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Morphea is associated with systemic manifestations and autoimmunity, but the prevalence of these findings remains unclear. With the goal of characterizing the frequency of these associations the prevalence of extra-cutaneous manifestations and autoimmunity in adult and pediatric morphea subjects was ascertained.
A retrospective review of 245 morphea subjects.
The University of Texas Southwestern Medical Center Affiliated Institutions
Patients with clinical findings consistent with morphea.
(a) prevalence of concomitant autoimmune diseases, (b) prevalence of familial autoimmune disease, (c) prevalence of extra-cutaneous manifestations, and (d) laboratory evidence of autoimmunity (ANA positivity). Secondary outcomes measures included demographic features.
In this group, adults and children were affected nearly equally and African-Americans were affected less frequently than expected. The prevalence of concomitant autoimmunity in the generalized subtype of morphea was statistically significantly greater than that found in all other subtypes combined (P = 0.01). Frequency of a family history of autoimmune disease showed a trend in favor of generalized and mixed subgroups. The linear subtype showed a significant association with neurologic manifestations. While general systemic manifestations were most common in the generalized subtype. ANA positivity was most frequent in mixed and generalized subtypes.
High prevalence of concomitant and familial autoimmune disease, systemic manifestations, and ANA positivity in the generalized and possibly mixed subtypes suggest that these are systemic autoimmune syndromes and not skin only phenomena. This has implications for the management and treatment of these patients.
Morphea is characterized by sclerosis of the skin and in some cases underlying tissue, but is generally thought to be an autoimmune disorder affecting a single organ; the skin. Consequently, current classification schemes divide morphea into categories based solely on cutaneous morphology, without reference to systemic disease or autoimmune phenomena. This classification is likely incomplete.
Rather, morphea may be a systemic autoimmune condition that has manifestations outside the skin.1,2,3,4,5,6,7,8 For example, case reports describe morphea coexisting with other autoimmune diseases, including systemic lupus erythematosus, vitiligo, primary biliary cirrhosis, autoimmune hepatitis,3 Hashimoto's thyroiditis, and myasthenia gravis.9,1,2,3,4,5 A retrospective review of 750 children with morphea revealed a greater than expected prevalence of familial autoimmune disease. The same pediatric study found systemic complaints outside the area of morphea in 22.4% of children including arthralgias and esophageal dysmotility. Data in adults is limited, with one case control study of 50 caucasian adult women reporting increased personal and familial autoimmunity, but ANA status and systemic manifestations were not reported. Many autoantibodies have been reported in patients with morphea, including antinuclear (ANA), anti-single stranded DNA (anti-ssDNA), anti-histone, anti-topoisomerase IIα, anti-phospholipid, and rheumatoid factor.10,11,12 The clinical and prognostic significance of these autoantibodies remains unclear.
Taken together, these reports suggest that morphea is an autoimmune disease with a spectrum of manifestations ranging from skin only to multiple organ involvement. What remains unclear is the prevalence of autoimmune and systemic disease in morphea and its subtypes and how these findings correlate with autoantibody profile. This uncertainty negatively impacts patient care as many patients are untreated or treated with skin directed therapy who may in fact require systemic therapy. This study aims to address this gap in knowledge by quantifying the prevalence of autoimmunity and systemic manifestations in adults and children with morphea.
Approval was obtained from the institutional review board to review the medical records of patients with morphea seen from 2001 to 2007 at all UTSW affiliated institutions (UT Southwestern faculty dermatology practice, Texas Scottish Rite Hospital, Children's Medical Center, and Parkland Memorial Hospital). 432 potential adult and pediatric subjects were identified by International Classification of Diseases, Ninth Revision diagnosis code for morphea/localized scleroderma and lichen sclerosus (701.0). After review of the medical record, all patients determined to meet the clinical criteria for morphea (histopathologic results were reviewed when present but were not necessary for inclusion) were included for analysis. Patients found on review of the medical record to have lichen sclerosus alone or sclerosing skin conditions other than morphea were excluded (186/431).
