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Treatment Options For Localized Scleroderma

J Dutz, MD, FRCPC
Divisions of Dermatology and Rheumatology, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada

ABSTRACT

Localized scleroderma, or morphea, is a chronic disease that causes a thickening and induration of the skin. For plaque type morphea, the treatments of choice include super-potent corticosteroids and calcipotriol. For the more generalized forms, as well as the linear forms, UVA is currently the best therapeutic modality. Patients with localized scleroderma are managed by both rheumatologists and dermatologists. There is still much therapeutic uncertainty in this disease.

Key Words: calcipotriol, corticosteroids, morphea, scleroderma, UVA, PUVA

Localized scleroderma (LS), or morphea, has been classified into plaque, generalized, linear, and deep forms1. The natural progression of the plaque form of LS is of a gradual softening to spontaneous resolution after a mean duration of 4 years with the plaque group having the shortest period of activity and the deep form the longest2. Significant disability occurs in both linear and deep forms of morphea. Both the plaque and generalized forms can also be disfiguring, since spontaneous resolution does not invariably occur. To prevent such outcomes, clinicians use topical corticosteroids, antimalarials, etretinate, penicillin, D-penicillamine, phenytoin, vitamin E and griseofulvin. Because none of these have been used in controlled studies, favorable improvement due to spontaneous resolution cannot be excluded3.

Treatment Morphea Type Number of cases Not improved

Bath PUVA4,6,10

P/G
L
D

13
6
1

2
1
-

Systemic PUVA7-9,11

P/G
L
D

5
3
1

1
1
-

High dose UVA111

P/G
L

9
1

-
-

Low dose UVA15,11,12

P/G
L
D

21
14
3

-
-
2

Table 1: Compilation of reported cases of morphea treated with UVA light modalities.
Legend: Generalized or plaque type morphea (P/G); linear morphea (L); Deep morphea (D).

Use of Ultraviolet A

Published reports suggest that high dose UVA1 may be the most efficacious form of light treatment followed in order, by low-dose UVA1, and UVA in conjunction with topical and systemic psoralens (PUVA) (see Table 1). UVA and UVA1 treatment have yet to be compared clinically. However, the potential long-term toxicity of long wave UVA is still unknown, and its light sources are not readily available in North America. Further, the long-term oncogenic potential of PUVA is well documented. Given the propensity for skin thickening to improve, double-blind, controlled, randomized studies are needed to confirm the efficacy of these treatment modalities.

Use of vitamin D derivatives

Calcitriol has an antisynthetic and antiproliferative effect on fibroblasts from sclerodermatous skin. Oral calcitriol also has a beneficial effect on localized scleroderma mediated through immune or local effects. Regular monitoring for hypercalcemia and hypercalciuria is required. A serial renal ultrasound may be required to detect potential nephrocalcinosis13. Calcipotriol/calcipotriene, a calcitriol analogue, has also been shown to inhibit the growth of fibroblasts from sclerodermatous skin.

Use of Systemic Immunomodulation

Because immune cell activation is believed to underlie the development of skin sclerosis, systemic immunosuppressants have been used to treat severe and refractory localized scleroderma. Methotrexate is a folic acid analogue with multiple anti-inflammatory effects and has been found to be beneficial for treatment of morphea.

Treatment Morphea type Numbers treated Dose and duration Outcome

Calcitriol20,21,27
(Oral)

G
D
L

2
2
7

0.25 – 1.25 µg OD for 3 – 10.5 months

Improved ↑ urinary calcium 6/7 improved

Calcipotriol22, 23
(Topical)

P/G and L

12

Nightly occlusion with ointment (0.005%) BID for 3 months

52% improvement in skin score

L

1

Cream (0.005%) BID for 6 months

50% decrease in surface area



Corticosteroids have been used systemically to treat severe disease. Treatment with antimalarials15,16, azathioprine17, sulfasalazine18, and D-penicillamine24 has also been described in anecdotal fashion. Use of combination antimalarial therapy, i.e., quinacrine with hydroxychloroquine or chloroquine, can be of benefit in patients with cutaneous lupus refractory to single agent therapy alone19. This may be a safe and worthwhile strategy in generalized morphea. These immunosuppressive drugs have potential side-effects and appropriate monitoring is required.

Treatment Morphea type Numbers treated Dose and duration Outcome Risks

Corticosteroids14

G
L

5
12

Prednisone 0.5–1 mg/kg/day, tapered over 14 months

14/17 improved

Osteoporosis, growth arrest, diabetes, hypertension, cataracts, infection

D-penicillamine24

G
L

3
8

2–5 mg/kg/day, for 15–53 months

7/11 improved

Bone marrow suppression, nephrotic syndrome, autoimmune disease

Antimalarials15,16,25

P/G
D

4
7

Hydroxychloroquine 200-400 mg OD or chloroquine 250 mg OD, duration not specified

2/4 improved
4/7 improved

Ocular toxicity, bone-marrow suppression, dyspigmentation

Methotrexate26

G

9

15mg/wk–25mg/wk for 24 weeks

6 completed, 5/6 improved

Hepatotoxicity, bone marrow suppression, infection

Table 3: Larger case series of morphea patients treated with other medications. Benefits claimed by any of these therapeutic options have been substantiated by proper clinical trials (cited above).

