12.5% SDS-PAA

gels and transferred electrophoretically onto ni-

trocellulose sheets. The blots were incubated

with the test sera (dilution 1:50) and the bound immunoglobulins were visualized by means of

peroxidase labeled anti-human IgG. Blots were read by two independent observers without knowl-

edge of the clinical data of the patients. For this study, only anti-Sm (BB’ and D) and anti- (Ul)RNP (70 kd, A and C) specific bands were

scored. Anti-Sm antibodies were considered in the presence of the D band with or without the BB’ band. Anti-(Ul)RNP antibodies were consid-

ANTI-RNP ANTIBODIES IN SLE

116- 97- 66- - 68K

45-

29-

21--

-A -Bb” =B

-- c

-D

Fig 1: Immunoblotting. Lane 1: negative control serum. Lane 2: reference serum consisting of anti-nRNP and anti-Sm positive sera. Lane 3: anti-Sm positive serum showing reactivity with BB’ and D proteins. Lane 4: anti-nRNP positive serum showing reactivity with 66 (70) kd, A and C proteins.

ered when the 70kd and/or the A and/or the C

band were present (Fig 1).

Statistical Analysis

Statistical analyses were performed with the

SPSS/PC + statistical package. Group compari- sons of continuous variables were performed with one way analysis of variance followed by Dun- can’s multiple range test. If necessary, the Mann- Whitney U-test was applied to nonparametri- tally distributed variables. Discontinuous variables were tested with x2 analysis. A P value of less than 0.05 (one sided) was considered

167

statistically significant. We also calculated 90% confidence intervals for the differences between

proportions and means.

RESULTS

Based on data from the previous and current history, physical examination, laboratory investigations, and additional studies, 9 of 58 (16%)

SLE patients fulfilled criteria for one or more additional diagnoses of a connective tissue disor-

der: systemic sclerosis (n = 3), and/or rheumatoid arthritis (n = 3), and/or polymyositis (n = 2), and/or definite MCTD (n = 3). These 9 patients were excluded from further analysis. None of the patients fulfilled criteria for dermatomyositis or CREST syndrome. The average age of the remaining 49 SLE patients (36 women

and 13 men) was 49 * 15 years (range 15 to 70 years). A diagnosis of SLE was made at an

average of 7 + 7 years (range 0.5 to 27 years) prior to the study.

Cumulative clinical characteristics at the start of the study according to the revised ARA SLE

criteria” are given in Table 1. Data on total

Table 1: Characteristics of SLE Patients Based on the Revised ARA Criteria

Number of Cases (%)

ARA Criteria Data Available Positive

Malar rash 49 16 (33)

Discoid rash 49 5 (10)

Photosensitivity 49 30 (6 1) Oral ulceration 49 12 (25)

Arthritis 49 29 (59)

Serositis 49 24 (49)

Pleuritis 49 18 (37)

Pericarditis 49 9 (18)

Renal disorder 49 26 (53)

Neurologic disorder 49 6 (12)

Hemolytic anemia 49 5 (10)

Leukopenia 49 37 (76)

Lymphopenia 39 22 (56)

Thrombocytopenia 49 19 (39)

Positive LE cell prepara-

tion 31 22 (7 7)

Anti-dsDNA antibodies 49 35 1711

Anti-Sm antibodies (CIE) 49 1 1.e (22)

False-positive serologic

test for syphilis 28 7 (25)

ANA 49 49 (100)

“In eight cases accompanied by anti-nRNP antibodies.

Data from reference 20.

168

lymphocyte counts were not evaluable in some

patients because they were already on corticosteroids at the time of referral to our hospital. In addition, in some cases LE cell and syphilis test

results are lacking as they are not routinely performed in our department.

