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Scleroderma
Scleroderma Vincent Falanga, MD, FACP Scleroderma means thickened skin, and has come to refer to clinical conditions characterized by the development of localized or widespread fibrosis or sclerosis. Diagnosis is based on clinical findings and specific abnormalities in laboratory test results.1 When dealing with rather symmetric and widespread cutaneous involvement, one should consider a variety of conditions besides systemic sclerosis, such as scleredema adultorum, scleromyxedema, eosinophilic fasciitis, and eosinophilia myalgia syndrome. When the involvement is patchy and asymmetrical, one should think of localized scleroderma and conditions associated with it, such as porphyria cutanea tarda. In this review, we will consider systemic sclerosis and localized scleroderma (TABLE) and briefly discuss some of the general concepts concerning scleroderma, with particular emphasis on what is new regarding pathogenesis and therapy.
Pathogenesis The key pathogenic events of systemic sclerosis are generally thought to be endothelial cell damage and excessive deposition of collagen and other matrix proteins into tissue. 2 The cause of endothelial cell injury remains unknown, and there continues to be speculation that the injury is, at least in part, the result of an immunologic response or a toxic agent. For example, the recent epidemic of eosinophilia myalgia syndrome, which was associated with ingestion of an over-thecounter L-tryptophan preparation, suggests that certain substances can lead to a scleroderma-like illness and fibrosis. 3 There is increasing evidence that certain cytokines, such as transforming growth factor-~3 (TGF-[3) and connective tissue growth factor, might play a fundamental role in the accumulation of collagen in the skin and internal organs. 4 Blocking the action of these peptides (ie, with antibodies, antisense-oligonucleotide approaches) is emerging as a new and potentially useful way to down-regulate the fibrotic response. 5,6 For example, interferons have become a promising therapeutic agent because they can block collagen synthesis and the action of TGF-[3. 7 As also shown by the presence of autoantibodies, immunologic abnormalities are common in systemic Curr Probl Dermatol, March/April 2000
sclerosis. Importantly, the observation that dense lymphocytic infiltration can occur in the skin early during the development of fibrosis points to a key role of the immune system in either initiating or sustaining the fibrotic response. Similarities in clinical observations and laboratory test results between graft versus host disease and scleroderma also suggest the possibility that immunologic responses are an important aspect of the pathogenesis.1 Most recently, fetal cells have been found in the blood and active skin lesions of women with systemic sclerosis, and it has been proposed that microchimerism is involved in the pathogenesis of the disease. One possible scenario is that fetal T cells, as a result of additional factors (environmental, viral), could stimulate fibroblast proliferation and synthetic activity. However, much more needs to be learned regarding this novel and interesting hypothesis. 8,9 Compared with systemic sclerosis, much less investigative work has been devoted to studying the pathogenesis of localized scleroderma. It is likely, however, that certain principles regarding excessive collagen deposition are operative in both conditions. Increased expression of type I procollagen has been demonstrated by in situ hybridization in the involved skin. 1° Observations have recently provided considerable evidence that dermal fibroblasts constitute a heterogeneous population of cells. It has been hypothesized that, as in the process of wound repair, the pathogenesis of scleroderma is characterized by the emergence of fibroblast clones having a higher synthetic phenotype. 11 There is also evidence that low oxygen tension, an established feature of sclerodermatous skin, stimulates the synthesis of collagen and TGF-131.12,13 It has been suggested that localized scleroderma may be linked to infection with Borrelia burgdorferi or Borrelia-like organisms. Much of this evidence is indirect. For example, in both its inflammatory and atrophic stages, acrodermatitis chronica atrophicans (ACA), a disease associated with tick bites, may mimic linear scleroderma (Figure 1). 2 Moreover, ACA might coexist with localized scleroderma and with lichen sclerosus.14'15 Clinically, ACA involves the acral areas of the body, is seen in elderly patients, and gives the skin a livid discoloration that is not well demarcated. ACA 95
TABLE M a i n clinical and l a b o r a t o r y manifestations of systemic sclerosis and localized scleroderma
Clinical variant Raynaud's phenomenon Symmetric induration Sclerodactyly Systemic involvement Skin biopsy results consistent with "scleroderma" ANA Anticentromere antibodies Antitopoisomerase I antibodies Antibodies to single-stranded DNA Antihistone antibodies Eosinophilia Spontaneous remission
Systemic sclerosis
Localized scleroderma
Limited Diffuse
Morphea Generalized morpheaLinear scleroderma
++ ++ ++ + ++
++
++ + + ~
+ + + + ++
-
++, almost always; +, frequently; ~-, sometimes; -, rarely.
