Circumscripts of scleroderma (overview) L94.0

Heterogeneous group of chronic, relapsing, sclerosing connective tissue diseases of the skin with varying involvement of skin-related structures such as adipose tissue, muscles, joints, and bones, depending on subtype and location. Involvement of internal organs such as the heart, lungs, kidneys or gastrointestinal tract is an absolute rarity in circumscritic scleroderma; transitions to systemic scleroderma are equally rare.

The clinical course is usually characterized by an initial, indistinct, livid redness, by centrifugal extension with central fading, by the formation of a plate-like sclerosis with a surrounding inflammatory rim(Lilac ring), which indicates further progression. The clinical spectrum is highly variable with respect to localization, severity, and recurrence frequency.

The linear/band variants represent a clinical peculiarity. Usually beginning in early childhood, they can lead to cutaneous-subcutaneous-osseous atrophy (en coup de sabre, Parry-Romberg syndrome) at the capillitium with orbital or even orodental involvement, and to osseous growth disorders at the extremities depending on the severity (these cases must be treated early with immunosuppressive therapy).

Depending on the shape, size and location of the sclerotic connective tissue hardening, 3 clinical types and various special forms are distinguished:

Type I Plaque Circumscribed Scleroderma (ZS) with variants (about 70% of adults and in about 30% of children):

• Variants:
  • Plaque or morphea type also limited form of ZS (about 60% of the total ZS collective).
  • generalized circumscritic scleroderma (maximum variant of plaque or morphea type)
  • bullous circumstrictive scleroderma (bullous variant of plaque type)
  • small-spotted circumscritic scleroderma (guttata type)
  • unilateral circumstrictive scleroderma
  • Atrophic type(Atrophodermia idiopathica et progressiva) (about 20% of the total ZS collective)

Type II Linear/banded circumscritic scleroderma (10-30% of adults and about 65% of children):

• Variants:
  • Extremity type (special form: pansclerotic circumscritic scleroderma, also: disabling pansclerotic morphea as maximum variant of type II) with potential disorder of extremity growth.
  • Sclérodermie en coup de sabre (together with Parry-Romberg syndrome, about 14% of children)
  • Parry-Romberg syndrome (hemiatrophia faciei progressiva)

Type III Profound circumscritic scleroderma (ca.12% of children):

• Special forms:
  • sclerofascia (deep morphea)
  • eosinophilic fasciitis (Shulman type).

In an AWF guideline 4 subgroups are distinguished (limited CS; generalized CS; linear CS, deep CS; as special forms are considered (see above): Pansclerotic disabling disease of children (foudroyant progressive generalized circumstrictive scleroderma); Parry-Romberg syndrome ; Eosinophilic fasciitis.

The incidence is 2/100,000 in the overall population, with analogous incidences reported in children and adolescents. The disease occurs predominantly in whites (85%), in blacks in 5%, and in Asians in 3%.

Unknown. Genetic (correlation with HLA-B8, DR1, DR5), immunological, autoimmunological, hormonal, viral, toxic, traumatic, medicinal, neurogenic or vascular factors are discussed.

In linear ZS, causes of development are thought to be trauma, infection, genetic factors, and embryonic disorders; among others, an epigenetic mosaic constellation (see below Mosaic, cutaneous). Cutaneous mosaic patterns can also be detected in the morphea type of circumscritic scleroderma.

Especially in young patients, Borrelia infections can initiate circumscritic scleroderma (Borrelia associated early-onset morphea) or progress under the picture of circumscritic scleroderma (Borrelia-specific antigens such as OspA or OspC have a high antigenic potential and can initiate autoreactive processes). See below Borrelia.

Increasingly, the opinion is gaining ground that an autoimmunological component is patheogenetically relevant (autoimmunological and rheumatic diseases in the family, concomitant rheumatic or autoimmunological diseases, ANA +).

Smad proteins appear to play a role in fibrosis processes at the molecular level. Studies have shown that after UVA1 phototherapy, Smad7 mRNA expression is decreased in clinically affected areas. Furthermore, antimicrobial peptides and proinflammatory cytokines such as IL-6 and IL-8 appear to play a pathogenetic role. IL-6 mRNA, IL-8 mRNA, and ß-defensin mRNA were decreased after UVA1 phototherapy similar to Smad proteins in clinically affected areas.

