Clin Rheumatol (2002) 21:114–118

ß 2002 Clinical Rheumatology

Clinical
Rheumatology

Original Article

Exposure to Solvents in Female Patients with Scleroderma

L. Czirják and G. Kumánovics
Clinical Immunology Unit, Medical Faculty, University of Pécs, Pécs, Hungary

Abstract: The role of exposure to solvents was Introduction

investigated in female patients with connective tissue
disease and Raynaud’s phenomenon using a question- Several occupational exposures, including vinyl chlor-
naire. Sixteen out of the 63 patients with systemic ide, silica dust, epoxy resin and solvents, have been
sclerosis had been exposed to solvents. A borderline described as potential provoking factors of systemic
significance was demonstrated compared to matched sclerosis (SSc) and scleroderma-like disorders [1,2]. An
female controls (P50.05). Fourteen out of the 66 exposure to aliphatic or hydrocarbon solvents, including
patients with undifferentiated connective tissue disease, trichloroethylene, perchloroethylene, toluene, benzene
18/86 of patients with Raynaud’s phenomenon, 6/45 and xylene, and also white spirits, diesel and aromatic
with systemic lupus erythematosus, 1/16 with dermato- mixes, seems to be an important provoking factor for
polymyositis, 1/15 with rheumatoid arthritis and 0/13 scleroderma-related disorders in different parts of the
with primary Sjögren’s syndrome had been exposed to world [1,3–12], including Hungary [5,6,13–15]. Among
solvents. None of these groups of patients showed a the solvents trichloroethylene is a considerable provok-
statistical significance compared to matched controls. ing factor [6,9,10,13,16–18]. Other agents, such as
Our present findings indicate that, at least in certain areas perchloroethylene, benzene [6,14], other organic com-
of the world, exposure to solvents may be a provoking pounds including amines [4], and formaldehyde deriva-
factor in female scleroderma, but it must be emphasised tives [4] are also capable of provoking scleroderma.
that only a borderline significance was found between Anti-Scl-70 positive scleroderma cases seem to be more
the scleroderma patients and controls. A large multi- susceptible to the effects of solvents [19,20]. Previous
center study seems to be required to clarify the studies, apart from that by Yamakage and Ishikawa [21]
importance of solvents as provoking factors of scler- and our previous East-Hungarian publications [22,23],
oderma. Furthermore, exposure to solvents does not have described predominantly male workers [1,3]
seem to be a provoking factor among females for the Only a few controlled studies are available about the
other connective tissue diseases. provoking effect of solvents in scleroderma. In a
population-based case reference study, Bovenzi et al.
Keywords: Connective tissue disease; Lupus; Ray- demonstrated a significant association between occupa-
naud’s phenomenon; Scleroderma; Solvents tional exposure and SSc with an odds ratio of 9.28 [7].
Based on the investigation of 178 cases, Nietert et al.
suggested that male scleroderma patients were more
likely to be exposed to solvents than were controls.
These cases had a high cumulative intensity score (odds
ratio [OR] 2.9, 95% confidence interval [CI] 1.1–7.6)
and a high maximum intensity score (OR 2.9, 95% CI
1.2–7.1) for any solvent exposure, including trichlor-
Correspondence and offprint requests to: Professor László Czirják, oethylene (OR 3.3, 95% CI 1.0–10.3). Furthermore,
University of Pécs, Medical Faculty, 2nd Department of Internal
Medicine, Clinical Immunology Unit, H-7624 Pécs, Pacsirta u. 1, among men and women significant solvent–disease
Hungary. Tel: (36)-72-536053; Fax: (36)-72-536052; E-mail: associations were observed among SSc patients who
laszlo.czirjak@aok.pte.hu tested positive for the anti-Scl-70 autoantibody [19].
Solvents in Scleroderma 115

