QJM Advance Access originally published online on April 4, 2006
QJM 2006 99(5):307-315; doi:10.1093/qjmed/hcl038
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Presenting characteristics as predictors of duration of treatment in sarcoidosis
From the 1University of Cincinnati Medical Center, Cincinnati, Ohio, 2Medical University of South Carolina, Charleston, South Carolina, 3Mount Sinai Medical Center, New York, New York, 4Georgetown University Medical Center, Washington DC, 5University of Pennsylvania and MCP-Hahnemann University Medical Centers, Philadelphia, Pennsylvania, and 6Clinical Trials and Surveys Corporation, Baltimore, Maryland, USA
Address correspondence to Dr R.P. Baughman, 1001 Holmes, Eden Ave, Cincinnati, OH 45267–0565, USA. email: bob.baughman{at}uc.edu
Received 29 July 2005 and in revised form 8 March 2006
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Background: Some sarcoidosis patients never need therapy, but many still require therapy more than 2 years after initial diagnosis.
Aim: To determine what features at initial presentation are associated with treatment 2 years later.
Methods: Patients with biopsy-confirmed sarcoidosis enrolled in the ACCESS (A Case Control Etiologic Study of Sarcoidosis) study were initially evaluated within 6 months of diagnosis. Pulmonary function, chest X-ray and dyspnoea score were measured, and systemic therapy for the sarcoidosis recorded. Organ involvement was assessed using a standardized instrument. A subset (n = 215) were seen 18–24 months later for follow-up, and these patients constitute our study group.
Results: Ten patients had only received therapy before the first visit, with no further therapy, and were excluded from analysis. Of the remaining 205, 95 were not on therapy at the initial visit and 75 (79%) of these were never treated during follow-up. Of the 110 initially on therapy, 52 (47%) remained on therapy at follow-up. Other initial features associated with continued therapy were the level of dyspnoea and predicted vital capacity. On logistic regression, only dyspnoea and therapy at initial visit remained significant. Patients on systemic therapy at initial evaluation were more likely to be on therapy at follow-up (OR 3.6, p = 0.003). Neither ethnicity nor gender independently predicted therapy at follow-up.
Discussion: This study group represents a sample of newly diagnosed sarcoidosis patients. However, this is a referral population, and there was no set protocol for treatment. Use of systemic therapy within the first 6 months after diagnosis appears to be strongly associated with continued use of therapy 2 years later.
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Introduction |
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Sarcoidosis is a disease with diverse clinical outcomes. Many patients will have resolution of their disease within 2 years of presentation.1 Although some patients never need therapy, there are many who require therapy more than 2 years after initial diagnosis. This latter group of patients with chronic disease is reported to represent from 20–60% of sarcoidosis patients.2 However, such reports are dominated by patients followed at subspecialty clinics, and may not be representative of unselected sarcoidosis patients.3
In a study with clinical follow-up for at least 2 years on all patients, Gottlieb et al. noted that patients placed on corticosteroid therapy within 6 months of presentation usually could not be withdrawn from therapy or had a high rate of relapse.4 Others have noted that patients who required initial therapy may also require long-term corticosteroids. In such situations, investigators have recommended the lowest possible dose of prednisone, rather than limiting the duration of therapy.5,6
The ACCESS study (A Case Control Etiologic Study of Sarcoidosis) consisted of well-defined newly diagnosed cases of sarcoidosis in the US.7 As part of ACCESS, we re-evaluated the first third of patients enrolled in the study, 2 years after their initial evaluations. The clinical outcome of these patients has been previously reported.8 ACCESS did not direct therapy for these patients. However, the study did allow us to survey the treatment given during the 2 years of observation, and the various clinical characteristics of the patients deemed to have needed treatment.
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Methods |
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Patients were recruited into ACCESS as previously described.9 Patients enrolled in the first year of the study were eligible for re-evaluation 18–24 months after the initial evaluation. All patients who participated in the first year of ACCESS were asked to return for this follow-up visit as part of their original informed consent statement, approved by the Institutional Review Boards of the participating centres.
