Changes in Disease Activity and Damage Over Time in Patients With Morphea

Key Points

Question  What is the disease course in patients with morphea?

Findings  In this cohort study of 130 adults and children with morphea, most achieved substantial improvement in disease activity using published treatment plans; disease activity improved rapidly with treatment (≤1 year), and overall disease damage stabilized (with improvement in sclerosis at >1 year and a slight increase in atrophy) even after discontinuation of treatment. Adults and patients with generalized subtype were more likely than children and patients with linear subtype to have recurrence of disease activity.

Meaning  Existing morphea treatment plans appear to improve disease activity and stabilize disease damage; however, some patients with morphea have a relapsing-remitting course over many years.

Importance  Prospective studies of the disease course in patients with morphea are lacking, particularly those comparing adults and children.

Objective  To investigate the disease course in patients with morphea treated with standard-of-care therapy using validated clinical outcome measures.

Design, Setting, and Participants  Prospective cohort study of 130 adults and children from the Morphea in Adults and Children cohort with at least 2 years of clinical follow-up and Localized Scleroderma Cutaneous Assessment Tool scores recorded at each study visit. Study patients were seen at a tertiary referral center (UT Southwestern Medical Center, Dallas, Texas) from November 1, 2008, through April 1, 2016. The dates of analysis were May 2016 through July 2019.

Exposures  All patients received standard-of-care therapy.

Main Outcomes and Measures  Patterns in disease activity and recurrence were examined. The time to recurrence of morphea disease activity from the first visit with inactive disease was assessed using survival analysis with the log-rank test to compare differences between morphea subtypes.

Results  In total, 130 adults and children (663 study visits) were included in this study. The mean (SD) age of patients was 34.4 (23.8) years, and 101 of 130 (78%) were female. The mean (SD) follow-up was 4.3 (1.7) years. Fifty patients had at least 5 years of follow-up. Most patients were white individuals (96 of 130 [74%]) and had linear subtype (72 of 130 [55%]) or generalized subtype (40 of 130 [31%]). Overall, 13 of 30 (43%) with generalized subtype had recurrence of disease activity compared with 14 of 66 (21%) with linear subtype (hazard ratio, 3.28; 95% CI, 1.38-7.79). The median (interquartile range) time to first recurrence of disease activity after initial resolution of disease activity was 1.1 (0.8-1.9) years for generalized subtype and 2.3 (1.0-3.3) years for linear subtype. Of the 50 patients followed up for at least 5 years, 18 (36%) had recurrence of disease activity.

Conclusions and Relevance  Disease activity appeared to improve in most patients with morphea over 6 to 12 months using previously published treatment plans, underscoring their effectiveness. Sclerosis improved more slowly (over 2-5 years), often after discontinuation of treatment, but atrophy increased slightly as sclerosis subsided. Standard-of-care therapy appears to improve disease activity, which allows sclerosis to improve, and provides relative stability of other features of disease damage. A substantial number of patients, particularly those with generalized subtype, have a relapsing-remitting course over many years. Patients with morphea should be monitored for recurrent disease activity over extended periods.

Morphea (localized scleroderma) is an autoimmune disease of the skin and underlying connective tissue that impairs quality of life and physical function in adults and children.^1-3 Disease activity in patients with morphea is characterized by periods of inflammation with new or expanding lesions, followed by sclerosis, permanent atrophy, contracture, or limb-length discrepancy (disease damage). Therefore, treatment of morphea, which consists predominantly of immunosuppressive therapies, is aimed at ceasing disease activity to prevent further disease damage.⁴

The natural history of morphea, particularly the evolution of disease activity and damage over time, has not been extensively studied. The time to resolution of disease activity with standard-of-care therapy is poorly described, making it difficult for clinicians to assess whether patients have had an adequate therapeutic trial. Even less is known about the duration of remission of active disease and whether disease damage stabilizes with prolonged remission of disease activity. Studies^5-7 indicate that adults with morphea may have persistent disease activity or a relapsing-remitting course, which has been mirrored in pediatric populations. For example, in patients treated with UV-A1 phototherapy, a 46% recurrence rate of morphea disease activity has been reported.⁸ These knowledge gaps impair the ability to optimally treat patients with morphea.

Prospective studies examining the course of morphea disease activity and damage over prolonged periods and across disease subtypes are essential for planning therapy and clinical follow-up. Furthermore, understanding the time to remission, its duration, and the association between disease activity and damage is integral to planning and conducting interventional and observational studies. To address this knowledge gap, we investigated the disease course of morphea as measured by the disease activity and damage components of the Localized Scleroderma Cutaneous Assessment Tool (LoSCAT), a validated clinical outcome measure,⁹ in a prospective cohort of patients with morphea and assessed whether there were differences based on patient age, morphea subtype, and treatment.

