close

Вход

Забыли?

вход по аккаунту

?

Evolution of primary raynaud's phenomenon raynaud's disease to connective tissue disease.

код для вставкиСкачать
EVOLUTION OF PRIMARY RAYNAUD’S
PHENOMENON (RAYNAUD’S DISEASE) TO
CONNECTIVE TISSUE DISEASE
DAVID D. GERBRACHT, VIRGINIA D. STEEN, GAYLE L. ZIEGLER,
THOMAS A. MEDSGER, JR., and GERALD P. RODNAN
Eighty-seven patients diagnosed as having primary Raynaud’s phenomenon (Raynaud’s disease) were
reexamined after this symptom had been present for a
mean of 8.8 years (range 2.0-34.5). One or more
additional clinical feature(s) suggesting an underlying
connective tissue disease were found in 12 patients
(14%)at first evaluation, and in 23 (26%) by the last
evaluation. The most frequent findings were puffy fingers (10 patients), digital tip pitting scars (8 patients),
and digital tip ulcerations (6 patients). Distal esophageal
hypomotility and/or decreased pulmonary diffusing capacity for carbon monoxide were found in 12 patients.
Only 4 individuals ( 5 % ) developed clear evidence of a
connective tissue disease, and in all cases, the diagnosis
was the CREST (calcinosis, Raynaud’s phenomenon,
esophageal dysmotility, sclerodactyly, telangiectasias)
syndrome variant of systemic sclerosis. This condition
became obvious 8-17 years after the onset of Raynaud’s
phenomenon. One or more serologic test values were
initially abnormal in 2 of these CREST syndrome patients;, as well as in 12 patients who continued to have
From the Department of Medicine, Division of Rheumatology arid Clinical Immunology, University of Pittsburgh School of
Medicine, Pittsburgh, Pennsylvania.
Supported by grants from the National Institutes of Health
(FR-00056 and AM-21393); The RGK Foundation, Austin, Texas;
and the Arthritis Foundation, Western Pennsylvania Chapter.
David D. Gerbracht, MD: Fellow in Rheumatology; Virginia D. Slteen, MD: Assistant Professor of Medicine; Gayle L. Ziegler,
RN, I3SN: Research Assistant; Thomas A. Medsger, Jr., MD:
Associate Professor of Medicine.
Dr. Rodnan is deceased.
Address reprint requests to Virginia D. Steen, MD, Department of Medicine, 985 Scaife Hall, University of Pittsburgh School
of Medicine, Pittsburgh, PA 15261.
Submitted for publication March 2, 1984; accepted in
revised form June 26, 1984.
Arthritis and Rheumatism, Vol. 28, No. 1 (January 1985)
primary Raynaud’s phenomenon at the .Ast eva.Jation.
The combination of puffy fingers, digital pitting scars,
and serum anticentromere antibody, all consistent with
CREST syndrome, occurred in a small group of patients. None of the 78 patients whose serologic tests were
repeated during followup had a change in the serologic
profile. These results suggest that only a small proportion of patients with primary Raynaud’s phenomenon
develop one of the connective tissue diseases during the
first decade after onset. When such a disorder does
appear, systemic sclerosis with the CREST syndrome
variant is the most likely eventual diagnosis.
Raynaud’s phenomenon is generally classified
as “primary” when no underlying cause or associated
condition explaining its presence can be identified (1).
This diagnosis is thus made with the realization that
some patients may subsequently develop evidence of a
connective tissue disease or other disorder with which
this circulatory condition is known to be associated,
such as systemic sclerosis (scleroderma), systemic
lupus erythematosus (SLE), or polymyositis-dermatomyositis (2,3). Our study presents initial and followup
information on a group of 87 patients who were
initially diagnosed as having primary Raynaud’s phenomenon and who had this condition for at least 2
years at the time of their final evaluation. Our objectives were to determine the subsequent frequency of
connective tissue disease in these patients, and to
identify clinical, laboratory, or serologic findings
which might serve to predict this outcome.