Patients returned 18–24 months after their initial ACCESS visit. Several of the items from the initial evaluation9 were repeated at the second visit, including a detailed assessment of organ involvement.10 Patients had to have either definite or probable organ involvement for that organ to be considered affected. We also collected dyspnoea score, pulmonary function studies, and chest X-ray. Not all patients had pulmonary function studies and chest X-ray at both visits. The dyspnoea score was previously reported.11,12 Patients were asked what activities caused them shortness of breath, and the answers were classified as: level 0, shortness of breath after strenuous exercise; level 1, shortness of breath after hurrying or hills; level 2, needing to walk slower than others; level 3, needing to stop after 100 yards; level 4, unable to leave house. Pulmonary function studies were done and the percentage predicted values were calculated as proposed by Hankinson et al.13 These predicted values, corrected for ethnicity, were used at all ten ACCESS sites. Lung diffusion of carbon monoxide was not measured for this study. Patients were also asked at each visit about medications they had received for their sarcoidosis. These included corticosteroids, methotrexate, azathioprine, hydroxychloroquine, cyclophosphamide, and pentoxifylline. Patients receiving topical therapy alone (e.g. inhaled corticosteroids, corticosteroid skin creams, corticosteroid eye drops) were not considered to be on therapy.
Of the 235 patients enrolled in the first year of the study, 215 (91%) provided sufficient information to assess their systemic therapy at the initial and follow-up visit. Ten patients had received therapy prior to their first ACCESS visit, but were not receiving therapy at the time of the first visit. These patients received <2 months of therapy and were excluded from further analysis, since the reason for therapy was unclear. Treatment was most commonly with systemic corticosteroids. Patients receiving alternatives to corticosteroids were also included. Table 1 lists drugs that were used on at least two patients with sarcoidosis during any time of their therapy. At baseline (B), interim (I), and follow-up (F), patients were either receiving therapy (+) or not (–), including methotrexate, hydroxychloroquine, or azathioprine.
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There was no interim follow-up visit. Information on therapy during the interim period was based on data collection at the follow-up visit. Five groups of patients were included in the analysis: (i) never treated, B– I– F–; (ii) no therapy at baseline, interim therapy only, B– I+ F–; (iii) no therapy at baseline, on therapy at follow-up, B– I+ F+; (iv) on therapy at baseline, off therapy at follow-up, B+ I+ F–; (v) always on therapy, B+ I+ F+. All patients who were on therapy at follow-up were counted as being on therapy during the interim period. All patients who were on therapy at baseline were counted as being on therapy in the interim. Thus there were no patients in the B– I– F+, B+ I– F– or B+ I– F+ groups, by definition.
Statistics
Means and percentages were used to describe the study population. Statistical comparisons when performed were calculated using the 
2 test for comparison of proportions, and using unpaired t-tests or Analysis of Variance (ANOVA) for univariate analyses comparing the different treatment status groups. Differences among groups were considered significant if the p value for the associated statistic was 
0.05.
Logistic regression was used to determine the independent baseline variables that were related to the outcome of medical therapy at the ACCESS follow-up visit. No intermediate treatment variables were included in the logistic regression, to prevent possible confounding by indication, nor was there any selection routine for pre-determining the variables that would be included in the model. There were a large number of variables collected in ACCESS. This analysis was carried out using only the variables presented in Table 5, to limit the multiple comparisons problem. All variables considered in the model are presented in Table 5. The percent predicted FVC was treated as a continuous variable in the regression analysis; all other variables were categorized. The reference group is the complement of the stated variable name for binary variables, and dyspnoea level 0 was used as the reference group for the baseline dyspnoea score. The effect for each dyspnoea group is presented in comparison to the beta coefficients for the dummy variable that was used in the model. An overall p value associated with dyspnoea level was calculated using the likelihood ratio test. The odds ratio, 95%CI and p value were calculated for each independent/dummy variable in the model.
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The characteristics of the patients in the study are summarized in Table 2. The patients were not different from the whole group of 736 patients enrolled into ACCESS.7
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The characteristics of the patients in the five treatment groups are summarized in Table 3. There were no important differences in the proportion of women in each treatment group. There was also no difference in the ages for patients in each treatment group (data not shown). Ethnicity (self-reported) varied among the groups. Of those patients who were never treated (B– I– F–), only 31% were African American, while 63% of those receiving continuous therapy (B+ I+ F+) were African American (ANOVA, p < 0.0001).
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Ninety-one percent of the patients in the study had intrathoracic involvement. Figure 1 demonstrates the percent predicted vital capacity at the initial visit for the 193 patients who had studies done both initially and at follow up. There was a significant difference between the various treatment groups, with patients receiving therapy more likely to have a reduced vital capacity (ANOVA, p < 0.05). All four patients with vital capacity <50% were still receiving therapy. Figure 2 compares the Scadding chest X-ray score14 versus the various treatment groups for the 196 patients who had X-rays at both time points. There was no significant difference between groups. The level of dyspnoea reported by the patients in each treatment group is shown in Figure 3. There was a significant difference between the groups (ANOVA, p < 0.001). Patients who received therapy had more dyspnoea than those who were not treated.
