Original Paper Dermatology 2015;230:213–221 DOI: 10.1159/000371546
Received: June 28, 2014 Accepted after revision: December 13, 2014 Published online: January 27, 2015
Association between Skin and Joint Involvement in Patients with Psoriatic Arthritis Treated with Adalimumab: Analysis of Data from a German Non-Interventional Study Diamant Thaçi a Frank Behrens b Gerd Greger c Harald Burkhardt b Holger Gnann d Rudolf Schopf e Bianca Maria Wittig c a
Comprehensive Center for Inflammation Medicine, University Hospital Schleswig-Holstein Campus Lübeck, Lübeck, b Department of Rheumatology, University Hospital Frankfurt, Goethe University, Frankfurt am Main, c AbbVie Deutschland GmbH & Co. KG, Wiesbaden, d Biostatistics, GKM Gesellschaft für Therapieforschung mbh, Munich, and e Department of Dermatology, Johannes Gutenberg University School of Medicine, Mainz, Germany
Abstract Background: The association between skin and joint manifestations in patients with psoriatic arthritis (PsA) requires further characterization. Objective: We evaluated the association between severity of skin disease and joint involvement and the effectiveness and safety of adalimumab in PsA patients by baseline psoriasis severity. Methods: Descriptive statistics and regression analyses were used to evaluate data from 1,918 PsA patients starting adalimumab treatment. Subgroup analyses were conducted on patients empirically grouped by baseline target lesion score as a marker of psoriasis severity. Results: Psoriasis severity was not associated with joint manifestations at baseline or after 12 months of treatment. All subgroups showed improvements in skin and joints during therapy, and adalimumab was safe and well tolerated in all subgroups. Conclusion: The severity of skin manifestations does not correlate with the severity of joint disease in PsA patients; even patients with mild skin disease may have extensive musculoskeletal involvement. © 2015 S. Karger AG, Basel
© 2015 S. Karger AG, Basel 1018–8665/15/2303–0213$39.50/0 E-Mail [email protected] www.karger.com/drm
Introduction
Psoriatic arthritis (PsA) is the musculoskeletal manifestation of psoriasis with involvement of entheses and peripheral joints. Skin symptoms precede joint symptoms in approximately 80% of patients [1]. However, initial presentations vary widely, often leading to diagnostic confusion. In Germany, approximately 20% of psoriasis patients are affected by PsA [2, 3]. This number may underestimate the actual prevalence as PsA often remains undiagnosed. In a recent observational study in which psoriasis patients were screened for joint involvement at 48 clinics in Germany, 85% of patients with PsA had not been previously diagnosed [3]. Since dermatologists are the main source of care for psoriasis patients, they have an important role to play in the early recognition and effective treatment of PsA. A better understanding of disease manifestations or patient characteristics associated with PsA would be highly useful in helping dermatologists detect this condition early, and would improve the timely referral of the patient for rheu-
D. Thaçi and F. Behrens contributed equally to this study.
Prof. Dr. med. Diamant Thaçi Comprehensive Center for Inflammation Medicine University Hospital Schleswig-Holstein, Campus Lübeck Ratzeburger Allee 160, DE–23538 Lübeck (Germany) E-Mail diamant.thaci @ uksh.de
Downloaded by: University of Pennsylvania 198.143.38.1 - 6/17/2015 9:44:04 AM
Key Words Adalimumab · Psoriasis · Psoriatic arthritis · Target lesion score · Treatment
214
Dermatology 2015;230:213–221 DOI: 10.1159/000371546