PATIENTS AND METHODS
All patients diagnosed as having primary Raynaud’s
phenomenon by faculty members of the Division of Rheuma-
GERBRACHT ET AL
88
tology and Clinical Immunology of the University of Pittsburgh from 1973 through 1981 were identified. This diagnosis
was based on history or observation of bilateral, coldinduced blanching andlor cyanosis of the fingers, or fingers
and toes. Individuals with historical or physical evidence of
arteriosclerosis, thoracic outlet syndrome, pneumatic tool
use, or other known causes of Raynaud’s phenomenon were
excluded, as were those with sufficient additional clinical
findings to warrant the diagnosis of one of the connective
tissue diseases. All patients had Raynaud’s phenomenon for
a minimum of 2 years by last evaluation.
Initial evaluation included a detailed history and
physical examination, and in most, but not all patients, the
following laboratory studies: a complete blood count with
platelet count, urinalysis, blood urea nitrogen and serum
creatinine concentrations, serum creatine phosphokinase
activity, dipstick examination or 24-hour urine collection for
protein excretion, a serologic test for syphilis (VDRL or
RPR), direct Coombs’ test, roentgenograms of the hands and
chest, cineesophagram, and pulmonary function tests with
diffusing capacity for carbon monoxide (DLco). Serum was
also tested for the presence of antinuclear antibody (ANA),
anti-ribonucleoprotein antibody (anti-RNP), anti-Sm antibody, anti-DNA, anticentromere antibody (ACA), rheumatoid factor (RF), and concentrations of serum complement
components (C3 and C4).
ANA, anti-DNA, and ACA were determined by the
indirect immunofluorescence technique using rat liver, the
kinetoplast of Crithidiu luciliue, and the HEp-2 cell line (4),
respectively, as substrates. Anti-RNP and anti-Sm antibodies were detected by passive hemagglutination ankl hemagglutination inhibition techniques, and rheumatoid factor assay was performed by latex agglutination (fixation). The
following titers were considered abnormal: ANA 2 1 : 32,
anti-RNP 2 1 : 10,000, anti-Sm 2 1 : 10, anti-DNA 2 1 : 10,
ACA r l : 4 0 , and RF r l : 8 0 .
Followup evaluation for this study was performed
either by return visit or by telephone interview. The former
included an interim history and physical examination designed to detect clinical features which might suggest the
development of one of the connective tissue diseases. These
features consisted of puffy fingers, sclerodactyly, digital
pitting scars, digital tip ulcerations, digital telangiectasias,
arthralgias, arthritis, pleuritislpericarditis, photosensitivity,
malar rash, and proximal muscle weakness. The definitions
used were those published by the Glossary Subcommittee of
the American Rheumatism Association (ARA) in the Dictionary of the Rheumatic Diseases (5).
In addition, arthralgia was defined as pain and morning stiffness in multiple peripheral joints without detectable
swelling and not accounted for by other conditions, e.g.,
osteoarthritis. Patients contacted by telephone answered a
questionnaire designed to reliably elicit the presence of these
features. When possible, we confirmed responses and collected interim data by obtaining similar information and
specific physical examination results from the patient’s
private physician.
Blood was obtained for repeat serologic testing or
females
1-1
males
evolved to connective
I
tissue disease
Figure 1. Evolution to connective tissue disease in relation to sex and age at onset of Raynaud’s
phenomenon.
EVOLUTION OF RP
was mailed from patients unable to return to Pittsburgh. If
the patient’s serum was found to have an abnormal serologic
test result in either the initial (stored frozen) or final (fresh)
serum sample, the specific test was repeated simultaneously
on both serum samples. In this way, we controlled for any
variation in laboratory test technique which might have
occurred over time. Additional laboratory studies were
ordered only if clinically indicated.
Published preliminary or revised ARA criteria were
used for classifying patients as having definite systemic
sclerosis, SLE, or definite rheumatoid arthritis at any time
during, the followup period (6-8). The criteria of Bohan and
colleagues were used for the diagnosis of polymyositisdermatomyositis (9). Patients having only Raynaud’s phenomenon and sclerodactyly were considered to have an
unclassifiable connective tissue disease most closely resembling the CREST syndrome variant of progressive systemic
sclerosis (10).
RESULTS
Ninety-one patients were diagnosed during
1973- 1981 as having primary Raynaud’s phenomenon.