and linear scleroderma cannot always be separated on the basis of histopathologic results. 16 It has been proposed that ACA is the result of infection with B burgdorferi. 17The possibility that this organism is also be the causal agent of morphea has been proposed by several authors. In one study, antibodies to B burgdorferi were found in 5 of 10 patients with morphea. 18 Other studies of patients with localized scleroderma have found no evidence of Borrelia infection; these conclusions were based on the results of histopathologic studies, cultures, and response to 1- to 2-week courses of systemic antibiotic treatment. 192° However, spirochetal forms have been detected in the dermis of 45% and 40% of patients with active lichen sclerosus et atrophicus (LSA) and morphea, respectively, but not in patients with older, nonactive lesions. 21 Variable results have also been obtained when testing for the presence of B burgdorferi in localized scleroderma by the polymerase chain reaction. 22,23 In summary, it remains unclear whether B burgdorferi infection plays a role in the pathogenesis of localized scleroderma.
Localized Scleroderma There are 3 main variants of localized scleroderma (TABLE). 14 Patches of morphea are said to have a violaceous border when active, but this is quite variable. Generalized morphea is characterized by the tendency for patches to become confluent. Patients with linear scleroderma lesions on the extremities are at risk for contractures, and thus can benefit from early intervention with physical therapy. On the face, linear lesions 96
(en coup de sabre) are often atrophic. Pigment changes are the rule in localized scleroderma. Atrophoderma of Pasini and Pierini, probably an aborted form of localized scleroderma, is characterized by the presence of hyperpigmented, slightly atrophic patches. Up to 50% of patients with active generalized morphea or linear scleroderma will have eosinophilia in their peripheral circulation. 14,24 Over the last several years, important predictors of prognosis--antinuclear antibodies (ANAs), anti-single-stranded DNA antibodies, and antihistone antibodies--have been described. The presence of ANAs suggests a longer disease course, generally yearsY Antibodies to singlestranded DNA are found in patients with extensive disease involving either a major portion of the skin or extending into the subcutaneous tissues. 14 The presence of antihistone antibodies also seems to correlate with more extensive disease.