Twenty-one patients (43%) used corticosteroids. Four patients used cytostatic agents, three of whom also used corticosteroids. Raynaud’s phenomenon was present in 26 of 49 patients (53%). Eight patients had swollen fingers (16%) and sclerodactyly was present in five cases. Four patients had dysphagia by history and three of these had an increased radionuclide transit time of the esophagus. Persistent dyspnea and/or

dyspnea on exertion was present in 12 cases. Chest roentgenograms showed interstitial ab-

normalities in 19 patients (39%). Nodular pat-

terns occurred most frequently. Interstitial abnormalities on chest roentgenograms were more frequently found in the patients with dyspnea (75%) compared with the patients without dyspnea (27%; P < .005; 90% confidence intervals

0.24 to 0.72). Roentgenograms of the hands and feet showed

ligamentous calcifications of the small finger

joints in six cases. Erosive changes, narrowing of joint spaces, acroosteolysis, subcutaneous calcifications, and loss of soft tissue of the finger tips were not observed. One patient had (nonerosive) deformities of the hands due to Jaccoud’s ar-

thropathy. Radionuclide transit time of the esophagus

was increased in 14 of 46 patients (30%). Only 3

of these 14 patients (2 1%) had dysphagia by history.

Nailfold capillary microscopy findings were evaluable in 42 patients. Mean (*SD) number of capillary loops per 5 mm was 38 + 6 loops (range 17 to 48). The average number of widened loops per 5 mm was 1.0 f 1.4 loops (range 0 to 6). Considering the whole distal row of the nailfold capillary wall, giant loops were observed in only 3

TER BORG ET AL

patients while bushy patterns and pearl necklaces of extravasates were seen in 12 and 11 patients, respectively.

Pulmonary function test results, expressed as percentage of the predicted value, are given in Table 2. DLCO and IVC were the pulmonary function variables most frequently decreased. The prevalence of one or more disturbed (~80% of the predicted value) pulmonary function test (n = 28) was much higher than the prevalence of dyspnea (n = 12). In Table 3, results of pulmonary function tests are compared for patients with (n = 19) and without (n = 30) interstitial abnormalities on chest roentgenogram. Values of IVC, TLC, and DLCO tended to be lower in the first group but the differences were not statistically significant.

Leukopenia (~4.0 x 109/1) and thrombocytopenia (cl00 x 109/1) were present in 11 and 5 cases, respectively. Fourteen patients had positive IgM-RF titers. Eight patients had increased

levels of serum creatinine (> 110 hmol/L) while levels of CPK were increased in three cases. Twenty-one and 13 cases had decreased levels of C3 and C4, respectively. Dip-stick method testing showed proteinuria in 16 patients. Microhe- maturia (>5 erythrocytes per high power field) and erythrocyte casts were observed in eight and

one cases, respectively. Forty-eight of 49 patients had a positive (21:

40) ANA test while anti-dsDNA was detected in

16 (33%) patients. Most patients had a homogeneous (n = 32, 65%) or coarsely speckled (n = 15, 31%) ANA pattern. One patient had a finely speckled pattern; nucleolar and rim patterns were not observed. By CIE, anti-SSA antibodies were detected in 18 patients. In two of

these cases anti-SSB was also found. Results of CIE and IB with respect to the detection of anti-RNP (anti-Sm/anti-nRNP) antibodies are

given in Table 4. CIE proved somewhat less sensitive for the detection of anti-RNP antibodies (n = 14,29%) than IB (n = 16,33%). IB

Table 2: Results of Pulmonary Function Tests Expressed as Percent of Predicted Value

No. No. of Patients

of Patients Mean f SD Range ~80% Predicted Value

WC 48 84 20 35-136 18 TLC 48 93 20 46-148 12 DLCO 45 88 19 59-135 18


Table 3: Pulmonary Function Tests (mean k

SEM; Percent of Predicted Value) in the Pres-

ence or Absence of Radiographic Interstitial

Abnormalities

Interstitial Abnormalities on Chest

Roentgenogram

IVC

TLC

DLCO

Absent

(n = 30)

95 + 3.6

88 -+ 3.6

90 + 3.4

Present

(n = 181

89 + 4.7

78 + 4.8

85 k 4.8

P Value

0.08

0.18

0.20

(39.6 v 35.9; P -c .05; 90% confidence intervals

0.66 to 6.74) than anti-SSA negative patients.

