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
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
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.