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We performed an analysis of the African American and Caucasian patients in the study. For these two groups, there was no significant difference between the percent vital capacity and the different treatment groups. There was a significant difference between treatment groups and level of dyspnoea for both the African American and Caucasian patient groups (ANOVA p < 0.0001 for both groups). Figure 4 shows the number of patients for both the African American and Caucasian groups. African American patients were more likely to have level 2–4 dyspnoea (19/92, 20.6%) than were Caucasians (8/113, 7.1%). This difference in severity was significant (
2 = 7.025, p < 0.01). The presence of more dyspnoea in the African American patients was associated with a higher need for therapy at follow-up (Table 3).
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There were no significant differences between the groups for any individual organ involvement (Table 4). There were only three cases in which either neurological or cardiac involvement were seen at the initial evaluation, and the patients were never treated. Six of eleven patients initially treated for neurological involvement were off therapy by follow-up evaluation. For cardiac disease, 3/6 treated patients were off therapy by follow-up evaluation. Also shown in Table 4 is the number of patients in each treatment group who developed one or more new organ involvement. There was a significant difference in the proportion of patients who developed new organ involvement (ANOVA, p < 0.001). Patients who developed new organ involvement were more likely to be treated at the follow-up visit.
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The clinical outcome of the patients varied depending on the initial therapy. Of the 95 patients who were not receiving treatment at the initial visit, only 8 (8%) were receiving therapy at the follow-up visit. Of the 110 patients who were receiving therapy at initial visit, 52 (47%) were still receiving therapy at follow-up (
2 35.32, p < 0.0005). Figure 5 does not include the 10 patients who were not on therapy either initially or at follow-up, but were treated in the interim.
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A logistic regression was performed comparing several of the initial presentation features vs. the need for therapy at the follow-up visit. Table 5 shows the odds ratio (OR), 95%CI and p value for the overall significance of the covariable. The only features on presentation which were significant were the presence of systemic therapy at the time of the initial visit and dyspnoea. Patients on systemic therapy at time of the initial evaluation were more likely to be on therapy at follow up visit (OR 3.6, p = 0.003). The table compares several levels of dyspnoea. Patients with dyspnoea levels 1 and 2 at presentation were twice as likely to be on systemic therapy at follow-up compared to the non dyspnoeic patients, and patients with dyspnoea level 3 or 4 were four times more likely to be on systemic therapy compared to the dyspnoea level 0 patients, although this interpretation is subject to question, since the overall
2 test (with three degrees of freedom) indicated that the dyspnoea factor was not significantly different from 0 (p = 0.097). |
Discussion |
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In the current study, not all sarcoidosis patients were treated. In prior single-centre studies, as few as a third of patients were treated.15–17 Gottlieb et al. found that over two-thirds of their patients required systemic therapy.4 In the current study, over half of the patients were eventually treated with systemic therapy. Fifty percent of patients who were on therapy at initial evaluation were on therapy at follow-up. Only ten percent of patients not on therapy at initial evaluation were on therapy at follow-up.
There have been several explanations for these differences in therapy.2 One difference is the criteria used by physicians to treat patients. Some authors claim that some patients are over-treated.3,15 One study treated only 4/159 patients for progression of their disease over a prolonged follow-up.18 While over-treatment may be a factor, another possibility is a difference in the clinical status of the patients treated. Honeybourne et al. noted a worse clinical outcome and higher need for corticosteroid therapy for West Indians of African descent versus other groups treated at one clinic in London.19 In a study of patients followed in the UK with new-onset sarcoidosis, 20% were started on therapy during the first 6 months after diagnosis because of clinical worsening of disease.17 In America, the rate of reported therapy was higher for clinics with mostly African Americans4,6 than for a clinic of mostly Caucasians.15 In this study, African Americans were more likely to receive therapy because of more severe disease.