Materials and Methods Study Design This report utilizes data from a single-arm, multicenter, prospective, non-interventional study of PsA patients who started adalimumab therapy at their clinician’s decision during routine clinical practice at 355 centers in Germany, including 234 rheumatology centers, 101 dermatology centers and 20 general practices. The data on all eligible patients who were enrolled between August 2005 and October 2009 are included in this report. The main objectives of this study were to explore the association between the severity of skin disease and joint involvement at baseline and during adalimumab treatment, and to evaluate the effectiveness and safety of adalimumab in PsA patients during routine clinical practice by baseline severity of psoriasis. Patients in the adalimumab non-interventional study had a diagnosis of PsA and active disease, and received adalimumab at the decision of and under the direction of their physician in accordance with the Summary of Product Characteristics [17]. Patients who had received prior treatment with adalimumab or did not have documentation of musculoskeletal disease were excluded from the analyses presented here. Patients who had received prior treatment with TNF-α inhibitors other than adalimumab were included. All patients were informed of the objectives of the study and gave written consent for their voluntary participation and the anonymous use of their personal data in statistical analyses. Because of the non-interventional nature of this study, ethics approval was not required by German law. Since patients with PsA do not necessarily have widespread skin involvement, an important component of some psoriasis assessments such as the Psoriasis Area and Severity Index (PASI) [18], we utilized the target lesion score (TLS) for the primary analysis of skin disease severity. The TLS has been used as an outcome measure in clinical trials [19, 20] and is preferred over the PASI in patients with low body surface area (BSA) involvement (20% BSA involvement (34.7 vs. 15.3%), higher mean TLS (8.5 vs. 5.9), higher mean TJC (23.4 vs. 13.3), less axial involvement (9.8 vs. 23.5%), less polyarthritis (50.2 vs. 65.1%) and less use of concomitant MTX (22.6 vs. 49.1%) than rheumatology clinic patients. In order to examine baseline characteristics associated with different levels of psoriasis severity, patients were empirically grouped into those with low (baseline TLS ≤3; n = 511), intermediate (baseline TLS 4–10; n = 1,045) or high (baseline TLS 11–15; n = 362) baseline TLS. These groups represented patients with mild, moderate or severe skin disease, respectively. Table 1 shows baseline demographic and disease characteristics by TLS group. The proportion of male patients increased with the severity of psoriasis (p < 0.0001). Although mean age was similar among the three groups, the mean age at psoriasis onset was higher in patients with low TLS (mild psoriasis) at baseline than in those with intermediate or high scores (moderate or severe psoriasis; p < 0.001). Other significant differences among TLS groups included duration of psoriasis, body mass index and distal interphalangeal involvement. As might be expected, BSA increased with increasing TLS, indicating that the TLS grouping provided an accurate representation of psoriasis severity. The proportion of patients seen in dermatology versus rheumatology clinics also increased with increasing TLS (p < 0.001 for both). The proportion of patients receiving concomitant DMARD therapy, including MTX, was significantly lower in patients with higher TLS (p < 0.001). There were no other consistent differences in baseline patient characteristics among the three groups. In all three groups, the most common type of joint involvement at baseline was polyarthritis. Additional baseline disease characteristics for each TLS group are presented in table 2. Mean joint counts showed only minor increases with higher TLS. The large standard deviations associated with mean joint counts suggested that these values were skewed by outliers. Evaluation of median joint counts also revealed only minor variations in joint involvement in patients with different baseline TLS. Slight increases in patient global assessment of overall disease activity and DAS28 scores were observed with increasing baseline psoriasis severity assessed by TLS, but the differences among groups were minimal. Regression analyses and Pearson correlations confirmed the lack of association between psoriasis severity and joint involvement at baseline (Pearson correlation coefficients of approximately 0.1 for the baseline association between TLS and TJC or SJC).