The frequency of xerophthalmia at the time of

the study, as assessed by history, was not statisti-

cally different between the anti-SSA positive and

the anti-SSA negative patients (29% v 15%) as

were the cumulative prevalences of photosensitiv-

ity and renal disease.

detected two cases with only anti-nRNP antibodies which could not be demonstrated by CIE.

Results of CIE and IB testing for anti-nRNP/ anti-Sm antibodies were compared for four sero-

logical groups (Table 5): I, positive for anti-

nRNP and/or anti-Sm; Ia, positive for anti-

nRNP only; Ib, positive for anti-Sm with or

without anti-nRNP; II, negative for both anti-

nRNP and anti-Sm.

Patients with a coarsely speckled ANA pat-

tern more frequently had Raynaud’s phenomenon (86% v 41%; P -c .005; 90% confidence intervals 0.26 to 0.66) and swollen fingers (47% v 3%; P < .OOl; 90% confidence intervals 0.22 to 0.65) as compared to patients with a homogeneous ANA pattern. The cumulative prevalence

of anti-dsDNA antibodies in the patients with a homogeneous ANA pattern was higher than in the patients with a coarsely speckled ANA pat-

tern (84% v 53%; P < .05; 90% confidence intervals 0.073 to 0.55) but both groups did not differ with respect to the results of the additional studies.

The frequency of positive IgM-RF levels was higher in the anti-SSA positive patients than in the anti-SSA negative patients (50% v 16%; P < .02; 90% confidence intervals 0.12 to 0.56). Anti-SSA positive patients had more frequently Raynaud’s phenomenon (72% v 42%; P -c .05; 90% confidence intervals 0.12 to 0.56) and had a lower mean number of nailfold capillary loops

Raynaud’s phenomenon occurred more frequently in group I and group Ib than in group II

(CIE and IB; P < ,005 for both) (Tables 6 and

7). Raynaud’s phenomenon was present in all of the patients of group Ib and in all but one of the

patients of group la. Sclerodactyly occurred more frequently in group Ia than in group II

(CIE; P < .05). The cumulative prevalence of

thrombocytopenia was higher in group Ib as compared with group II and Ia (CIE; P <: .05).

The cumulative prevalence of arthritis was higher

in group I and la than in group II (IB; P -z .05) while IgM-RF positivity was found more fre-

quently in group I as compared with group !I

(CIE; 50% v 20%; P < .05; 90% confidence intervals 0.053 to 0.55). With respect to the other

clinical features and cumulative ARA criteria,

no differences in prevalence were found among the four serological groups.

Interstitial abnormalities on chest roentgeno-

grams were more frequently observed in group Ib

as compared with group II (CIE; P < .05). The

Table 4: Comparison of lmmunoblotting and CIE Results for the Detection of Anti-Sm/Anti-nRNP

Antibodies in 49 SLE Patients -

Immunoblotting’

nRNP Sm + Sm CIE Negative Only nRNP Only Total

Negative 32 2 0 1 35

nRNP only 0 3 1 0 4

Sm + nRNP 0 0 5 0 5

Sm only 1 0 2 2 5

Total 33 5 8 3 49

j ‘Anti-nRNP only is defined as anti-70kd, and/or anti-A, and/or anti-C without anti-D; anti-Sm only is defined as anti-D (with or 3without

anti-BB’) without ant!-70kd. or anti-A or anti-C.