Manifestation summit: 1st-4th decade of life

V.a. trunk (58%), lower extremities (24%), upper extremities (12%) or head (6%) are affected. Mucosal changes are rarely present. Characteristic is an exclusion of the perimamillary and genitoanal regions.

In circumscritic scleroderma type I (limited form), several variants are observed:

• Classic plaque or morphea type: Usually painless, chronically stationary or progressive, localized on the trunk and extremities, varying in size (0.5-30.0 cm or larger), roundish or oval, also confluent over a large area, extending centrifugally, sharply demarcated, white, red or brown planar indurations. In the center of the indurations, there is often the formation of a white or yellow, hard plate caked to the base, in which the follicular structure is absent (destruction of the hair follicles). Often these plate-like indurations are surrounded by a ring-shaped, blue-purple to lilac erythema = Lilac Ring (sign of progression). The lesions of circumscritic scleroderma may be roundish to oval, also landmark-like in structure.
• Atrophodermia idiopathica et progressiva is a primary atrophic variant of the plaque type with extensive, barely indurated, red-brown or red, slightly sunken atrophic areas.
• The guttata form (also confetti type) of circumscritic scleroderma(morphea guttata) usually shows disseminated, rump-emphasized yellowish-white, superficially shiny, sparsely indurated patches, papules, or plaques barely 1 cm in size. Initially, tender red spots may appear.
• According to the AWF guideline, the"generalized form of circumscritic scleroderma" is present when at least three anatomical localizations are affected. The trunk, thigh, and lumbosacral regions are preferentially affected. The plaques often occur symmetrically and can confluence into larger areas, then associated with movement disorders. The very rare"disabling pansclerotic morphea", which is the maximum variant of generalized CS, is extremely severe (see Fig.). The combination of linear and disseminated large areas with only a slight regression tendency of fibrosis often leads to contractures and wound healing disorders already in childhood.

Circumstrict scleroderma type II(linear or band-like circumstrict scleroderma):

• Strip-like or band-like or systematized indurations with progression in longitudinal direction (segmental alignment? Blaschko -lines?). Localization: found mainly on the extremities (band-like circumscritic scleroderma) or on the capillitium (often on the forehead: scleroderma en coup de sabre). These may heal as mild forms with hyperpigmentation. More common, however, are coarse sclerotic streaks that extend across joints and lead to limited range of motion. Linear circumscritic scleroderma of the "en coup de sabre" type is usually found frontoparietally, usually paramedian from the eyebrows into the hairy scalp (lesional alopecia). In this case, focal CNS involvement must be excluded. A variant of linear circumskripten scleroderma is the so-called progressive facial hemiatrophy(Hemiatrophia faciei progressiva).

Type III of circumskripten scleroderma:

• Profound circumscritic scleroderma(deep morphea) is the rarest subtype of circumscritic scleroderma (<5% of patients). In this case, platelike or nodular indurations can be palpated in the subcutaneous adipose tissue and adjacent fascia ( sclerofascia, eosinophilic fasciitis). In this case, the overlying skin may be uninvolved and shifting over the induration. The changes occasionally manifest symmetrically, preferentially on the extremities. It may occur in infancy and sometimes manifest without an antecedent inflammatory reaction.

Extracutaneous manifestations were observed in about 20% in a review of adults (see also Scleroderma, Circumscribed Juvenile), although these (apart from skeletal and muscular changes in the linear forms) are not clinically important:

• Skeletal (25-44%): Polyarthritis, osteoporosis.
• Gastrointestinal (about 12%): Dysphagia, gastroesophageal reflux, diarrhea, constipation.
• Genital tract: 38% of pat. suffer from lichen sclerosus et atrophicans.
• Lungs (7%): Fibrosis (exertional and resting dyspnea), cough, cyanosis.
• Muscle: myopathy (feeling of weakness), pain.
• Heart: arrhythmias, heart failure, pericardial effusion.
• Kidney: proteinuria, insufficiency, hypertension.
• Liver: primary biliary cirrhosis.
• Neurological symptoms: MS (7-10 fold increased risk compared to normal population).

Autoimmunologic comorbidities: lupus erythematosus, systemic (58-fold increased risk compared to normal population); vitiligo (3.5-fold increased risk compared to normal population; psoriasis vulgaris (1.4-5-fold increased risk compared to normal population).