Management Consistently effective therapy for localized scleroderma does not exist yet, and commonly used agents have not been tested in randomized and controlled clinical trials. There have been obstacles to proper trials in localized scleroderma. One problem is that enrolling enough patients with localized scleroderma to evaluate the efficacy of old or new treatments would require substantial collaboration and organizational efforts among many referral centers. The second is that the clinical manifestations of localized scleroderma are quite heterogeneous; stratification according to different clinical variants may be necessary and might further dilute the population being studied. Some of the therapies used with reported improvement in the cutaneous lesions or joint contractures include the following: D-penicillamine,26 cyclosporine,27 aminobenzoate potassium, 28 phenytoin, 29 etretinate,3° 1,25 dihydroxyvitamin D3,31 antimalarial medications, 32 corticosteroids, 32 surgical grafting and transplantation, 33 and psoralen plus ultraviolet A (PUVA) baths. 31 When justified by the severity of localized scleroderma, D-penicillamine has been found to be effective in a retrospective study of selected patients. 34 However, the nephrotic syndrome and bone marrow suppression are common adverse effects of D-penicillamine. Vitamin D 3 has recently been proposed as an effective therapy for localized scleroderma. This vitamin might play a role in fibroblast differentiation and has immunologic effects. Although topical vitamin D, (for Curr Probl Dermatol, March/April 2 0 0 0
treating psoriasis) has been used in the treatment of limited morphea plaques, the oral calcitriol form has been used to treat more extensive disease. The dosage of oral calcitriol is 0.5 to 0.75 gg/day. In one report, 2 patients with widespread morphea had a remarkable response to this therapy. 35 In our experience, oral calcitriol is also useful in the management of en coup de sabre resistant to treatment with plaquenyl, our firstline drug. 32 A double-blind, placebo-controlled multicenter trial of interferon-,/in the treatment of localized scleroderma was recently completed. Although no therapeutic response was observed in the existing lesions, the number of new lesions in the interferon-7 group was lower than in the placebo group. 36 In another recent report, methotrexate was helpful in softening the lesions of morphea and generalized morphea, as determined clinically and by the use of a durometer. 37 This therapy holds considerable promise, and there is now some interest in initiating a double-blind trial to test its efficacy. Other immunologic approaches to treating localized scleroderma have been tried. In 13 of 17 patients with localized scleroderma, it was found that systemic (oral) steroids improved the lesions when given at 0.5 to 1.0 mg/kg over 6 weeks. 38 We have often used even smaller doses of oral prednisone (0.25 mg/kg) in treating active and extensive generalized morphea or rapidly disfiguring linear scleroderma and en coup de sabre. In our experience, oral prednisone seems to be most helpful in the first few months of therapy, and we generally use it in combination with plaquenyl. 32 Not surprisingly, there have also been some anecdotal reports of the successful use of cyclosporine in the treatment of disabling morphea. 39 It remains to be seen whether this immunosuppressive agent, particularly if used at low (safer) doses, can bring about remissions in difficult cases. A rather exciting development in the management of localized scleroderma is the increasing use of ultraviolet light therapy. Although no controlled trials have been done, reports detailing this therapy are promising. PUVA baths have been reported to be successful. In a recent report, a PUVA bath improved 13 of 17 patients. 4° Perhaps more exciting and novel is the use of narrow-band UVA. In a recent report of 17 patients, high doses of narrow-band UVA (130 J/cm 2) were found to be superior to lower doses (20 J/cm2). Narrow-band UVA may act by stimulating the production of interstitial collagenase. 41 Curr Probl Dermatol, March/April 2000
FIG 1. The atrophic stage of linear scleroderma in the ankle.
Systemic Sclerosis Systemic sclerosis involves internal organs and is often life-threatening. It is generally preceded by the development of Raynaud's phenomenon and eventually leads to cutaneous induration and internal organ involvement from excessive collagen deposition. This condition is up to 15 times more common in women than in men, and it generally occurs in people aged 30 to 50 years. 1 There is a rather substantial uniformity in the ways in which systemic sclerosis presents clinically. Common clinical features include Raynaud's phenomenon, early induration of digits (sclerodactyly) and face, and esophageal symptoms. Many investigators and clinicians separate systemic sclerosis into 2 clinical variants: (1) limited disease and (2) diffuse disease. 1 In the latter, truncal skin or proximal portions of the extremities are involved, and patients have a worse prognosis. Some patients with limited cutaneous disease have the CREST syndrome (C, calcinosis; R, Raynaud's phenomenon; E, esophageal involvement; S, sclerodactyly; T, telangiectasia). Changes in skin pigmentation are almost the rule in systemic sclerosis, and hyperpigmentation can be diffuse or concentrated in areas of pressure, such as the patient's belt line. The most commonly affected internal organs are the esophagus, lungs, heart, and kidney. Since angiotensin converting enzyme inhibitors became available, hypertensive renal crisis has become less common, and death from fulminant renal failure is unusual. However, lung involvement has now emerged as a major cause of fatal 97
1:1133. Bioengineered skin Graftskin [Organogenesis (Canton, MA)] after it has been meshed and just before application to an ulcer. 1:1132. Ulcers near the tip of the digits.
