Contribution from the Field
Prevalence and clinical correlates of pruritus in patients with systemic sclerosis
There are no studies of pruritus prevalence or clinical correlates in systemic sclerosis (SSc). The objectives of this study were to document the proportion of SSc patients with pruritus on most days, to determine when in the course of the disease pruritus is most prevalent, and to identify clinical correlates.
We performed a cross-sectional, multicenter study of 400 SSc patients from the Canadian Scleroderma Research Group Registry ≥1 year after Registry enrollment. Patients indicated whether they experienced pruritus during the past month on most days and underwent clinical histories and medical examinations. Multiple logistic regression was used to assess the association between sociodemographic and clinical variables and pruritus.
A total of 179 patients (45%) reported pruritus on most days, including 69% (11 of 16) among patients 1.0–1.9 years from onset of non-Raynaud's symptoms, 41% (38 of 93) for 2.0–4.9 years, 47% (44 of 94) for 5.0–9.9 years, 43% (60 of 140) for 10.0–19.9 years, and 46% (26 of 57) for ≥20 years. In post hoc analysis, patients 1.0–1.9 years from disease onset were significantly more likely to report pruritus (P = 0.049). Patients with pruritus had significantly more skin involvement (P = 0.029), more gastrointestinal (GI) symptoms (P < 0.001), worse breathing problems (P = 0.001), worse Raynaud's symptoms (P = 0.002), and more severe finger ulcers (P = 0.009). Only the number of GI symptoms predicted pruritus in multiple logistic regression analysis (odds ratio 1.25, 95% confidence interval 1.13–1.37; P < 0.001).
Pruritus is common in SSc and is independently associated with GI symptoms. Focused research on sources of pruritus and its management in SSc is needed.
Systemic sclerosis (SSc) is a chronic, multisystem, connective tissue disorder characterized by thickening and fibrosis of the skin and internal organ involvement (1). Patients with SSc report high levels of pain, fatigue, depressive symptoms, and disability (2). As described in clinical reviews (3–5) and patient testimonials (6), pruritus also appears to present a major problem for many SSc patients.
Pruritus has been defined as a “poorly localized, non-adapting, usually unpleasant sensation that provokes a desire to scratch” (7). Biologically, the purpose of pruritus is thought to relate to inducing scratching in order to remove pruritogens, a response that may have originated when pruritogens were typically parasites. The neurophysiologic mechanisms, however, are not well understood, and for many years, pruritus was considered a subliminal form of pain, since both sensations share common features. Current evidence recognizes the important differences between pain and pruritus, and the two are probably best understood as distinct, but interacting, phenomena (7).
Pruritus is thought to be common during the early stages of SSc, and for many patients it is their most bothersome symptom (3–5). Clinical reviews agree that pruritus tends to subside as the disease progresses, although different time periods for this have been suggested, including 2–3 years (5), 3–4 years (4), or up to 5 years (3). In some cases, pruritus may persist for many years (3). Patient accounts of severe pruritus in SSc include descriptions of unbearable itching, bleeding and sores from scratching, and sleepless nights. Descriptions on one Web site (6) include: “I was constantly itching so badly that I would dig sores into my arms,” “Itching seemed unbearable. I clawed at myself, sometimes drawing blood,” and “I went from tailored clothing to baggy jumpers, loose silk blouses and trouser stockings. Anything that rubbed against my skin made me cringe.”
A June 2009 Medline search did not uncover any empirical studies on pruritus in SSc. In other systemic and dermatologic diseases, however, pruritus is associated with significant disability (8), including disruptions in sleep, concentration, and sexual functioning, and feelings of helplessness and negative affect (9, 10). The objectives of this study were to document the proportion of patients with SSc who experience pruritus on most days across the course of the disease and to identify clinical correlates of pruritus.
PATIENTS AND METHODS
The study sample consisted of patients enrolled in the Canadian Scleroderma Research Group Registry who completed their first annual followup visit and responded to an item (described below) assessing the presence of pruritus on most days in the past month. The item was administered at followup visits, but not at the initial Registry visit. Patients in the Registry were recruited from 15 centers across Canada. To be eligible for the Registry, patients must have a diagnosis of SSc made by the referring rheumatologist, be age ≥18 years, and be fluent in English or French. Registry patients undergo an extensive clinical history, physical evaluation, and laboratory investigations, and complete a series of self-report questionnaires. Patients from all centers provided informed consent, and the research ethics board of each center approved the data collection protocol.