For subjects (n=245) who met the inclusion criteria, data was entered electronically into a Microsoft Access database. Data extraction included demographics; clinical parameters; histological data; laboratory data; past medical history of rheumatic or other autoimmune disease; family history of rheumatic or other autoimmune diseases in 1st and 2nd degree relatives; and review-of-systems.
Morphea subtypes were determined from the medical record when specified or from the physical examination findings when not specified in the record. The subtypes investigated were plaque, linear (including En Coup de Sabre and progressive hemifacial atrophy), generalized, mixed (defined by presence of 2 subtypes in the same patient but if 1 subtype was generalized patients were categorized as generalized), lichen sclerosus/morphea overlap (LS/M), guttate, bullous, and deep, using established clinical criteria.13
Summary statistics were used for reporting demographic, clinical, and laboratory characteristics. The Fisher's Exact test was used to test the association between the five subtypes of morphea and the presence or absence of autoimmune disease and family history of autoimmune disease, and systemic findings. Because antinuclear antibodies were tested in relatively few subjects results are reported as frequency counts. A P-value less than 0.05 was considered statistically significant. SAS software version 9.1.3 (SAS Institute, Cary, NC) was used for data analysis.
Table 1 shows the demographic characteristics and subtype distribution of subjects in detail. Similar to prior reports, there were 199 females (81%) and 46 males (19%) with a female-to-male ratio of 4.2:1 overall.
The racial distribution in morphea subjects overall was 73% Caucasian, 14% Hispanic, 4% African American 2% Asian, and 6.5% other (Pacific Islander, Native American, etc.). 50% of patients (123/245) had onset of morphea as adults and 50% (122/245) developed morphea as children. The mean age-of-onset for children was 9 years as compared to adults with a mean onset at 44 years.
The most common subtype overall was plaque then linear at 36% (88/245) and 26% (63/245) respectively. Deep and guttate subtypes were seen in less than 2% (both 3/245) of all subjects and were not included in subsequent analyses. Subtypes were distributed differently between adults and children (Table 1).
Table 2 shows the details of the autoimmune disorders present in morphea subjects or their families. Among all subjects, (18%) 43/245 reported concomitant rheumatic or other autoimmune disease. Concomitant rheumatic or other autoimmune disease was significantly more prevalent among adults (29%) than children (3%) (p=<0.001). When analyzed by subtype, the frequency of concomitant autoimmune disorders among generalized morphea subjects (adult and pediatric) was 49% (17/35), which was significantly greater (p=0.01) than the prevalence in the other subtypes combined (9%).
Among all subjects 16% (40/245) reported a family history of autoimmune disorders. Significantly more children (22%) than adults (11%) had a family history of a rheumatic or other autoimmune disease in a first or second degree relative (P <0.001). In adults the generalized subtype had the highest frequency of familial disease (22%). In children, mixed (24%) and generalized (22%) had the highest frequency of family history of autoimmunity. Despite trends in favor of generalized and mixed subtypes association with familial autoimmunity, this was not statistically significant.Of note, five children (2% of overall subjects) reported a family history of morphea in a 1st or 2nd degree relative.
Table 3 displays symptoms reported outside the area of morphea in detail. Symptoms outside the area affected by morphea were common in generalized morphea with the highest frequency of dysphagia 14% (5/35) p>0.05, dyspnea 20% (7/35) p=0.03, and vascular 31% (11/35) complaints (Raynaud's phenomenon) p=0.03. Patients with the mixed subtype had a high level of musculoskeletal manifestations (12-36% related to the distribution of the lesions). The linear subtype, was associated with neurologic 31% (27/86) and ophthalmologic 8% (7/86) complications related to the affected site on the face/scalp (p=0.05 for all, see Table 3).
Anti-nuclear antibodies were tested in 36% (89/245) of subjects and were positive, (titer ≥1:160) in 39% (35/89) of those tested. The percentage of patients with ANA positivity was highest in the generalized and mixed subtypes (58% 11/19 and 54% 7/13 respectively). Adults had a higher frequency of ANA positivity with 53% (19/36) testing positive as compared to 30% (16/53) of children.