Summary and an approach to treatment

The clinician is faced with considerable uncertainty when choosing a treatment modality for localized scleroderma. Given the benign natural progression of plaque type morphea, treatment with topical modalities such as super-potent corticosteroids or calcipotriol is prudent. Although no studies of the effectiveness of topical corticosteroids in localized morphea have been published, these agents have been shown to be very effective in lichen sclerosus et atrophicus, a clinically associated condition. For the more generalized forms and the linear forms, the use of UVA (either long wave alone or PUVA) is currently the best documented therapeutic modality. In the absence of access to these modalities and in the face of very active inflammatory disease involving deeper structures, oral calciferol or systemic immunosuppression may be contemplated. Recent studies support the use of methotrexate and systemic corticosteroids but controls are lacking. There remains a great amount of therapeutic uncertainty in this disease, and resolution must await the organization and completion of controlled/blinded multicenter therapeutic trials.

References

  1. Peterson LS, Nelson AM, Su WP. Classification of morphea. Mayo Clin Proc 70(11):1068-76 (1995 Nov).
  2. Peterson LS, Nelson AM, Su WP, Mason T, O’Fallon WM, Gabriel SE. The epidemiology of morphea (localized scleroderma) in Olmsted County 1960-1993. J Rheumatol 24(1):73-80 (1997 Jan).
  3. Falanga V. Localized scleroderma. Med Clin North Am 73(5):1143-56 (1989 Sep).
  4. Kerscher M, Volkenandt M, Meurer M, Lehmann P, Plewig G, Rocken M. Treatment of localised scleroderma with PUVA bath photochemotherapy. Lancet 343(8907):1233 (1994 May).
  5. Kerscher M, Dirschka T, Volkenandt M. Treatment of localised scleroderma by UVA1 phototherapy. Lancet 346(8983):1166 (1995 Oct).
  6. Kerscher M, Meurer M, Sander C, et al. PUVA bath photochemotherapy for localized scleroderma. Evaluation of 17 consecutive patients. Arch Dermatol 132(11):1280-2 (1996 Nov).
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  11. Stege H, Berneburg M, Humke S, et al. High-dose UVA1 radiation therapy for localized scleroderma. J Am Acad Dermatol 36(6 Pt 1):938-44 (1997 Jun).
  12. Kerscher M, Volkenandt M, Gruss C, et al. Low-dose UVA phototherapy for treatment of localized scleroderma. J Am Acad Dermatol 38(1):21-6 (1998 Jan).
  13. Weber G, Cazzuffi MA, Frisone F, et al. Nephrocalcinosis in children and adolescents: sonographic evaluation during long-term treatment with 1,25- dihydroxycholecalciferol. Child Nephrol Urol 9(5):273-6 (1988-89).
  14. Joly P, Bamberger N, Crickx B, Belaich S. Treatment of severe forms of localized scleroderma with oral corticosteroids: follow-up study on 17 patients. Arch Dermatol 130(5):663-4 (1994 May).
  15. Wuthrich RC, Roenigk HH, Steck WD. Localized scleroderma. Arch Dermatol 111(1):98-100 (1975 Jan).
  16. Person JR, Su WP. Subcutaneous morphoea: a clinical study of sixteen cases. Br J Dermatol 100(4):371-80 (1979 Apr).
  17. Nachbar F, Stolz W, Volkenandt M, Meurer M. Squamous cell carcinoma in localized scleroderma following immunosuppressive therapy with azathioprine. Acta Derm Venereol 73(3):217-9 (1993 Jun).
  18. Taveira M, Selores M, Costa V, Massa A. Generalized morphea and lichen sclerosus et atrophicus successfully treated with sulphasalazine. J Eur Acad WE’RE ON THE NET! http://www.derm.ubc.ca Dermatol Venereol 12(3):283-4 (1999 May).
  19. Chung HS, Hann SK. Lupus panniculitis treated by a combination therapy of hydroxychloroquine and quinacrine. J Dermatol 24(9):569-72 (1997 Sep).
  20. Humbert PG, Dupond JL, Rochefort A, et al. Localized scleroderma—response to 1,25-dihydroxyvitamin D3. Clin Exp Dermatol 15(5):396-8 (1990 Sep).
  21. Humbert PG, Dupond JL, Rochefort A, et al. Localized scleroderma—response to 1,25-dihydroxyvitamin D3. Clin Exp Dermatol 15(5):396-8 (1990 Sep).
  22. Cunningham BB, Landells ID, Langman C, Sailer DE, Paller AS. Topical calcipotriene for morphea/linear scleroderma. J Am Acad Dermatol 39(2 Pt 1):211-5 (1998 Aug).
  23. Koeger AC, Rozenberg S, Fautrel B. Effectiveness of topical calcitriol for localized scleroderma. J Rheumatol 26(1):239-40 (1999 Jan).
  24. Falanga V, Medsger TA Jr. D-penicillamine in the treatment of localized scleroderma. Arch Dermatol 126(5):609-12 (1990 May).
  25. Winkelmann RK, Connolly SM, Doyle JA. Carpal tunnel syndrome in cutaneous connective tissue disease: generalized morphea, lichen sclerosus, fasciitis, discoid lupus erythematosus, and lupus panniculitis. J Am Acad Dermatol 7(1):94-9 (1982 Jul).
  26. Seyger MM, van den Hoogen FH, de Boo T, de Jong EM. Low-dose methotrexate in the treatment of widespread morphea. J Am Acad Dermatol 39(2 Pt 1):220-5 (1998 Aug).
  27. Hulshof MM, Pavel S, Breedveld FC, Dijkmans BA, Vermeer BJ. Oral calcitriol as a new therapeutic modality for generalized morphea. Arch Dermatol 130(10):1290-3 (1994 Oct).

In this issue:

  1. Topical Antipsoriatics
  2. Treatment Options For Localized Scleroderma
  3. Update on Drugs and Drug News - Number 2 1999