In this prospective cohort study, patients were enrolled from the Morphea in Adults and Children cohort, a registry designed to better understand the demographic characteristics and clinical outcomes of patients with morphea. The study was approved by the UT Southwestern Medical Center institutional review board, and written informed consent was obtained from all participants. Some patients have been included in prior publications.¹⁰ Patients underwent study visits at a tertiary referral center (UT Southwestern Medical Center, Dallas, Texas) from November 1, 2008, through April 1, 2016. The dates of analysis were May 2016 through July 2019. Inclusion criteria were at least 2 years of clinical follow-up, with relevant demographic and clinical information and physical examination data, including LoSCAT scores recorded at each study visit.

All patients were examined by 1 of us (H.T.J.), were assigned a morphea subtype according to the Padua criteria,¹¹ and were assessed for disease activity and damage based on the LoSCAT score. Additional data included demographic and clinical features, physical examination findings, and treatment type and duration. Study visits occurred at 6-month to 12-month intervals.

Consistent with the observational study design, patients received standard-of-care therapy, including methotrexate sodium (with or without corticosteroids) or UV-A1 phototherapy. All patients were managed by 1 of us (H.T.J.). The Childhood Arthritis and Rheumatology Research Alliance Consensus Treatment Plan was used to guide the indication for methotrexate sodium,⁴ which includes recommended dosing of 1 mg/kg per week, with a maximum of 25 mg per week for children. Adults received 15 to 25 mg per week. Patients receiving methotrexate typically were treated for 9 to 18 months, and the dose was then gradually tapered over the following 6 to 12 months. For UV-A1 phototherapy, administration was performed according to the previously published Morphea in Adults and Children cohort UV-A1 phototherapy protocol,⁸ which uses medium-dose to high-dose UV-A1. The standard of care was to discontinue UV-A1 phototherapy after 30 to 40 treatments. The decision to treat with methotrexate vs UV-A1 phototherapy is based on the clinical presentation of morphea. Methotrexate is used in most patients with deeper lesions, which often includes those with linear subtype. Corticosteroids are coadministered with methotrexate for the first 2 to 3 months in patients with severe or rapidly progressive disease threatening function. In contrast, UV-A1 phototherapy is offered to patients with more superficial involvement, which is more common in adults with generalized subtype in our cohort. Patients with mild disease (dermal circumscribed lesions) were offered topical therapy; in the case of inactive disease, no treatment was prescribed.

All patients were assigned LoSCAT scores¹² at each study visit. Active disease was defined as a score greater than 0 on either of the LoSCAT disease activity components, including the modified Localized Scleroderma Skin Severity Index (mLoSSI) or the Physician’s Global Assessment of Activity (PGA-A). The mLoSSI includes 3 components (erythema, induration, and new or expanding lesions) and is calculated based on total body sites involved.⁹ The PGA-A is a visual analog scale of the physician’s assessment of disease activity. Response to treatment was defined as reaching an mLoSSI of 0 (inactive disease). Recurrence was defined as any increase above 0 on both the mLoSSI and the PGA-A after response to treatment. Persistent disease activity was defined as active disease at all study visits. Disease damage was assessed with the Localized Scleroderma Skin Damage Index (LoSDI) and the Physician’s Global Assessment of Damage (PGA-D) components of the LoSCAT.

Means (SDs) and medians (interquartile ranges [IQRs]) were calculated for continuous variables. Frequency counts (percentages) were obtained for categorical variables. The primary outcome of this study was the time to recurrence of morphea disease activity from the first visit with inactive disease, comparing patients with linear subtype vs generalized subtype using survival analysis with the log-rank (Mantel-Cox) test. A similar analysis was performed that compared patients with pediatric-onset morphea vs adult-onset morphea and treatment with methotrexate vs UV-A1 phototherapy. The time to recurrence was assessed by the period elapsed between relevant study visits. Frequency counts of the proportions of patients with active vs inactive disease at years 1 to 7 of follow-up were obtained. Additional subgroup analyses were performed among patients with at least 5 years of follow-up, allowing for more uniform assessment of year-to-year changes and 5-year outcomes. Among these patients, changes in disease damage over time were also examined, including the LoSDI components (sclerosis, dermal atrophy, and subcutaneous atrophy). Percentage improvement or exacerbation from the baseline visit was assessed for clinical outcomes at each year of follow-up. P < .05 was considered statistically significant. All statistical analyses were performed using GraphPad Prism 7.0 (GraphPad Software).