Four patients were excluded, 2 because no followup
information was obtainable and 2 because the duration
of Raynaud’s phenomenon was less than 2 years by
last evaluation. Sixty-seven patients were reexamined,
and 20 individuals were contacted by telephone.
The final study group thus consisted of 87
individuals, 78 women and 9 men (fema1e:male ratio
8.6:l). The sex and the age at onset of Raynaud’s
phenomenon according to patient history are shown in
Figure 1. The mean age at onset was 30.2 years with a
range of 10-61 years. Forty-eight patients (55%) experienced the onset of Raynaud’s phenomenon before
age 30. Women were younger at onset with a mean age
of 28.9, compared with 33.0 years in the men.
These patients had had Raynaud’s phenomenon
for an average of 5.1 years (median 3 .O) at the time of
our initial evaluation, with a range of 0.1-34.0 years.
Thirty-six patients (41%) were first seen within 2 years
(mean 0.8) of the onset of Raynaud’s phenomenon
symptoms. The total duration of Raynaud’s phenomenon from its onset to our final evaluation ranged from
2.0-34.5 years (mean 8.8, median 6.8).
Table 1 lists those individuals who exhibited 1
or more of the clinical features or laboratory abnormalities mentioned above. Initially, 12 patients (14%)
were found to have 1 or more clinical findings frequently observed in connective tissue diseases, in
addition to Raynaud’s phenomenon. This was true of
23 patients (26%) by the time of the final evaluation.
Puffy fingers (10 patients), sclerodactyly (4 patients),
digital pitting scars (8 patients), digital tip ulcerations
89
(6 patients), arthralgias (5 patients), digital telangiectasias (4 patients), and pleurisy (1 patient) were detected, but no patients had arthritis, malar rash, photosensitivity, or proximal muscle weakness. The mean
duration of Raynaud’s phenomenon by the last visit
was similar in the 23 patients with clinical findings (9.4
years) and the 64 without such findings (8.6 years).
Table 1. Clinical and laboratory abnormalitiesidentified in patients
with primary Raynaud’s phenomenon (RP)*
Patient
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
31
Detected at first
visit
DP, DU, ANA, anti-RNP,
DC
PF, DP, ACA, DC
A
DP, ACA
PF, ACA
A
PF
A
PF
DPE, DC
DU
A
ANA, RF
DC
ACA
ANA, anti-RNP
ACA, DC
ANA, anti-RNP
ANA
ANA
RF
RF
E
DC
ANA, anti-RNP, DC
DC
DC
DC
DC
Developed
during course
PF
S , DP, DU, T, A
T
DP
DP
S, DU, DP, T
DU
P
S
S
PF, DU
PF
PF
T
PF
PF
Duration
of RP at
final
visit
(years)
5.8
2.8
15.6
3.5
7.8t
16.3
5.8
13.9
4.9
5.5
5.1
6.8
8.6t
13.9
4.5
16.8$
14.0$
5.8
6.6
4.9
32.7
9.1
6.8
5.1
4.9
5.2
34.5
23.6
16.9
11.5
3.9
9.5
8.2
5.1
4.4
9.7
29.4
* DP = digital pitting scars; DU = digital tip ulceration; ANA =
antinuclear antibodies; RNP = ribonucleoprotein; PF = puffy
fingers; ACA = anticentromere antibodies; A = arthralgias; S =
sclerodactyly; T = telangiectasias; RF = rheumatoid factor; P =
pleurisy; DC = DLco <80% predicted normal; E = esophageal
hypomotility.
t Time after the onset of Raynaud’s phenomenon that criteria were
satisfied for definite systemic sclerosis.
$ Time after the onset of Raynaud’s phenomenon that diagnosis of
unclassified connective tissue disease was made.
90
In 4 of the 23 patients with the above clinical
and/or laboratory abnormalities, a connective tissue
disease was diagnosed during the followup period.
Two individuals (patients 5 and 13) developed sclerodactyly and digital pitting scars and satisfied ARA
minor criteria for definite systemic sclerosis (6), 7.8
and 8.6 years, respectively, after the onset of Raynaud’s phenomenon. Two others (patients 16 and 17)
also developed sclerodactyly after 16.8 and 14.0 years
of Raynaud’s phenomenon, respectively, but had insufficient additional evidence to satisfy criteria for
systemic sclerosis. The latter patients appear to have a
disorder most consistent with systemic sclerosis with
incomplete CREST syndrome. One of these individuals (patient 5) had a clinical finding (puffy fingers)
when first evaluated 4.0 years after the onset of
Raynaud’s phenomenon, but the other 3 had no clinical findings at the time of the first evaluation.