170 TER BORG ET AL

Table 5: Serological Results of CIE and lmmunoblotting Testing for Anti-nRNP and Anti-Sm

Group

I II Anti-nRNP la lb Negative

and/or Anti-nRNP Anti-Sm for Anti- Serological Anti-Sm Only With/ Without nRNP/Sm

Characteristics Anti-nRNP

CIE (n = 49) 14 4 10 35

IB (n = 49) 1 6 5 11 33

mean number of nailfold capillary loops was

lower in group I and group Ib than in group II (CIE and IB; P < .05). Nailfold capiIlary loops were decreased in group Ib (33 * 9) compared to group II (40 f 5; IB; P -c .05). In groups I and Ia, more cases were observed with one or more pearl necklaces of extravasates (Fig 2) than in

group II (P -c .05). The mean number of enlarged nailfold capillary loops and the prevalences of giant loops and bushy patterns were not

different among the various groups. No differ-

ences were found among the four serological groups with respect to the results of radionuclide studies of the esophagus or pulmonary function tests. The prevalence of a decreased value of

IVC, however, was higher in group Ia compared with group II (IB; 80% v 40%; p < .05; 90% confidence intervals 0.17 to 0.82).

DISCUSSION

The prevalence of Raynaud’s phenomenon and

swollen fingers in our population was comparable

Table 6: Results of CIE in Relation to Clinical and Laboratory Disease Features

Serological Groups

I II la II lb II la lb

Feature n 14 35 P 435 P 10 35 P 410 P

Raynaud’s phenomenon 13 13 l 3 13 10 13 l 3 10

(.38/.73) (.49/.76)

Sclerodactyly 3 2 22 l 1 2 2 1

(.03/.86)

Arthritis 11 18 4 18 7 18 4 7

Thrombocytopenia 7 12 0 12 7 12 t 07 t (.08/.63) (.46/.94)

Renal disorder 6 20 1 20 5 20 1 5

Anti-dsDNA 10 25 3 25 7 25 3 7

Interstitial changes on chest

roentgenogram 8 11 1 11 7 11 t 1 7

(. 1 l/.66)

Presence of pearl necklaces of

extravasates 5 6 36 t 2 6 3 2

(. 16,‘.921

Number of nailfold capillary

loops (mean) 35 40 t 40 40 33 40 t 40 33

(1.1/7.9) (2.6/10.4)

IVC (mean) 79 86 80 86 79 86 80 79

TLC (mean) 87 95 90 95 86 95 90 86

DLCO (mean) 90 87 95 87 87 87 95 87

Note. Within brackets: 90% confidence intervals for the differences between proportions or means.

l P < .005.

tP < .05.


Table 7: Results of lmmunoblotting in Relation to Clinical and Laboratory Disease Features

Serological Groups

I II la II lb II la lb Feature n 16 33 P 5 33 P 11 33 P 5 11 P

Raynaud’s phenomenon 1511 + 4 11 1111 l 4 1’1

C.441.77) (.53/.80)

Scterodactyly 3 2 2 2 1 2 2 1

Arthritis 13 16 t 5 16 t 8 16 5 8

(. 111.54) (.37/.66)

Thrombocytopenia 7 12 1 12 6 12 1 6

Renal disorder 6 20 1 20 5 20 1 5

Anti-dsDNA 12 23 4 23 8 23 4 6

Interstitial changes on chest

roentgenogram 8 11 2 11 6 11 2 6

Presence of pearl necklaces of

extravasates 7 4 t 3 4 t 44 3 4

(.08/.56) (.07/.83)

Number of nailfold capillary

loops (mean) 36 40 t 40 40 33 40 t 40 33

(.89/7.5) (2.5/10.1)

IVC (mean) 83 85 80 85 85 85 80 85

TLC (mean) 91 93 89 93 92 93 89 9’1

DLCO (mean) 89 87 86 87 90 87 86 90

Note. Within brackets: 90% confidence intervals for the differences between proportions or means

fP < ,005.

tP < .05.