Of the 588 patients enrolled in the Morphea in Adults and Children cohort, 130 adults and children with a total of 663 study visits met inclusion criteria for this study. The mean (SD) age of patients was 34.4 (23.8) years, and 101 of 130 (78%) were female. Reasons for exclusion included single study visit (n = 191), enrollment within 2 years of study inception (n = 119), enrollment before development of the LoSCAT (n = 89), multiple study visits but less than 2 years of follow-up (n = 51), and missing demographic or clinical data (n = 8) (eFigure 1 in the Supplement). Patients excluded had similar demographic and clinical features as those included in the study (Table 1). The mean (SD) follow-up was 4.3 (1.7) years. Fifty patients had at least 5 years of follow-up and were included in additional subgroup analyses. The 50 patients had demographic and clinical features similar to those of the cohort overall. Among all included patients, most were white individuals (96 of 130 [74%]) and had linear subtype (72 of 130 [55%]) or generalized subtype (40 of 130 [31%]). Table 1 lists additional details of the demographic and clinical features of patients.

In total, 32 of 48 patients (67%) treated with methotrexate and 15 of 32 patients (47%) treated with UV-A1 phototherapy had a complete response to treatment at 1 year, defined as an mLoSSI of 0. Compared with complete responders, partial responders were older (51.8 [IQR, 23-62] vs 18.0 [IQR, 11-54] years; P = .007), were more often male (10 of 36 [28%] vs 7 of 51 [14%]; P = .10), and had higher baseline disease activity based on mLoSSI (median, 12.5 [IQR, 4-26] vs 5 [IQR, 4-15]; P = .03) and PGA-A (median, 60 [IQR, 30-75] vs 20 [IQR, 10-40]; P < .001). Patients with linear subtype, who predominantly had pediatric-onset morphea, were more likely to have complete response to treatment at 1 year vs patients with generalized subtype, who predominantly had adult-onset morphea (33 of 51 [65%] vs 13 of 51 [25%]; P = .004) (Table 2).

To be included in the survival analysis, patients had to reach an mLoSSI of 0 during follow-up and have at least 1 follow-up visit afterward. In total, 94 of the 102 patients reached an mLoSSI of 0, most (51 of 87 [59%]) within 1 year. Of those, 51 of 55 patients initially treated with methotrexate had resolution of disease activity during follow-up, and 34 of 37 patients treated with UV-A1 phototherapy as monotherapy had inactive disease during follow-up. Eight patients (7 with generalized subtype) had active disease at all study visits and were excluded from the survival analysis. Seventeen patients did not have a study visit after resolution of disease activity and also were excluded. Therefore, 105 patients were included in the survival analysis (eFigure 1 in the Supplement).

Overall, 30 of 105 patients (29%) had recurrence of disease activity. Recurrence of disease activity occurred at a median of 1.7 (IQR, 0.9-2.6) years after documented disease inactivity. The median time to first recurrence after documented disease inactivity was 1.1 (IQR, 0.8-1.9) years for those with generalized subtype and 2.3 (IQR, 1.0-3.3) years for those with linear subtype. Overall, 13 of 30 (43%) with generalized subtype had recurrence of disease activity compared with 14 of 66 (21%) with linear subtype (hazard ratio [HR], 3.28; 95% CI, 1.38-7.79) (Figure 1A). Recurrence in those treated with UV-A1 phototherapy occurred at a median of 1.4 (IQR, 1.0-1.9) years after disease inactivity, and recurrence in those treated with methotrexate occurred at a median of 2.2 (IQR, 1.1-3.3) years after disease inactivity (HR, 2.33; 95% CI, 1.03-5.31) (Figure 1B). Recurrence of disease activity occurred in 15 of 55 (27%) of those treated with methotrexate and in 13 of 33 (39%) of those treated with UV-A1 phototherapy. More adults than children had recurrent disease activity (HR, 3.03; 95% CI, 1.48-6.22) or active disease throughout follow-up (Figure 1C). Percentages of patients with active disease in a given year of follow-up are shown in Figure 1D-F.

To assess long-term outcomes (eg, late disease flare and changes in disease damage), a subgroup analysis was performed of the 50 patients with at least 5 years of follow-up. Most patients had improvement in disease activity (Figure 2A and B). Recurrence of disease activity occurred in 18 of 50 (36%) (8 had ≥2 late disease flares). Of those with recurrent disease activity, most (18 of 22 [82%]) had reactivation or extension of an existing plaque. Only 4 patients with recurrent disease activity developed lesions at a new noncontiguous body site. Two additional patients had continued disease activity at 1 year, with multiple new areas of disease involvement before reaching clinical remission. In addition, 18 of 22 (82%) had milder disease activity at 1 year compared with their baseline visit as defined by lower mLoSSI and PGA-A during reactivation or extension of an existing plaque.