Distal esophageal hypomotility (2 of 49 patients) and DLco <80% of predicted normal (1 l of 43
patients) were the only laboratory abnormalities detected. Interestingly, none of the individuals with
these abnormalities had esophageal or pulmonary
complaints; all had normal chest roentgenogram results; and none subsequently developed further evidence of a connective tissue disease. Pulmonary fibrosis (0/63) and digital calcinosis ( 0 / 5 0 ) by
roentgenographic examination, urine protein >300 mg
in 24 hours (0/39), platelet count < 100,000/mm3(0/42),
positive VDRL or RPR (0/50),positive direct Coombs’
test (0/29), and elevated serum creatinine phosphokinase activity (0/53)were sought in many patients but
not found.
Fourteen patients accounted for 19 abnormal
serologic results as defined above (Table 1). ANA was
found in 7 (8%) of 84 patients, ACA in 5 of 82 (6%),
anti-RNP in 4 of 84 (5%), and RF in 3 of 84 (4%). AntiDNA and anti-Sm antibodies were not present in any
of these patients. Two patients (1 with ANA and RF
[patient 131 and 1 with ACA [patient 51) developed
systemic sclerosis with CREST syndrome. Twelve of
the 14 remained free of a connective tissue disease
after a mean duration of 11.3 years. A significant
correlation was found between the occurrence of ACA
and puffy fingers (P < 0.05) and ACA and digital
pitting scars (P< 0.05), as well as between the latter
physical findings ( P < 0.05).
Seventy-eight of the original 84 patients with
serologic studies had all of these tests repeated. Individual titers of anti-RNP and ACA were identical on
repeat testing, while 2 ANA and 2 RF titers had 1-2
GERBRACHT ET AL
tube-dilution differences between the initial and final
samples. None of the followup changes in titers in
these 4 patients altered the initial designation as normal or abnormal.
DISCUSSION
It is generally thought (1 1,12), and it is also our
own experience, that the majority of patients with
Raynaud’s phenomenon who develop a connective
tissue disease do so within the first 2 years after the
onset of this symptom. In this study, we evaluated a
large group of patients who were initially diagnosed as
having primary Raynaud’s phenomenon; patients were
evaluated an average of 5.1 years after the onset of
symptoms. We were interested in the frequency of
evolution to a connective tissue disease in these patients, as well as any clinical, laboratory, or serologic
clues at the first visit which might predict such an
outcome.
Requirements for the diagnosis of a connective
tissue disease vary considerably in the medical literature. We demanded fulfillment of established published ARA criteria (6-9), which, admittedly, is arbitrary. These criteria were promulgated for purposes of
classification rather than for early diagnosis and, as
shown previously, will exclude some patients believed
clinically to have 1 of these conditions. Our 2 study
patients who developed sclerodactyly but failed to
meet criteria for systemic sclerosis would be considered by many, if not most, observers to have the
CREST syndrome variant of this disorder (10,12).
Gifford and Hines (2) performed a medical
record review, questionnaire, and reexamination of
377 women and girls with Raynaud’s disease seen at
the Mayo Clinic during the period 1920-1945. Two
hundred eighty had adequate followup (mean 12
years), of whom 10 (3%) developed a clear-cut connective tissue disease. Five patients were considered to
have rheumatoid arthritis and 4 had systemic sclerosis
of the “acrosclerosis” (CREST syndrome) type; 3 of
the latter patients had skin thickening limited to the
digits (sclerodactyly alone). One patient developed
polyarteritis nodosa.
In a prospective study, Harper et a1 (3) recorded that 3 (8%) of 39 patients had developed a connective tissue disease after a mean of 2 years followup (7
years mean total duration of Raynaud’s phenomenon).