Two studies have examined the effect of 18 months of corticosteroid therapy for asymptomatic patients with persistent parenchymal lung disease (stage 2 or 3). Patients were treated with either systemic steroids for 18 months17 or 3 months of systemic steroids followed by 15 months of inhaled corticosteroids (budesonide).20 Both studies showed mild improvement in lung function after the 18 months of therapy. For both studies, this improvement persisted for 5 years of observation after the study. In addition, patients treated with corticosteroids for 18 months were less likely to have a clinical relapse requiring institution of systemic therapy during this 5-year observation period.20 These studies would seem to refute the concept that corticosteroid therapy by itself causes the need for long-term treatment, and support the idea that initial treatment is only a marker for more severe disease.
This study did not include a protocol for therapy. We recorded whether patients were treated, but did not attempt to determine the rationale for therapy. However, since we only enrolled patients who were referred to us, this could have confounded our results. Physicians in a given geographic area unaware of the ACCESS study or patients unwilling to enrol in the study may have a different clinical outcome.
Therapy was usually given if the patient was symptomatic, in accordance with published guidelines.21 Dyspnoea had the best association with future treatment in this study. Although the overall 2 was not significant, this could have been due to sample size restrictions. Overall, a good ordinal relationship was established and the highest dyspnoea categories show a substantially higher propensity to lead to treatment than the lowest category. The chest X-ray did not predict therapy.
This study was designed to prospectively follow patients who had been diagnosed within 6 months of initial evaluation. The ACCESS study had strict criteria for diagnosis and patients were well defined at the time of initial evaluation.7 However, the study was not a prospective study of all newly diagnosed sarcoidosis patients. Patients were specifically referred to the study, and therefore a referral bias is present.
Pulmonary involvement was common for all groups. Pulmonary status in this study was evaluated using three methods of assessment: chest X-ray, vital capacity measurement, and dyspnoea score.7 The chest radiograph pattern was not different between the different groups of patients. However, the pulmonary function studies and dyspnoea score were both significantly different between groups. Given the previously noted ethnic difference in percentage of patients treated for sarcoidosis, we analysed the ethnic subgroups with regard to dyspnoea. Dyspnoea was observed in both African Americans and Caucasians, and in both groups, higher levels of dyspnoea were associated with a higher likelihood of therapy. However, African Americans were more likely to be dyspnoeic.
The size of our study allowed us to perform a logistic regression analysis to see what features at the initial evaluation were associated with the presence of therapy at the follow up visit (Table 5). Using this approach, we no longer found that vital capacity was predictive of the presence of therapy at follow-up. This may be because dyspnoea was more predictive of the presence of therapy at follow-up. For example, patients with level 3 or 4 dyspnoea, compared to those with no dyspnoea, had an OR of 4.04 to be on therapy at follow-up. We are not aware of any previous report that initial dyspnoea is an independent predictor of the presence of therapy 2 years after initial evaluation. The presence of systemic therapy at the initial visit was highly associated with the presence of therapy at follow-up.
We could not demonstrate that the presence of cardiac or neurological disease at initial evaluation was associated with the need for therapy at follow-up. However, this was only 10% of the whole group. The study contained a high proportion of females, African Americans, and older patients, but none of these factors was independently associated with the presence of therapy at follow-up.
The difference in clinical outcome for those treated initially vs. those treated subsequently is summarized in Figure 4. Patients who were on therapy at the initial evaluation had a 50% chance of still being on therapy after 2 years. This was significantly higher than the 10% found to still be on therapy at 2-year follow up if the patient was not on initial therapy. This observation supports the longer study by Gottlieb et al.4
Therapy for at least 2 years was encountered in approximately 25% of patients in this study, similar to the findings in other studies.15,16 Prolonged therapy can be associated with significant toxicity.22,23 In one study of acute sarcoidosis patients treated with systemic corticosteroids for up to 1 year, a third of patients complained of one or more severe side-effects due to corticosteroids.24 Alternatives to corticosteroids may lead to significantly less toxicity.22,23,25
The patients in this study group represent a sample of newly diagnosed sarcoidosis patients. The limitations of the study include the fact that this is a referral population, and that there was no set protocol for treatment. Only 91% of the potential study patients returned for their follow-up visit. Most patients had pulmonary disease. Using a logistic regression analysis, we found that initial therapy and dyspnoea were independently associated with the likelihood of chronic therapy, while chest X-ray stage at presentation had no association with therapy. African Americans were more likely to require therapy, because they had more severe disease. The need for therapy at 2 years was strongly associated with initial decision to treat.
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This study received funding from the National Heart Lung and Blood Institute. Supported by contracts NO1-HR-56065, 56066, 56067, 56068, 56069, 56070, 56071, 56072, 56073, 56074, and 56075.
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References |
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