Analyses included sociodemographic variables (e.g., age, sex, marital status, and education) and disease variables (e.g., disease duration, number of tender joints, number of gastrointestinal [GI] symptoms, skin involvement, respiratory problems, Raynaud's phenomenon, and pruritus).
SSc disease duration was defined as the time from the onset of non-Raynaud's symptoms based on the clinical history obtained by the study rheumatologists. Because pruritus was measured only at annual followup visits and not the initial Registry visit, the disease duration for all of the patients was at least 1 year. Based on published estimates of when pruritus is most common (3–5), rates of pruritus were reported by year for a disease duration of 1.0–1.9 years, 2.0–2.9 years, 3.0–3.9 years, and 4.0–4.9 years. Rates were also reported for broader categories of 5.0–9.9 years, 10.0–19.9 years, and ≥20.0 years. Skin involvement was assessed using the modified Rodnan skin score (MRSS; range 0–51) (11). Limited skin disease was defined as skin involvement distal to the elbows and knees with or without facial involvement. SSc global disease severity was rated on a 0–10 numerical rating scale by study rheumatologists, a scale that has been shown to be a valid measure of severity in SSc (12). Tender joint count was recorded by study physicians using a 28-joint count (13). Shortness of breath (In the past week, how much have your breathing problems interfered with your daily activities?), severity of Raynaud's symptoms (In the past week, how much have the Raynaud's attacks interfered with your daily activities?), and severity of finger ulcers (In the past week, how much have your finger ulcers interfered with your daily activities?) were assessed by patients on 0–10 numerical rating scales (14). The number of GI symptoms was determined by patient report from a checklist of 14 symptoms that included poor appetite, difficulty swallowing, acid reflux, nocturnal choking, heartburn, early satiety, abdominal bloating, nausea and vomiting, chronic constipation, chronic diarrhea, antibiotics for bacterial overgrowth, greasy stools, fecal incontinence, and parenteral nutrition. In addition, the severity/functional impact of GI symptoms was measured with a single item on a 0–10 numerical rating scale (In the past week, how much have your intestinal problems interfered with your daily activities?) (14).
The presence of pruritus was evaluated with a dichotomously scored item (I have or I have had in the past month itchiness in my skin, on most days). Similar questions have been used to establish the prevalence of pruritus in dermatologic diseases (9).
Patients who reported pruritus on most days in the last month were compared with patients without pruritus on demographic and disease variables. Categorical variables were compared using the chi-square statistic and continuous variables with 2-tailed t-tests. The associations between sociodemographic (step 1) and disease variables (step 2) with pruritus were assessed using hierarchical multiple logistic regression. Age, sex, marital status (married or living as married versus single/ divorced/widowed), and education (more than high school versus high school or less) were entered in step 1. Time since onset of non-Raynaud's symptoms, skin score, number of tender joints, number of GI symptoms, severity of breathing problems, severity of Raynaud's symptoms, and severity of finger ulcers were entered in step 2. In addition, 2 post hoc logistic regression analyses were run in which diffuse/limited status was included as a predictor rather than the MRSS and in which the severity of GI symptoms was substituted for the number of GI symptoms. Discrimination and calibration of the models were assessed based on the c-index and the Hosmer-Lemeshow goodness-of-fit test statistic, respectively (15). The c-index is the percentage of comparisons in which patients with pruritus had a higher predicted probability of having pruritus than patients without pruritus for all possible pairs of patients discrepant on pruritus status. The Hosmer-Lemeshow test is a measure of the accuracy of the predicted number of pruritus cases compared with the number of patients who actually reported pruritus across the spectrum of probabilities. A relatively large P value indicates reasonably good model fit. Analyses were conducted using SPSS, version 16.0 (SPSS, Chicago, IL), and statistical tests were 2-sided with a significance level of P values less than 0.05.
A total of 400 patients completed the measures used in the study. Table 1 shows demographics and disease characteristics. Approximately 88% of the patients were women, 94% were white, and 32% had diffuse SSc. The mean age was 56.3 years and the mean time since the onset of non-Raynaud's symptoms was 11.5 years. Sample characteristics were similar to those reported from other large North American and European cohorts (16). Of the 400 patients, 179 (44.8%) reported experiencing pruritus during the past month on most days.