None of these 3 patients fully met criteria for 1 of the
connective tissue diseases (6-9) and thus their disease
was considered “undifferentiated.” Based on the de-
EVOLUTION OF RP
scriptions of these patients, we believe that 1 had
probable CREST syndrome and the others had features of SLE. Several other studies (13-16) contain
important information concerning the evolution of
connective tissue disease in patients with Raynaud’s
phenomenon. However, data from these studies are
presented in such a way that the duration of Raynaud’s
phenomenon prior to the development of these associated conditions cannot be determined.
We have reached similar conclusions regarding
the frequency of evolution to a connective tissue
disease; 4 (5%) of 87 primary Raynaud’s phenomenon
patients ultimately developed a connective tissue disease. In contrast, we did not find the diversity of
outcomes noted by other authors. All of our 4 patients
were considered to have systemic sclerosis with the
CRE,ST syndrome (10,17).
Pitted scars and ulcerations of the fingertips are
occasionally noted in patients with primary Raynaud’s
phenomenon (2,3,6,16,18). Their occurrence has been
looked upon as concomitant with severe Raynaud’s
phenomenon rather than an indicator of an underlying
disorder (2,16). Three of our 4 patients who developed
systemic sclerosis had such scars or ulcerations during
followup, but 9 other patients with continued primary
Raynaud’s phenomenon also had one or both of these
findings.
Puffy fingers, which may antedate the development of systemic sclerosis by months or many years
(lo), were noted in 10 of the 87 patients, only 1 of
whom developed systemic sclerosis with the CREST
syndrome. Anticentromere antibody has been reported in 49-96% of patients with the CREST syndrome
(4,17.19). In our patients, ACA was associated with
puffy fingers and with digital pitting scars. This combination of findings may identify a subset of patients
destined to develop systemic sclerosis. Thus far, 4 of
our 5 patients with ACA have not yet developed
systeimic sclerosis after 2.8-9.1 years (mean 5.1).
More prolonged followup may be required.
Distal esophageal hypomotility and diminished
carbon monoxide diffusing capacity have been welldocumented as occurring in patients with primary
Raynaud’s phenomenon (16,18,20). The frequency of
these abnormalities in our study was comparable.
Although such changes are often found in patients with
established connective tissue disease (18,20), none of
the 12 patients in this study, with 1 or both of these
abnormalities, has yet shown such evolution.
Other authors have noted a low frequency of
serum autoantibodies in patients with primary Ray-
91
naud’s phenomenon (3,17,18,21). In those studies,
ANA was present in a total of 23 (26%) of 83 patients
(3,21). Our results proved similar; only 17% of patients
had autoantibodies. Raynaud’s phenomenon and an
abnormal serologic test result may coexist for many
years before the onset of a connective tissue disease
(17). Although 2 of our patients had 1 or more of these
abnormal serologic test values prior to the development of systemic sclerosis, 12 others with 1 or more
serologic abnormalities did not develop connective
tissue disease after a mean followup of 11.3 years. We
were surprised to find the serologic profiles of these
patients so remarkably constant over time.
We did not perform nailfold capillary microscopy on our patients, although an abnormal capillary
pattern has been considered a useful prognostic indicator of the subsequent development of systemic sclerosis (3). In 2 recent studies, a combined total of 3 of 11
patients with “isolated” Raynaud’s phenomenon and
an abnormal nailfold capillary pattern developed connective tissue disease. However, this transition also
occurred in 2 of 72 individuals with Raynaud’s phenomenon and a normal capillary pattern (3,22). Prolonged observation and better correlation of capillary
microscopy with clinical findings, such as puffy fingers, digital tip lesions, and ACA, are needed to
determine the specificity and predictive value of these
vascular changes.
We conclude that it is infrequent for patients
considered to have primary Raynaud’s phenomenon to
develop a connective tissue disease during the first
decade of their disease. Such transition does occur
occasionally, however, and even more time may be
required than the 9 years mean duration of Raynaud’s
phenomenon in this study. Of those who do develop
additional findings during the followup period, the
clinical features are most commonly those seen in the
CREST syndrome variant of progressive systemic
sclerosis. Laboratory and serologic abnormalities
were nonspecific and, in this study, were not helpful in
predicting evolution to connective tissue disease.