Antinuclear antibodies are positive (varying according to literature and type) in 7-81% (?) of cases, without this constellation giving any indication of systemic involvement. DNA-AK, SCL70-AK and ENA are negative.

Recent prospective studies of serum cytokines in LS patients have identified potential blood markers of disease activity, including CXCL9 (Torok KS et al. 2019/s.a. CXCL9 gene). However, the value of these markers is unclear; they are not yet widely available in clinical practice.

Inflammatory stage: Dense inflammatory infiltrate, mainly of lymphocytes. Edematous swelling of the collagen fiber bundles. Septal panniculitis in the upper portions of the adipose tissue with sparse or even nodular round cell infiltrates at the dermo-subcutaneous border. Rarely, formation of germinal centers. Enclosure of adipose tissue globules by collagenous bundles.

Sclerotic stage: Broad proliferation of dermal connective tissue at the expense of subcutaneous adipose tissue. Homogenized widened collagen fiber bundles run parallel to the skin surface. Atrophic adnexa, slit-like narrowed vessels. Incarcerated eccrine sweat glands. Rather sparse perivascular and diffuse lymphocytic infiltrates. Nodular thickening of the infiltrates at the border with the subcutis. Broad, homogenized and also edematized adipose tissue septa with sparse round cell infiltrates.

Characteristic clinical picture. The histological examination is diagnostic but rarely conclusive.

Early inflammatory phase of limited CS (Morphea) 

• lichen sclerosus
• Vitiligo (important differentiation in case of infestation of the genitoanal region; histology is diagnostic in this case)  
• Erythema chronicum migrans
• cutane Mastozytose  
• Granuloma anulare  
• Bestrahlungsdermatitis  
• Mycosis fungoides  
• Drug reactions

Late stage of limited ZS (Morphea) with leading hyperpigmentation.

• post-inflammatory Hyperpigmentierung  
• Lichen planus actinicus  
• Café-au-Lait-Flecken  
• Erythema dyschromicum perstans

Late stage of limited ZS (Morphea) with leading Atrophie  

• Acrodermatitis chronica atrophicans  
• Lipodystrophie  
• Lichen sclerosus: (important DD for the small spotted circumscript scleroderma; histology is helpful but not always conclusive; circumscript scleroderma never affects the mucous membranes of the genitalia in contrast to Lichen sclerosus et atrophicus)  
• Scar
• Necrobiosis lipoidica (histology is diagnostic in connection with the clinical findings).

Generalized ZS  

• systemic scleroderma (in circumscribed scleroderma, ANA and organ involvement are missing)  
• Pseudosklerodermien  
• Scleroderma adultorum Buschke  
• Skleromyxödem  
• sclerodermiform graft-versus-host disease  
• Mischkollagenose  
• nephrogenic systemic fibrosis (leading symptoms: renal insufficiency, rapid progression, use of gadolinium in MRI examinations).

Linear CS of the type en coup de sabre  

• Pannikulitiden  
• progressive partial Lipodystrophie  
• focal dermal Hypoplasie  
• Steroid atrophy
• Lupus erythematosus profundus

In childhood, type II and III scleroderma, particularly in the case of foci involving multiple joints, can lead to growth disturbances in the affected body part (see below Scleroderma, circumscripte juvenile).

Carpal tunnel syndrome, movement restrictions (esp. in striated circumstrictive scleroderma).

Association with other autoimmunological and rheumatological diseases, esp. psoriasis vulgaris, systemic lupus erythematosus, multiple sclerosis and vitiligo. Parryy-Romberg syndrome may be associated with Rassmussen encephalitis. It is manifested by unilateral cerebral involvement and intractable seizures.

Associations with genital lichen sclerosus have been described.

Physiotherapy: Lymphatic drainage, massage, physiotherapy are helpful. Especially in linear, inter-joint forms, the joint mobility must be maintained by physical therapy. Biomechanical stimulation (BMS) supports the promotion of blood circulation and deep massage with loosening of the tissue.

Avoidance of local pressure and injuries (e.g. tight waistband, pressing shoes on the back of the foot). Permanent pressure can lead to the formation of new foci in existing scleroderma.