Table 1. Patient demographics and disease characteristics
|Women, no. (%)||351 (87.8)||156 (87.2)||195 (88.2)||0.742|
|White, no. (%)||375 (93.8)||167 (93.3)||208 (94.1)||0.736|
|More than high school education, no. (%)||205 (51.2)||94 (52.5)||111 (50.2)||0.649|
|Married or living as married, no. (%)||116 (29.0)||54 (30.2)||62 (28.1)||0.643|
|Diffuse systemic sclerosis, no. (%)||128 (32.0)||59 (33.0)||69 (31.2)||0.711|
|Age, mean ± SD years||56.3 ± 12.1||55.9 ± 11.9||56.5 ± 12.2||0.603|
|Time since onset of non-Raynaud's symptoms, mean ± SD years||11.5 ± 8.8||11.5 ± 9.1||11.4 ± 8.5||0.906|
|Modified Rodnan skin score (range 0–51), mean ± SD||10.5 ± 9.1||11.6 ± 10.5||9.6 ± 7.7||0.029|
|Number of tender joints (range 0–28), mean ± SD||1.1 ± 3.1||1.1 ± 2.8||1.0 ± 3.4||0.784|
|Number of gastrointestinal symptoms (range 0–14), mean ± SD||2.8 ± 2.5||3.6 ± 2.7||2.1 ± 2.2||< 0.001|
|Severity of gastrointestinal symptoms (range 0–10), mean ± SD||1.7 ± 2.6||2.2 ± 2.7||1.4 ± 2.4||0.003|
|Severity of breathing problems (range 0–10), mean ± SD||2.1 ± 2.7||2.6 ± 2.7||1.7 ± 2.6||0.001|
|Severity of Raynaud's symptoms (range 0–10), mean ± SD||3.0 ± 2.9||3.5 ± 3.1||2.6 ± 2.8||0.002|
|Severity of finger ulcers (range 0–10), mean ± SD||2.0 ± 2.9||2.4 ± 3.2||1.6 ± 2.6||0.009|
Pruritus by disease duration.
The prevalence of pruritus on most days in the last month was 69% (11 of 16) among patients 1.0–1.9 years from the onset of non-Raynaud's symptoms, 45% (18 of 40) for 2.0–2.9 years, 45% (10 of 22) for 3.0–3.9 years, 32% (10 of 31) for 4.0–4.9 years, 47% (44 of 94) for 5.0–9.9 years, 43% (60 of 140) for 10.0–19.9 years, and 46% (26 of 57) for ≥20.0 years. In post hoc analysis, compared with patients ≥2 years from the onset of non-Raynaud's symptoms, patients 1.0–1.9 years from the onset of non-Raynaud's symptoms were significantly more likely to report pruritus (P = 0.049).
Clinical correlates of pruritus.
As shown in Table 1, patients with pruritus had significantly more skin involvement (P = 0.029), more GI symptoms (P < 0.001), worse GI symptoms (P = 0.003), worse breathing problems (P = 0.001), worse Raynaud's symptoms (P = 0.002), and more severe finger ulcers (P = 0.009). Results from the multiple logistic regression analysis are shown in Table 2. The only independent predictor of pruritus was the number of GI symptoms (P < 0.001). The final model had adequate discriminative power (c-index = 0.64) and calibration (P = 0.279 for the Hosmer-Lemeshow statistic). Model estimates for the number of GI symptoms (odds ratio 1.25, P < 0.001) and other correlates did not change substantively if the physician global SSc severity estimates were included (data not shown). The severity of GI symptoms was not significantly related to pruritus in multivariable analysis (odds ratio 1.07, 95% confidence interval 0.98–1.17; P = 0.157). When diffuse/limited disease status was substituted for the MRSS in post hoc analysis, it was not significantly related to pruritus (P = 0.859).