The ANA patterns segregated by subtype with 83% (17/21) of linear and 66% (17/25) of plaque having a speckled pattern and 57% (4/7) of mixed having a nucleolar pattern.
In contrast to prior reports only 1 of 26 of patients tested had ssDNA antibodies (generalized morphea). Scl-70 was positive in 1/39 subjects (generalized morphea). This subject did not develop any signs or symptoms of scleroderma over a nine year follow up period. Three of 19 patients tested (14%) had anti-dsDNA antibodies; one each linear, generalized and mixed subtype (prior reports link the presence of anti-dsDNA to the generalized subtype). None of these patients developed any signs or symptoms of SLE after one year of follow up.
This study represents the largest collection of adults and children with morphea to address the prevalence of autoimmunity and systemic disease with stratification by morphea subtype. As in prior reports, there was a female predominance and age dependent difference in subtype distributions. Of note, morphea occurred nearly equally in adults and children (prior reports cite the disease is favored in childhood by 2 to 1).14 Although this is not a population based study, it likely represents a fair estimation of distribution between adults and children because subjects were enrolled from all university affiliated institutions including 2 children's medical centers and included patients seen by all specialties. Prior reports may be biased in favor of pediatric subjects who present with linear lesions more frequently and are subsequently diagnosed and brought to medical attention more frequently. The racial distribution of morphea has not been widely addressed. In this cohort morphea was less frequent in African Americans. The percentage affected in this cohort (4.5%) is lower than expected based on the racial distribution of metropolitan Dallas, Texas (20.9% African American, 2005 estimate of the U.S. Census Bureau) and the racial distribution of patients seen at UT Southwestern affiliated institutions. Population based studies are needed to fully address age and racial distribution in morphea
Overall, 18% of subjects had a concomitant rheumatic or other autoimmune disorder, an occurrence four fold higher than that in the general population including all races and socioeconomic strata. But when analyzed by subtype, generalized morphea had a statistically significant association with autoimmune disease with 49% of generalized morphea subjects affected representing 12 times the risk of the general population. Children with morphea were relatively spared of concomitant autoimmune disease (only6% versus 37% of adults).7 It is unknown whether children with morphea will develop autoimmune disorders at an increased rate as they reach adulthood.
Very little is known whether specific disorders aggregate with morphea. In this cohort, several disorders occurred with greater frequency than expected as compared to published population based prevalence estimates including: psoriasis (1.5 to 4.5 fold increase), systemic lupus erythematosus (58 fold increase), multiple sclerosis (7-8 fold increase), and vitiligo (3.5 fold increase).15,16,17
The statistically significant difference in family histories of autoimmune disorders between children (22%) and adults (11%) with all subtypes of morphea is likely confounded by differences in data acquisition at the study sites (family history was collected more thoroughly in the pediatric patients). Thus, the frequency of a positive family history is likely underestimated in adults. Of note, although not statistically significant, the generalized subtype had the highest frequency of familial disease in adults and second highest in children (lack of statistical significance may be the result of relatively low numbers). Zulian et al. reported similar findings in a pediatric cohort with a statistically significant association of familial autoimmunity in the generalized subtype (23.5% compared to 12.5%, 12.3% and 8.8% in deep, linear and plaque-type morphea).7 Familial autoimmune diseases also occurred more frequently in the mixed subtype (both adults and children), which was not reported by Zulian et al. Thus, familial autoimmunity is more prevalent in generalized, and to a lesser degree mixed, subtypes.