In the 50 patients with at least 5 years of follow-up, changes were also examined in individual measures of disease damage (sclerosis, dermal atrophy, and subcutaneous atrophy, which constitute the LoSDI (along with dyspigmentation). The LoSDI was stable over time (Figure 2C), as was the PGA-D (Figure 2D). However, improvement in sclerosis and worsening of atrophy contributed to stability of the LoSDI (Figure 3). Most patients (36 of 48 [75%]) had at least 50% improvement in sclerosis over time, which tended to be most apparent in the third year of follow-up. In contrast, dermal atrophy and subcutaneous atrophy remained stable or worsened in some patients. Atrophy often worsened as sclerosis improved. No patients had complete resolution of subcutaneous atrophy because none achieved an atrophy score of 0 during follow-up. The body site of the morphea lesions was associated with different rates of improvement in sclerosis. Lesions on the upper extremities had faster resolution of sclerosis than lesions on the trunk or lower extremities. At 1 year, upper extremity lesions had complete resolution of sclerosis in 12 of 18 patients (67%), but lower extremity lesions had complete resolution of sclerosis in 9 of 20 patients (45%) (eFigure 2 in the Supplement).

This prospective study of patients in the Morphea in Adults and Children cohort included 130 adults and children (663 study visits) with at least 2 years of clinical follow-up. Although most patients responded well to treatment and achieved inactive disease, a substantial proportion had reactivation or extension of an existing plaque of morphea, suggesting that a subgroup of patients with morphea have a relapsing-remitting course, which differs depending on morphea subtype.

The results herein mirrored those previously published that demonstrate frequent remission of morphea disease activity with methotrexate or UV-A1 phototherapy in both adults and children. Standard-of-care therapy as recommended by the Childhood Arthritis and Rheumatology Research Alliance Consensus Treatment Plan with methotrexate (with or without corticosteroids)⁴ or with UV-A1 phototherapy using the Morphea in Adults and Children cohort protocol⁸ appears to improve clinical disease activity in most patients (51 of 87 [59%]) at 1 year. These findings are similar to the rate of disease activity resolution in the pediatric morphea randomized clinical trial¹³ using methotrexate, which reported 67% resolution at 1 year using a composite outcome, as well as the 60% resolution previously reported for UV-A1 phototherapy.⁸ Our results provide further support for the effectiveness of these therapies and the use of previously published treatment plans.

A novel finding herein is that specific demographic and clinical features were associated with remission of morphea disease activity. Patients with high levels of disease activity as measured by the LoSCAT disease activity components, which largely aligned with generalized subtype of morphea, were more likely than patients with low levels of disease activity to have active disease at 1 year after treatment initiation. Adults, who predominantly had generalized subtype, and individuals treated with UV-A1 phototherapy also had more frequent residual morphea disease activity at 1 year. Despite the continued presence of some disease activity, most of these patients still had substantial improvement in disease activity at 1 year compared with their baseline visit and eventually reached clinical remission (94 of 102 patients [92%] had complete resolution of disease activity at some point during follow-up). Therefore, the presence of generalized subtype of morphea, which predominates in adults, and treatment with UV-A1 phototherapy may be associated with a longer time to disease remission compared with others with morphea.

We also examined the frequency of recurrence of active morphea lesions after remission. The overall recurrence rate of morphea disease activity of 29% (30 of 105 patients) found in this study is consistent with other reports.^14-16 In the present study, treatment with methotrexate resulted in more frequent long-term remission in disease activity than UV-A1 phototherapy (27% [15 of 55] of patients treated with methotrexate had recurrence of disease activity vs 39% [13 of 33] of patients treated with UV-A1 phototherapy). Because the present study was observational and not randomized, it is possible that factors associated with treatment choice may have contributed to this difference. For example, UV-A1 phototherapy was typically administered over 3 to 4 months and then discontinued, but methotrexate was generally administered for 24 months, including taper. It is possible that the longer duration of methotrexate treatment suppressed late disease flares compared with UV-A1 phototherapy. Adults with generalized morphea received UV-A1 phototherapy at greater frequency (48% [15 of 31]) than children with the linear subtype (15% [4 of 27]). Therefore, differences in the frequency of recurrence may reflect incomplete treatment of active disease with UV-A1 phototherapy. In contrast to a prior study⁸ examining recurrence after UV-A1 phototherapy, we were able herein to better compare differences in treatment response between morphea subtypes because of a larger sample size and found that patients with generalized subtype had more frequent recurrence after UV-A1 phototherapy than patients with linear subtype. Prospective studies evaluating UV-A1 phototherapy in patients with morphea over a longer duration of treatment are warranted.