Table 2. Results from hierarchical multiple logistic regression analysis predicting pruritus
|Step 1: sociodemographic variables|| || |
| Age, years||1.00 (0.98–1.01)||0.553|
| Female sex||1.10 (0.60–2.01)||0.763|
| Married or living as married||1.12 (0.73–1.73)||0.609|
| More than high school education||0.90 (0.60–1.34)||0.593|
|Step 2: sociodemographic and disease variables|| || |
| Age, years||1.00 (0.98–1.02)||0.949|
| Female sex||1.10 (0.58–2.10)||0.769|
| Married or living as married||0.99 (0.62–1.57)||0.960|
| More than high school education||1.02 (0.66–1.56)||0.942|
| Years since onset of non-Raynaud's symptoms||1.00 (0.97–1.03)||0.903|
| Modified Rodnan skin score (range 0–51)||1.02 (0.99–1.04)||0.141|
| Number of tender joints (range 0–28)||0.98 (0.92–1.05)||0.566|
| Number of gastrointestinal symptoms (range 0–14)||1.25 (1.13–1.37)||< 0.001|
| Severity of Raynaud's symptoms (range 0–10)||1.02 (0.93–1.11)||0.677|
| Severity of finger ulcers (range 0–10)||1.03 (0.94–1.13)||0.569|
| Breathing problems (range 0–10)||1.04 (0.95–1.14)||0.374|
Because the number of reported GI symptoms significantly predicted pruritus, we conducted post hoc analyses to determine which GI symptoms were associated with pruritus (Table 3). Of the 14 specific GI indicators assessed, all were more likely to be present among patients who reported pruritus.
Table 3. Association of individual gastrointestinal symptoms with pruritus
|Poor appetite||91 (22.8)||57 (32.0)||34 (15.4)||2.59 (1.60–4.20)|
|Difficulty swallowing||166 (41.5)||89 (49.7)||77 (34.8)||1.85 (1.24–2.77)|
|Acid reflux||191 (47.8)||99 (55.3)||92 (41.6)||1.74 (1.17–2.58)|
|Nocturnal choking||72 (18.0)||40 (22.3)||32 (14.5)||1.69 (1.01–2.83)|
|Heartburn||88 (22.1)||48 (26.8)||40 (18.2)||1.65 (1.02–2.65)|
|Early satiety||116 (29.0)||70 (39.1)||46 (20.8)||2.44 (1.57–3.80)|
|Abdominal bloating||122 (30.5)||68 (38.0)||54 (24.4)||1.90 (1.23–2.91)|
|Nausea and vomiting||43 (10.8)||31 (17.3)||12 (5.4)||3.65 (1.81–7.34)|
|Chronic constipation||76 (19.0)||55 (30.7)||21 (9.5)||4.22 (2.44–7.33)|
|Chronic diarrhea||68 (17.0)||40 (22.3)||28 (12.7)||1.98 (1.17–3.37)|
|Antibiotics for bacterial overgrowth||14 (3.5)||7 (3.9)||7 (3.2)||1.24 (0.43–3.62)|
|Greasy stools||73 (18.2)||40 (22.3)||33 (14.9)||1.64 (0.98–2.73)|
|Fecal incontinence||69 (17.2)||39 (21.8)||30 (13.6)||1.77 (1.05–2.99)|
|Parenteral nutrition||3 (0.8)||2 (1.1)||1 (0.5)||2.49 (0.22–27.64)|
This is the first study to investigate the prevalence and correlates of pruritus in SSc. Slightly less than half of all of the SSc patients reported pruritus on most days, although this rate was higher among patients 1.0–1.9 years from the onset of non-Raynaud's symptoms. Other studies have found that pruritus was present daily in 77% of patients with extensive psoriasis (17), 87% of patients with atopic dermatitis (9), and 67% to 87% of patients 3 months to 2 years after burn injury (18). A population-based study from Norway reported that itch was present at least “a little” in the past week in 8% of 18,770 respondents (19). The at least “a little” criterion in the past week in that study, however, was a lower threshold than that used in the current study and in previous studies of patients with skin problems (9, 18, 19).
Patients who reported pruritus had significantly more skin involvement, more severe finger ulcers, worse breathing problems, more severe Raynaud's phenomenon, and a greater number of GI symptoms. In the multivariable analysis, only the number of GI symptoms significantly predicted pruritus. Data were not available, however, on the presence of primary biliary cirrhosis (PBC). PBC is a cholestatic, autoimmune liver disease for which a primary symptom is pruritus (20). In the absence of specific tests such as serum alkaline phosphatase or antimitochondrial antibodies to assess possible PBC, it is possible that PBC accounted for some cases of pruritus. However, several GI symptoms that were associated with pruritus in this analysis (e.g., difficulty swallowing, choking, heartburn, constipation, incontinence) would not be expected to be related to PBC. Furthermore, although PBC occurs more commonly in SSc than in the normal population, its prevalence is thought to be <10% in SSc (21), which makes it unlikely that it accounted for the high prevalence of pruritus we found. Similarly, data were not available on the use of antihistamines or low-dose steroids that may be prescribed to treat pruritus and could be associated with some GI symptoms (e.g., dyspepsia, constipation). However, antihistamines and low-dose steroids are not linked to most of the GI symptoms that were associated with pruritus in this study, so it is unlikely that their inclusion would have explained these associations.