REFERENCES
review of the
clinical problem. Ann R Coll Surg Engl 9:35-51, 1951
2 . Gifford RW, Hines EA: Raynaud’s disease among women and girls. Circulation 16:1012-1021, 1957
3. Harper FE, Maricq HR, Turner RE, Lidman RW,
1. Jepson RP: Raynaud‘s phenomenon-a
92
LeRoy EC: A prospective study of Raynaud’s phenomenon and early connective tissue disease. Am J Med
72:883-888, 1982
4. Tan EM, Rodnan GP, Garcia I, Moroi Y, Fritzler MJ,
Peebles C: Diversity of antinuclear antibodies in scleroderma: anti-centromere antibody and its relationship to
CREST. Arthritis Rheum 23:617-625, 1980
5. Dictionary of the Rheumatic Diseases. Vol. 1: Signs and
Symptoms. New York, Contact Associates International, Ltd., 1982
6. Subcommittee for Scleroderma Criteria of the American
Rheumatism Association Diagnostic and Therapeutic
Criteria Committee: Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis
Rheum 23581-590, 1980
7. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ,
Rothfield NF, Schaller JG, Tala1 N, Winchester RJ: The
1982 revised criteria for the classification of systemic
lupus erythematosus. Arthritis Rheum 25: 1271-1277,
1982
8. Ropes MW, Bennett GA, Cobb S, Jacox R, Jessar RA:
1958 revision of the diagnostic criteria for rheumatoid
arthritis. Bull Rheum Dis 9:175-176, 1958
9. Bohan A, Peter JB, Bowman RL, Pearson CM: A
computer assisted analysis of 153 patients with polymyositis and dermatomyositis. Medicine (Baltimore)
56:255-286, 1977
10. Rodnan GP: Progressive systemic sclerosis (scleroderma), Arthritis and Allied Conditions. Ninth edition.
Edited by DJ McCarty Jr. Philadelphia, Lea & Febiger,
1979, pp 762-809
1 1 . Allen EV, Brown GE: Raynaud’s disease: a critical
review of minimal requisites for diagnosis. Am J Med
Sci 183:187-200, 1932
GERBRACHT ET AL
12. Blain A 111, Coller FA, Carver GB: Raynaud’s diseasea study of criteria for prognosis. Surgery 29:387-397,
1951
13. De Takats G, Fowler EF: Raynaud’s phenomenon.
JAMA 179:99-106, 1962
14. Porter JM, Bardana EJ, Baur GM, Wesche DH, Andrasch RH, Rosch J: The clinical significance of Raynaud’s syndrome. Surgery 80:756-764, 1976
15. Blunt RJ, Porter JM: Raynaud syndrome. Semin Arthritis Rheum 10:282-308, 1981
16. Velayos EE, Robinson H , Prociuncula FE, Masi AT:
Clinical correlation analysis of 137 patients with Raynaud’s phenomenon. Am J Med Sci 262:347-356, 1971
17. Fritzler MJ, Kinsella TD, Garbutt E: The CREST syndrome: a distinct serologic entity with anticentromere
antibodies. Am J Med 69520-526, 1980
18. Kallenberg CGM, Wouda AA, The TH: Systemic involvement and immunologic findings in patients with
Raynaud’s phenomenon. Am J Med 69:675-680, 1980
19. Steen VD, Ziegler GL, Rodnan GP, Medsger TA Jr:
Clinical and laboratory associations of anticentromere
antibody in patients with progressive systemic sclerosis.
Arthritis Rheum 27:125-131, 1984
20. Stevens MB, Hookman P, Siege1 CL, Esterly JR, Shulman LE, Hendrik TR: Aperistalsis of the esophagus in
patients with connective tissue disorders and Raynaud‘s
phenomenon. N Engl J Med 270:1218-1222, 1964
21. Kallenberg CGM, Pastoor GW, Wouda AA, The TH:
Antinuclear antibodies in patients with Raynaud’s phenomenon: clinical significance of anticentromere antibodies. Ann Rheum Dis 41:382-387, 1982
22. Spencer-Green G, Hess EV: Prospective analysis of
nailfold capillary pattern in Raynaud’s phenomenon
(abstract). Arthritis Rheum (suppl) 25:S127, 1982
Документ
Категория
Без категории
Просмотров
2
Размер файла
553 Кб
Теги
connection, phenomena, raynaud, evolution, primary, disease, tissue
1/--страниц
Пожаловаться на содержимое документа