outcome. Pulmonary hypertension is a dreaded complication of systemic sclerosis, and is more common in patients with limited disease. Pulmonary interstitial disease can be rapidly progressive.1 Most patients with systemic sclerosis have elevated ANA titers as shown by indirect immunofluorescence. 3-6 The antinucleolar pattern is most specific for systemic sclerosis. The antitopoisomerase I antibody (Scl 70) is more commonly detected in diffuse disease and is associated with a worse prognosis. Anticentromere antibodies are more common in patients with limited disease. Autoantibodies to RNA polymerases I and III can be exclusive of both anticentromere and antitopoisomerase I (10% of cases). 1
Management Systemic sclerosis remains a condition in which the clinician can provide treatment of only specific symptoms and complications. A true disease-modifying agent or approach has yet to be found. Contrary to what is commonly thought, many patients do quite well with supportive care. At presentation, certain factors are predictive of a poor outcome: male sex, black race, diffuse disease, proteinuria, and evidence of lung, cardiac, or renal involvement at presentation. 42 Here we will focus on recent advances in therapeutic modalities for different complications of systemic sclerosis.
Raynaud's Phenomenon The most important approach is to instruct patients to avoid cold exposure and to discontinue the use of 98
tobacco products. Calcium channel blockers, such as sustained-release preparations of nifedipine, are firstline pharmacologic agents for the treatment of Raynaud's phenomenon. In difficult situations, one can combine calcium channel blockers with other drugs such as prazosin and reserpine. Pentoxifylline has been tried but its effectiveness has not been shown. Topical nitrates are often used, but they may actually divert blood flow from areas of ischemia. Intravenous prostaglandin E 1 can be useful in cases in which the condition is refractory to treatment. 43 An oral preparation of the prostacyclin analog iloprost has given mixed results in double-blind randomized trials. 44 Repeated nerve blocks are necessary in a minority of patients with severe Raynaud's phenomenon. Conditioning measures are probably a useful approach but they require substantial compliance and effort.
Cutaneous Ulcers Cutaneous ulcers can remain unhealed for months or years. Ulcers on or near the tip of the digits are probably the result of ischemia (Figure 2), whereas those on the interphalangeal joints axe more likely to persist because of continued trauma. Regardless of ulcer location, however, approaches to increase blood flow (see Raynaud's Phenomenon section) are usually indicated. Calcium channel blockers (nifedipine) have proved useful in this regard, but care must be taken not to decrease systemic blood pressure so much as to diminish perfusion in the already compromised digital vessels. Occlusive dressings can relieve ulcer pain and speed up Curr Probl Dermatol, March/April 2000
FIG 4. A persistent digital ulcer being treated with bioengineered skin (Graftskin or Apligraf, meshed at a 1.5:1 ratio). Immediate pain relief and complete healing resulted after 2 weeks of application.
debridement but have proved difficult for patients to apply by themselves. Bioengineered skin holds considerable promise as a way to stimulate ulcer healing. Laboratory-grown living skin [Graftskin (Organogenesis, Canton, MA)], approved for use in the treatment of ulcers of the lower extremities,45 is a new and attractive way to treat scleroderma ulcers (Figure 3). Our own experience suggests that bioengineered skin relieves pain dramatically and stimulates ulcer healing (Figure 4). The use of topical nitrates to heal ulcers has been disappointing. As with Raynaud's phenomenon, improvement of ulcers can be expected by stopping cigarette smoking. Sympathetic blocks are unlikely to be effective in improving blood flow sufficiently to heal intractable ulcers. Little can be done for ulcers caused by calcinosis other than removing as much of the calcium deposit as possible, then gaffing. Some pharmacologic approaches are interesting, as described in the following sections.