Silman et al. also detected an increased risk for autoimmune disease, a special group of 61 patients with
developing scleroderma among 56 male cases [24]. secondary Raynaud’s phenomenon were also included
Only a few data are available about the potential role [38]. Clinically, all of these cases exhibited Raynaud’s
of solvents in the other connective tissue disease groups phenomenon as the sole predominant clinical symptom.
[25–26]. A long-term exposure to trichloroethylene These cases also had either antinuclear antibody
increased the symptoms of SLE [25]. Another previous positivity, scleroderma capillary pattern or pitting
study indicated that exposure to petroleum distillate ulcerations/gangrene, but they definitely did not exhibit
solvents may be a provoking factor for undifferentiated any internal organ manifestation (e.g. pulmonary
connective tissue disease (UCTD) [26]. interstitial changes, oesophageal dysmotility, colonic
In the present study, the exposure to solvents was abnormalities, renal symptoms etc.).
investigated in patients with scleroderma, Raynaud’s We investigated 95 cases as controls. A control group
phenomenon, systemic lupus erythematosus and UCTD. consisted of two patient subgroups. Female patients with
We have demonstrated that exposure to solvents may be a solitary kidney were included. These patients were
a provoking factor for female systemic scleroderma. followed up at the nephrology unit of the university.
Conversely, exposure does not seem to play a role in the Patients who needed surgery for malignancy were
other connective tissue diseases. excluded. The other subgroup of control cases consisted
of female patients with type 2 diabetes mellitus attending
one of the two diabetic units of the university. Both
Patients and Methods outpatients and inpatients were included in both
subgroups. The inclusion of two different subgroups of
This report is based on the analysis of the clinical controls was necessary in order to achieve age matching.
laboratory findings of patients encountered at the In general, control cases with a solitary kidney belonged
Clinical Immunology Unit of the Second Department to the younger group of cases, whereas type 2 diabetic
of Internal Medicine of the University of Pécs between cases belonged to the elderly population of patients. The
1995 and April 2000. In this tertiary reference centre geographical distribution of cases, as well as the
both outpatient and inpatient records were systematically proportion of rural/urban domiciles, was similar between
investigated. patients and controls. The controls (95 patients) were age
For the clinical investigation of the patients with matched for SSc, SLE, UCTD and Sjögren’s syndrome.
systemic sclerosis, a standard protocol was used [27,28]. The distribution of domicile and school record of the
Sixty-three female patients with SSc who fulfilled the controls was similar to that of the patients.
diagnostic criteria for systemic sclerosis [29] were For the investigation of Raynaud’s syndrome, another
included in the study. Their mean age was 52
12.6 control group consisting of 90 patients was randomly
years. Fifty-three patients had limited cutaneous selected so as to achieve age matching, because the
systemic sclerosis, and 10 had diffuse cutaneous mean age of these patients was lower.
systemic sclerosis [30]. Seventeen additional patients
with limited cutaneous systemic sclerosis who did not
fulfil the preliminary criteria for scleroderma were also
investigated: these patients did not fulfil the ARA Data Acquisition
criteria for systemic sclerosis [29] but they uniformly
had limited cutaneous systemic sclerosis [30].
Both outpatients and inpatients were included in the
Sixty-six female patients with UCTD were also
study. The questionnaire about all previous working
investigated. The diagnosis of UCTD was based on
conditions, and exposure to all solvents. A list of
criteria used by previous investigators, including Calvo-
solvents was also included in the questionnaire, which
Alén et al. and Alarcón et al. [31,32] with modifications
was sent to all groups of patients and controls described
[33].
above. The proportion of received answers was above
Forty-five female patients with systemic lupus
90%. In all cases where there had been an exposure to
erythematosus, 16 females with dermatopolymyositis,
solvents a second specific questionnaire was also sent, in
13 patients with primary Sjögren’s syndrome and 15
order to confirm the information or to clarify the answers
cases with rheumatoid arthritis were also included. All
previously received. Cases where exposure to solvents
these cases fulfilled the conventional international
was questionable were not included in the exposure
criteria [34–36].
category. The evaluation was performed without any
Eighty-six female cases with Raynaud’s phenomenon
prior knowledge of the diagnosis of the particular case.
were also investigated. With regard to the patients with
primary Raynaud’s phenomenon (pRp), the criteria of
Medger and LeRoy were used [37]. Patients with the
following characteristics were placed into this category:
episodic attacks of acral pallor or cyanosis, and strong Data Analysis
symmetric peripheral pulses. Beside the 25 patients with
primary Raynaud’s phenomenon who did not show any The w2 test was used for group comparisons. Yates’
clinical or laboratory signs of the presence of a systemic correction was also used when necessary.
116 L. Czirják and G. Kumánovics

Results the total group of systemic scleroderma patients and

controls did not reach the level of statistical significance
With regard to patients fulfilling the criteria for (data not shown).
scleroderma [29], 16 out of the 63 cases with SSc had Fourteen out of the 66 patients with UCTD also were
been exposed to solvents, and 11 of the 95 matched previously exposed to solvents. The difference compared
controls had an exposure to solvents in their case history. to controls was not statistically significant. Eighteen out
A borderline significance could be demonstrated of the 86 patients with Raynaud’s had an exposure to
between patients and controls (P<0.05) (Fig. 1). No solvents, whereas 10 out of the 90 matched controls were
difference was detected between cases with lcSSc and exposed (Fig. 2). No statistical difference was found
those with dcSSc. Two of the dcSSc patients had been between the Raynaud’s group and controls.
exposed to solvents. The presence of antitopoisomerase Six out of the 45 patients in the SLE group, one of the
or anticentromere antibody was similarly demonstrated 16 patients with dermatopolymyositis, and another one
between the cases with and without exposure (data not of the 15 patients with rheumatoid arthritis exhibited an
shown). exposure to solvents, whereas none of the 13 cases with
With regard to the 17 cases with lcSSc that did not primary Sjögren’s syndrome had an exposure to solvents
fulfil the scleroderma criteria [29], three had previous in their occupational history (Fig. 1). None of these
exposure to solvents. If these cases were also added to groups showed a statistical significance compared to
the cases with lcSSc and dcSSc, the difference between matched controls.

Fig. 1. Proportion of the patients with exposure to solvents in different systemic autoimmune diseases.

Fig. 2. Proportion of the patients with exposure to solvents in patients with Raynaud’s phenomenon.
Solvents in Scleroderma 117

Discussion following occupational exposure to organic solvents [letter]. Clin

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Received for publication 3 January 2001

Accepted in revised form 18 September 2001