When a single item that assessed severity/functional impairment from GI symptoms was used instead of the number of GI symptoms, it was not significantly related to pruritus. Therefore, it is possible that the presence of GI symptoms, but not the severity of GI symptoms per se, is associated with pruritus. One reason for this may be that the severity of GI symptoms in this sample was generally low even though many patients reported the presence of GI symptoms.
An additional limitation was that GI symptoms and pruritus were measured by self-report. Severity of Raynaud's phenomenon, finger ulcers, and breathing problems were also measured by self-report, but were not independently associated with pruritus. Nonetheless, it is possible that the self-report of GI symptoms may have affected the association with pruritus.
The finding that the MRSS was significantly related to pruritus in bivariable, but not in multivariable, analyses may have occurred because pruritus was measured dichotomously. Therefore, patients who had only minor itching and patients who itched so much that they bled, for instance, received the same rating for pruritus, which is a limitation. Currently, however, to our knowledge there are no feasibly implemented, validated measures of pruritus available. Several measurement scales for pruritus have been proposed, but most of them are difficult to use and/or not well validated. The Eppendorf Itch Questionnaire (22), for instance, assesses sensory, affective, temporal, and spatial dimensions of itch, as well as scratching. However, it takes ∼30 minutes to complete and is laborious to score. The Questionnaire for the Assessment of Pruritus (23) is lengthy, interviewer administered, laborious to score, and does not generate a single overall summary score. The Itch Severity Scale (24) is the self-report version of the Questionnaire for the Assessment of Pruritus, but has only weak evidence of validity and is complex to score. Long questionnaires that require complex manual scoring are difficult to implement in large registries such as the Canadian Scleroderma Research Group that collect data on many aspects of disease and related outcomes for large numbers of patients. Recently, a pilot study was conducted on the ItchyQoL (25), a 22-item, multidimensional tool that assesses symptoms, functional limitations, and emotions related to pruritus. It is quickly and easily scored and provides either a single total score or factor scores, but only rudimentary validation data are available for a sample of mixed dermatologic patients. Currently, we are collecting data to refine and validate this tool for SSc.
Another limitation of the current study is that there were no patients in the first year since the onset of non-Raynaud's symptoms because pruritus was assessed at the first annual followup visit. Furthermore, there were only 16 patients 1.0–1.9 years from the onset of non-Raynaud's symptoms, so the high rate of pruritus detected during this period should be interpreted cautiously. It was, however, consistent with what would be expected based on clinical reviews (3–5) and patient reports (6).
In summary, approximately half of the patients with SSc reported itching on most days during the past month, which is high compared with a general population estimate of ∼8% for at least “a little” itching (19). The rate of pruritus was highest among patients 1–1.9 years from disease onset and was independently associated with self-reported GI symptoms, controlling for sociodemographic and other disease characteristics. The results of this initial study emphasize the need for more focused research on pruritus in SSc.
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr. Thombs had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study conception and design. Razykov, Thombs, Hudson, Baron.
Acquisition of data. Thombs, Hudson, Bassel.
Analysis and interpretation of data. Razykov, Thombs, Hudson, Bassel, Baron.
ROLE OF THE STUDY SPONSOR
Actelion, Pfizer, and Inova had no role in the design of the study, collection or analysis of the data, preparation of the manuscript, content of the manuscript, or decision to submit the manuscript for publication. Publication of this article was not contingent upon approval of Pfizer, Actelion, or Inova.
INVESTIGATORS OF THE CANADIAN SCLERODERMA RESEARCH GROUP
Investigators of the Canadian Scleroderma Research Group, in addition to the authors, are as follows: J. Pope, London, Ontario; J. Markland, Saskatoon, Saskatchewan; N. Khalidi, E. Kaminska, Hamilton, Ontario; D. Robinson, S. Mittoo, Winnipeg, Manitoba; N. Jones, Edmonton, Alberta; A. Masetto, Sherbrooke, Quebec; E. Sutton, Halifax, Nova Scotia; P. Docherty, Moncton, New Brunswick; J.-P. Mathieu, S. Ligier, Montreal, Quebec; M. Abu-Hakima, S. LeClercq, Calgary, Alberta; D. Smith, Ottawa, Ontario, Canada.