Similar disorders to those reported in morphea subjects were reported in their family members. Rheumatoid arthritis, systemic lupus erythematosus and psoriasis were observed with the highest frequency in 1st and 2nd degree relatives of morphea patients overall. These findings are similar to those reported by Zulian et al. Taken together, the increased frequency of pseronal and familial autoimmunity in the generalized subtype may indicate a common susceptibility locus for this group of disorders as was recently described in vitiligo and its association with NALP1.18
We found that 1% (4 families) of morphea subjects had first or second degrees relative with morphea, representing a higher risk than present in the general population (when compared with estimated prevalence reported by Peterson et al. to be 0.2% odds ratio 6.8 with a 95% CI: 1.15-40.56 p=0.014). Multicase families with morphea have been reported independently in the literature19,20 and as in our study were in a non-Mendelian pattern suggestive of a multifactorial, polygenic inheritance. There was no family history of scleroderma in this cohort, although this has been reported in Zulian's pediatric group.
The systemic symptoms and signs observed in the patients in this study are similar to prior reports in terms of organ systems of involvement. A novel observation, however, is that manifestations occurring outside the area affected by morphea (such as dysphagia, joint pain, and Raynaud's phenomen) are most common in the generalized subtype. While subjects with linear disease often have neurologic and ophthalmologic manifestations correlating with the area of morphea involvement.8 Prior reports describe morphea as a relatively painless disorder, this cohort, however, reported pain in areas affected by morphea particularly in the generalized subgroup. This underscores the need to address pain as a potential symptom in morphea.
ANA positivity of 39% (of patients tested) is comparable with previous studies.11 Generalized and mixed subtypes had the highest frequency (58% and 54%, respectively). In contrast to prior reports linking anti-ssDNA to linear and generalized morphea (50%), only 1/26 subjects tested had a positive result.11,12 Prior reports indicate no clear association between subtype and ANA pattern, this cohort, however demonstrated a trend toward segregation by subtype (generalized with a homogenous pattern, linear and plaque with a speckled pattern, and mixed with nucleolar pattern). This may indicate morphea subtypes are distinct phenomenon with distinct antigenic targets. As antinuclear antibodies were not tested in all subjects and may have been drawn only in more severely affected subjects, conclusions are limited.
Limitations of the study are those inherent in a retrospective review including ascertainment bias in acquisition of medical/family histories and laboratory testing as well as recall bias in reporting of information by subjects/families. Subtype classification was dependent on the treating physician and may not reflect standard criteria. Conclusions regarding autoantibodies are limited by the relatively low numbers tested. Prospective longitudinal studies examining these findings in greater detail are indicated.
In conclusion, there is a strong association between generalized morphea, and to a lesser extent mixed, morphea with markers of a systemic rather than skin limited autoimmune process autoimmune process (high frequency of concomitant autoimmune disease, systemic findings, and positive ANA) and to a lesser degree mixed morphea vs. a single organ (skin only) autoimmune process (which seems to correlate more with plaque type morphea). This has implications for the management of these patients. Specifically, results of this study suggest that patients with generalized and mixed subtypes should be aggressively monitored for the presence of autoimmune disorders and systemic manifestations and treated with systemic immunosuppressives when indicated. These findings may warrant a re-examination of the current classification of morphea from the perspective of inclusion of extracutaneous disorders.
Author Contributions: Dr(s) Haley, Bergstresser and Jacobe and Mr/Ms Leitenberger, Cayce and Adams-Huet 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. Study concept and design: Dr Jacobe and Ms Adams-Huet. Acquisition of data: Mr. Leitenberger, Ms Cayce and Adams-Huet and Dr Jacobe. Analysis and interpretation of the data and the accuracy of the data analysis: Ms. Cayce, Dr Jacobe and Ms. Adams-Huet. Drafting of the manuscript: Mr. Leitenberger, Ms. Cayce, Dr(s) Jacobe and Bergstresser. Critical revision of the manuscript for important intellectual content: Dr(s) Bergstresser, Haley and Jacobe. Statistical analysis: Ms. Adams-Huet. Obtained funding: none. Administrative, technical, or material support: Ms. Cayce and Dr Jacobe. Study supervision: Dr. Jacobe The sponsors had no role in the design and conduct of the study; in the collection, analysis, and interpretation of data; or in the preparation, review, or approval of the manuscript.
Financial Disclosure: None reported.