Skin and Joint Association in Psoriatic Arthritis
Dermatology 2015;230:213–221 DOI: 10.1159/000371546
Statistical Analyses Statistical analyses were performed using SAS® statistical software (version 9.2). Descriptive statistics or frequencies were computed for all data as appropriate. Due to the documentary nature of the study, data were not available for all assessments, and thus the sample size differed among parameters. Missing data were not imputed. Since the patient groups were heterogeneous and not matched with respect to confounding factors such as age, disease duration and disease activity, stepwise multiple regression analysis (forward selection and backward elimination) was the statistical method of choice to identify associations among relevant variables [23, 24]. Regression models were used to identify variables with significant correlations to TLS at baseline (n = 1,771) and at month 12 (n = 708) [25]. Approximately 40 possible explanatory variables were evaluated, including joint parameters (TJC and SJC). Pearson correlation coefficients provided an estimate of the strength of association between variables. Pearson correlation coefficients range from –1.0 (perfect negative correlation) to +1.0 (perfect positive correlation). Differences in baseline characteristics were additionally evaluated by an analysis of variance (ANOVA) F-test for continuous variables and by a χ2 test for independence of two variables for categorical variables. p values
Received: June 28, 2014 Accepted after revision: December 13, 2014 Published online: January 27, 2015
Association between Skin and Joint Involvement in Patients with Psoriatic Arthritis Treated with Adalimumab: Analysis of Data from a German Non-Interventional Study Diamant Thaçi a Frank Behrens b Gerd Greger c Harald Burkhardt b Holger Gnann d Rudolf Schopf e Bianca Maria Wittig c a
Comprehensive Center for Inflammation Medicine, University Hospital Schleswig-Holstein Campus Lübeck, Lübeck, b Department of Rheumatology, University Hospital Frankfurt, Goethe University, Frankfurt am Main, c AbbVie Deutschland GmbH & Co. KG, Wiesbaden, d Biostatistics, GKM Gesellschaft für Therapieforschung mbh, Munich, and e Department of Dermatology, Johannes Gutenberg University School of Medicine, Mainz, Germany
Abstract Background: The association between skin and joint manifestations in patients with psoriatic arthritis (PsA) requires further characterization. Objective: We evaluated the association between severity of skin disease and joint involvement and the effectiveness and safety of adalimumab in PsA patients by baseline psoriasis severity. Methods: Descriptive statistics and regression analyses were used to evaluate data from 1,918 PsA patients starting adalimumab treatment. Subgroup analyses were conducted on patients empirically grouped by baseline target lesion score as a marker of psoriasis severity. Results: Psoriasis severity was not associated with joint manifestations at baseline or after 12 months of treatment. All subgroups showed improvements in skin and joints during therapy, and adalimumab was safe and well tolerated in all subgroups. Conclusion: The severity of skin manifestations does not correlate with the severity of joint disease in PsA patients; even patients with mild skin disease may have extensive musculoskeletal involvement. © 2015 S. Karger AG, Basel
© 2015 S. Karger AG, Basel 1018–8665/15/2303–0213$39.50/0 E-Mail [email protected] www.karger.com/drm
Introduction
Psoriatic arthritis (PsA) is the musculoskeletal manifestation of psoriasis with involvement of entheses and peripheral joints. Skin symptoms precede joint symptoms in approximately 80% of patients [1]. However, initial presentations vary widely, often leading to diagnostic confusion. In Germany, approximately 20% of psoriasis patients are affected by PsA [2, 3]. This number may underestimate the actual prevalence as PsA often remains undiagnosed. In a recent observational study in which psoriasis patients were screened for joint involvement at 48 clinics in Germany, 85% of patients with PsA had not been previously diagnosed [3]. Since dermatologists are the main source of care for psoriasis patients, they have an important role to play in the early recognition and effective treatment of PsA. A better understanding of disease manifestations or patient characteristics associated with PsA would be highly useful in helping dermatologists detect this condition early, and would improve the timely referral of the patient for rheu-
D. Thaçi and F. Behrens contributed equally to this study.
Prof. Dr. med. Diamant Thaçi Comprehensive Center for Inflammation Medicine University Hospital Schleswig-Holstein, Campus Lübeck Ratzeburger Allee 160, DE–23538 Lübeck (Germany) E-Mail diamant.thaci @ uksh.de
Downloaded by: University of Pennsylvania 198.143.38.1 - 6/17/2015 9:44:04 AM
Key Words Adalimumab · Psoriasis · Psoriatic arthritis · Target lesion score · Treatment
214
Dermatology 2015;230:213–221 DOI: 10.1159/000371546