When specifically examining the frequency of morphea flares after treatment with methotrexate, we found differences compared with prior reports. In contrast to a retrospective study by Martini et al⁷ that reported a 22% rate of juvenile localized scleroderma recurrence in 133 pediatric patients who were treated with methotrexate, we observed a slightly higher recurrence rate (27% [15 of 55]) in our cohort. The 27% recurrence rate herein was lower than the 45% recurrence rate reported by Kurzinski et al⁶ in a prospective study of 77 pediatric patients with juvenile localized scleroderma. However, there are substantial differences in patient age, methotrexate route, outcome measures, and duration of follow-up in these studies, which makes it difficult to compare them directly. These results underscore the need for further studies examining the optimal dose, route, and duration of methotrexate treatment across different morphea subtypes using standardized outcomes.

Long-term follow-up of at least 5 years among 50 patients herein revealed important observations. First, 36% (18 of 50) of those who achieved remission eventually had recurrence of disease activity, in some cases more than once. This finding further confirms that morphea has a relapsing-remitting course in a substantial number of patients. Second, we mapped the anatomic location of recurrent morphea lesions and found that 82% (18 of 22) occurred at the site of prior lesions either via extension of existing lesions or development of new plaques in the same anatomic location, rather than at new sites. As measured by the LoSCAT disease activity components, these flares were milder than the initial morphea presentation, perhaps because of earlier detection and treatment.

Although the overall disease activity and damage scores of the LoSCAT stabilized over 5 years, there are important differences in the individual components of these scores. The sclerosis component, particularly on the upper extremities and trunk, substantially decreased at 3 years. Over the same interval, we observed increases in dermal atrophy and subcutaneous atrophy. This result indicates that successful morphea treatment produces improvement in sclerosis, often after discontinuation of treatment; however, sclerosis is replaced by atrophy. These findings highlight the importance of distinguishing features of disease activity (which are responsive to morphea treatment over short periods) from features of disease damage (which evolve slowly, even after morphea treatment is discontinued).

Our study has some limitations, including a small sample size and those inherent to observational studies. Despite the robust number of patients for a rare disease, subgroup analyses and logistic regression were limited because of loss of power and the association of outliers in subgroups. Given that the study was performed at a tertiary referral center, referral bias may have resulted in overestimates of morphea disease severity. In addition, treatment bias may account for differences in morphea response. For example, patients with morphea involvement of subcutaneous tissue were treated with methotrexate and not offered UV-A1 phototherapy.

The results of the present study have important implications for clinical practice. First, patients with morphea have a relapsing-remitting course, particularly those with generalized subtype, necessitating long-term follow-up. Second, disease activity improves in most patients with morphea receiving standard-of-care therapy over 6 to 12 months using previously published treatment plans, often within the first 3 to 12 months, but sclerosis improves more slowly over 2 to 5 years, accompanied by some progression of atrophy, even after morphea treatment is discontinued. Additional studies are needed to identify optimal treatment dose, duration, and effectiveness across morphea subtypes, as well as standardization of outcome measures to facilitate multisite trials in this rare disease.

Accepted for Publication: February 9, 2020.

Corresponding Author: Heidi T. Jacobe, MD, MSCS, Department of Dermatology, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390 (heidi.jacobe@utsouthwestern.edu).

Published Online: April 1, 2020. doi:10.1001/jamadermatol.2020.0034

Author Contributions: Drs O’Brien and Jacobe had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: O’Brien, Jacobe.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: O’Brien, Nymeyer, Green.

Critical revision of the manuscript for important intellectual content: O’Brien, Jacobe.

Statistical analysis: O’Brien, Jacobe.

Obtained funding: Jacobe.

Administrative, technical, or material support: Nymeyer, Green, Jacobe.

Supervision: Jacobe.

Conflict of Interest Disclosures: None reported.

Funding/Support: Research reported in this publication was supported in part by the National Institutes of Health (NIH) (grant K23AR056303-5), by the National Center for Advancing Translational Sciences (NCATS) of the NIH (award TL1TR001104), and with support from the University of Texas Science and Technology Acquisition and Retention program (UT-STAR) (NIH/National Center for Research Resources [NCRR]/NCATS grant UL1TR000451).

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of UT-STAR, UT Southwestern Medical Center and its affiliated academic and health care centers, the NCRR, or the NIH.