with figures from literature.33 Not surprisingly, SLE patients with a homogeneous ANA pattern had a lower frequency of Raynaud’s phenomenon and swollen fingers than patients with a coarsely

speckled ANA pattern. Sclerodermalike features such as Raynaud’s phenomenon, sclerodactyly, interstitial changes on chest roentgenogram, increased prevalence of pearl necklaces of extravasates and decreased numbers of nailfold capillary loops were associated with the presence of anti- RNP (anti-nRNP with or without anti-Sm) antibodies. Thus, even within a relatively homogeneous SLE population, a subset of patients characterized by sclerodermalike features and anti-RNP antibodies can be recognized.

The cumulative prevalence of thrombocytopenia and arthritis also was higher in patients with anti-RNP antibodies than in those without. Al- though the incidence of renal disease in SLE may be lower in patients with anti-nRNP antibodies,16

the cumulative prevalence of renal disorder in this study was not different in patients with and without anti-RNP antibodies, in agreement with a recent report.’ In addition, no increased prevalence of any specific type of ANA was found in

another study of Oriental lupus patients with renal manifestations. 34 The number of patients with only anti-Sm antibodies or with only anti- nRNP antibodies in this study was small and did not allow statistical analysis of the prevalence of clinical findings in patients with a single antibody

specificity. Anti-SSA positive patients more frequently

had a positive test for IgM-RF than anti-SSA negative patients, as previously reported.” Raynaud’s phenomenon was more common in anti-SSA positive patients while their number of

nailfold capillary loops were lower. Many SLE patients have subclinical lung

involvement without radiological abnormalities, as assessed by functional investigation.35-37 Previ- ous reports have not shown a correlation between pulmonary involvement and any laboratory test.37 Although the prevalence of a reduced IVC was higher in patients with anti-nRNP than in those without anti-nRNP or anti-Sm, the mean results of all pulmonary function tests in the present study were statistically similar in the various serological groups. Interstitial changes on chest roentgenogram correlated highly with dyspnea.

172 TER BORG ET AL

Fig 2: Nailfold capillary microscopy showing a

row of capillary loops with multiple pearl neck-

laces of extravasates. The bold arrow indicates

the row of capillary loops while the small arrow

indicates one of the pearl necklaces of extrava-

sates.

The prevalence of decreased pulmonary function tests was more common than interstitial abnormalities on chest roentgenogram or dyspnea, confirming the findings of others.37 Thus, pulmonary function tests detect subclinical pulmonary

involvement in SLE, in accordance with an earlier study.36 In contrast to that report,36 restrictive lung disease was common in our patients. However, restrictive pulmonary disease in SLE may result from causes other than interstitial

lung disease such as pleurisy and diaphram dysfunction.

Radionuclide transit studies of the esophagus are reportedly sensitive for the evaluation of

esophageal dysfunction in connective tissue disease.38 In this study, the prevalence of an increased radionuclide transit time far exceeded the prevalence of dysphagia, confirming that observation.

The recently introduced IB technique may be more sensitive for detecting of anti-RNP antibodies than conventional methods.8*9”9 In an

earlier study from our group, CIE and IB proved equally sensitive for the detection of anti-nRNP/ anti-Sm antibodies.40 We now demonstrated that CIE was nearly as sensitive for the detection of these antibodies as IB, and the clinical associations of the antibodies with disease findings is maintained. As CIE is widely available, cheap, and easy to perform, this technique is recommended for routine practice in SLE.

In conclusion, within a relatively homogeneous SLE population without other connective tissue

diseases, a subset of patients can be recognized characterized by the presence of anti-RNP

(anti-Sm and/or anti-nRNP) antibodies and by scleroderma-associated features. CIE has similar sensitivity for the detection of anti-RNP anti-

bodies as IB and defines the clinical features of SLE as well as IB.

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Documents

Clinical associations of antiribonucleoprotein antibodies in patients with systemic lupus erythematosus