Materials and Methods Study Design This report utilizes data from a single-arm, multicenter, prospective, non-interventional study of PsA patients who started adalimumab therapy at their clinician’s decision during routine clinical practice at 355 centers in Germany, including 234 rheumatology centers, 101 dermatology centers and 20 general practices. The data on all eligible patients who were enrolled between August 2005 and October 2009 are included in this report. The main objectives of this study were to explore the association between the severity of skin disease and joint involvement at baseline and during adalimumab treatment, and to evaluate the effectiveness and safety of adalimumab in PsA patients during routine clinical practice by baseline severity of psoriasis. Patients in the adalimumab non-interventional study had a diagnosis of PsA and active disease, and received adalimumab at the decision of and under the direction of their physician in accordance with the Summary of Product Characteristics [17]. Patients who had received prior treatment with adalimumab or did not have documentation of musculoskeletal disease were excluded from the analyses presented here. Patients who had received prior treatment with TNF-α inhibitors other than adalimumab were included. All patients were informed of the objectives of the study and gave written consent for their voluntary participation and the anonymous use of their personal data in statistical analyses. Because of the non-interventional nature of this study, ethics approval was not required by German law. Since patients with PsA do not necessarily have widespread skin involvement, an important component of some psoriasis assessments such as the Psoriasis Area and Severity Index (PASI) [18], we utilized the target lesion score (TLS) for the primary analysis of skin disease severity. The TLS has been used as an outcome measure in clinical trials [19, 20] and is preferred over the PASI in patients with low body surface area (BSA) involvement (20% BSA involvement (34.7 vs. 15.3%), higher mean TLS (8.5 vs. 5.9), higher mean TJC (23.4 vs. 13.3), less axial involvement (9.8 vs. 23.5%), less polyarthritis (50.2 vs. 65.1%) and less use of concomitant MTX (22.6 vs. 49.1%) than rheumatology clinic patients. In order to examine baseline characteristics associated with different levels of psoriasis severity, patients were empirically grouped into those with low (baseline TLS ≤3; n = 511), intermediate (baseline TLS 4–10; n = 1,045) or high (baseline TLS 11–15; n = 362) baseline TLS. These groups represented patients with mild, moderate or severe skin disease, respectively. Table 1 shows baseline demographic and disease characteristics by TLS group. The proportion of male patients increased with the severity of psoriasis (p < 0.0001). Although mean age was similar among the three groups, the mean age at psoriasis onset was higher in patients with low TLS (mild psoriasis) at baseline than in those with intermediate or high scores (moderate or severe psoriasis; p < 0.001). Other significant differences among TLS groups included duration of psoriasis, body mass index and distal interphalangeal involvement. As might be expected, BSA increased with increasing TLS, indicating that the TLS grouping provided an accurate representation of psoriasis severity. The proportion of patients seen in dermatology versus rheumatology clinics also increased with increasing TLS (p < 0.001 for both). The proportion of patients receiving concomitant DMARD therapy, including MTX, was significantly lower in patients with higher TLS (p < 0.001). There were no other consistent differences in baseline patient characteristics among the three groups. In all three groups, the most common type of joint involvement at baseline was polyarthritis. Additional baseline disease characteristics for each TLS group are presented in table 2. Mean joint counts showed only minor increases with higher TLS. The large standard deviations associated with mean joint counts suggested that these values were skewed by outliers. Evaluation of median joint counts also revealed only minor variations in joint involvement in patients with different baseline TLS. Slight increases in patient global assessment of overall disease activity and DAS28 scores were observed with increasing baseline psoriasis severity assessed by TLS, but the differences among groups were minimal. Regression analyses and Pearson correlations confirmed the lack of association between psoriasis severity and joint involvement at baseline (Pearson correlation coefficients of approximately 0.1 for the baseline association between TLS and TJC or SJC).
Skin and Joint Association in Psoriatic Arthritis
Dermatology 2015;230:213–221 DOI: 10.1159/000371546
Statistical Analyses Statistical analyses were performed using SAS® statistical software (version 9.2). Descriptive statistics or frequencies were computed for all data as appropriate. Due to the documentary nature of the study, data were not available for all assessments, and thus the sample size differed among parameters. Missing data were not imputed. Since the patient groups were heterogeneous and not matched with respect to confounding factors such as age, disease duration and disease activity, stepwise multiple regression analysis (forward selection and backward elimination) was the statistical method of choice to identify associations among relevant variables [23, 24]. Regression models were used to identify variables with significant correlations to TLS at baseline (n = 1,771) and at month 12 (n = 708) [25]. Approximately 40 possible explanatory variables were evaluated, including joint parameters (TJC and SJC). Pearson correlation coefficients provided an estimate of the strength of association between variables. Pearson correlation coefficients range from –1.0 (perfect negative correlation) to +1.0 (perfect positive correlation). Differences in baseline characteristics were additionally evaluated by an analysis of variance (ANOVA) F-test for continuous variables and by a χ2 test for independence of two variables for categorical variables. p values