Physiotherapy: Studies on the efficacy of physiotherapy in circumscritic scleroderma do not exist for various reasons. Reasons not. Nevertheless, the measures are an important accompanying component in the multimodal treatment of the disease and are frequently used in clinical practice.

• In particular, cross-joint linear circumstrictive scleroderma should be treated with physiotherapy.
• Connective tissue massage and manual lymphatic drainage can be performed in the sclerotic stage concomitantly to system therapy or following system therapy (1-2x/ week for 3-6 months).
• Physiotherapy and muscle building are mandatory in the linear subtype of the extremities.

Glucocorticoids: Especially for plaque type in an active phase, topical steroids are effective. Duration of therapy: about 3 months, apply medium- to high-potency topical steroids 1-2x/day strictly lesionally.

Intralesional glucocorticoid applications are usually performed only in the rare linear subtype en coup de sabre in the active marginal area. Triamcinolone acetonide 10-40 mg diluted with lidocaine 1:2 - 1:4 is most commonly injected intralesionally.

Vitamin D ₃ -analogues ( calcipotriol or tacalcitol) can produce a tissue-softening effect. Creams and lotions containing urea (Eucerin Urea Lotion, Lipoderm Urea) or evening primrose seed oil (Eucerin Omega 12% Lotion, Lipoderm Omega) are suitable for the care of dry, vulnerable skin.

Topical calcineurin inhibitors: Small pilot studies and case reports describe the successful use of tacrolimus 0.1% under occlusion in morphea. The efficacy of this therapeutic approach is not adequately established.

Imiquimod: Few case series and some case reports exist. After 3-6 months of therapy a significant improvement of dyspigmentation, sclerosis and erythema was described. The efficacy of this therapeutic approach is not sufficiently proven.

Consistent irradiation with UVA1 in an ascending dosage is recommended, starting with 5 J/cm² up to 20 J/cm². The inflammatory component can thus be controlled after only 10-15 treatments. If sclerosis has already occurred, UVA1 irradiation should be maintained at the above dose until the tissue has softened. In addition to the anti-inflammatory effect, UVA1 irradiation results in the release of collagenase with corresponding softening of collagenous connective tissue.

In adulthood, high-dose UVA1 therapy can be performed, taking into account the side effects. This may also regress sclerosis and hypopigmentation.

In a controlled study of phototherapy for circumskripten scleroderma, UVA1 was shown to be significantly more effective than narrow band UVB phototherapy.

In the linear subtype with facial involvement or joint involvement, or compromise of length growth, therapy with methotrexate in combination with systemic glucocorticoid pulse therapy should be used early (prednisolone 1.0 g i.v. for 3 days/ 6-month therapy regimen).

In generalized circumscritical scleroderma, high-dose protocols with steroid pulse therapy (1.0 g prednisolone/day i.v. for 3 days) in combination with MTX continuous therapy (15 mg/week MTX p.o.) have been used with good success. With this variant, therapy should also be started as early as possible.

Encouraging results have been achieved with low-dose methotrexate (mono) therapy (15 mg/week MTX p.o. over a period of 24 weeks).

In the meantime, the previously frequently used systemic therapy with penicillin G 10 mega IU/day i.v. for 10 days (3 cycles at intervals of 4 weeks) has been largely abandoned. Exception: V.a. in the presence of a Borrelia infection.

D-Penicillamine: International literature still claims a certain value (personal experience is negative in this respect).

In case of sclerotic growth disorders, dermatogenous contracture, scarring alopecia, timely surgical intervention is indicated.

In the facial region, a specialized center of oral and maxillofacial surgery should be consulted, and in the case of involvement of the joints and extremities, a specialized pediatric surgeon or orthopedist should be consulted.

Generally active course over several years, after which the disease burns out, leaving the sclerosis or atrophy that has developed.

25% of patients suffer a recurrence, which can occur even after years of latency. The linear form shows a particularly high recurrence rate.

In Anglo-American literature, the term morphea is increasingly used instead of circumscritic scleroderma.

Of note in a familial LEMD3 mutation is the case description of osteopoikilosis(Buschke-Ollendorf syndrome) associated with late-onset localized morphea-type scleroderma (Korman B et al 2016). DNA sequencing of this case revealed a previously undescribed nonsense mutation (Trp621X) in the LEMD3 gene encoding Man1.

S.a. Newsletter: Juvenile Circumscribed Scleroderma.

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