Skin Involvement Conclusions regarding the effectiveness of therapeutic interventions for skin involvement and fibrosis in systemic sclerosis have been made mostly with a clinical scoring system that assesses skin induration. We have recently shown that the durometer, a simple device to measure induration of skin, might be useful as an Curr Probl Dermatol, March/April 2000
FIG 5, Cutaneous ulcers complicated by substantial calcinosis. The white material on the third finger represents calcium deposits. The pain was severe, but seemed to improve with giving low-dose warfarin.
adjunctive method for assessing skin involvement in systemic sclerosis. 46 No therapeutic approach has convincingly shown that one can alter the clinical course of cutaneous fibrosis. Most therapies have been based on either the notion that the inflammatory component of the disease plays a fundamental role in pathogenesis, or that fibroblast activation and increased collagen deposition must be the therapeutic target. Clinical trials have at least told us what does not work. 1,47 For many years, on the basis of retrospective evidence, D-penicillamine was used to both control inflammation and to interfere with the formation and crosslinking of collagen. 47 In a recent multicenter prospective trial of 143 patients with diffuse disease, high dosage (750 to 1,000 rag/day) versus low dosage (62.5 mg/day) of D-penicillamine were tested. The results of this trial cast considerable doubt on the effectiveness of D-penicillamine, 48 although it remains possible that a few selected patients will respond favorably to this treatment. Interferonqx and interferon-7 have been tested in small trials. These agents appear to have little or no effectiveness. Relaxin, which can promote collagenase activity, has recently undergone testing in a phase II trial. Low-dosage relaxin (25 gg/kg/day) decreased skin scores when compared with high-dosage (100 99
gg/kg/day) or placebo. Further studies are needed with relaxin. No other outcome measures, including internal organ involvement, were improved by relaxin. 49 Some interventions have been based mainly on the notion that the inflammatory or immunologic component of systemic sclerosis is a key player in the pathogenesis and progression of the disease. Photophoresis has led to an improvement in skin scores after 6 months o f therapy) ° However, the results are not impressive, and further work should be done to test this interesting approach. Systemic corticosteroids given as monthly injections of dexamethasone (100 mg) have led to a decrease in skin scores. 47 However, there have also been reports that corticosteroids may hasten or bring on renal crisis. Methotrexate is an interesting therapeutic possibility that should be pursued further. The results of a small, randomized trial of 29 patients suggests that 15 mg of methotrexate per week might lead .to improvement in some variables, including skin scores. 51 Cyclosporine has not been tested extensively, perhaps because of the renal dysfunction associated with this agent. The alkylating agent chlorambucil has proved to be largely ineffective, as have 5-fluorouracil and ketotifen. 47 In addition to cutaneous fibrosis and digital ulceration, there are other complications related to skin in systemic sclerosis. Dryness, pruritus, hyperpigmentation, are all common. Colchicine has been empirically found to decrease pruritus; the mechanism of action is unknown. PUVA therapy can be used to decrease pruritus in patients in whom colchicine or topical steroids are not effective. Calcinosis is a difficult problem to deal with. Some calcium deposits are associated with ulcerations, which may be quite inflamed and painful (Figure 5). The use of diltiazam and low-dose warfarin in the treatment of calcinosis is controversial. 1,47 However, given that little can be done for calcinosis other than surgical removal, one tends to try these therapies. Lasers are an effective treatment of cutaneous telengiectasia.
Internal Organ Involvement Encouraging results have been obtained in the last few years in managing complications. For example, much progress has been made in the management and prevention of renal crisis. In large part, this is the result of the development and use of angiotensin converting enzyme inhibitors. Some clinicians use these antihypertensive agents in all patients with diffuse disease. Proton pump inhibitors are now the therapy of choice 100
to treat esophageal symptoms. To increase gastric motility, cisapride is generally used; and often empirically. Cisapride can also improve small bowel hypomotility. Advances in total parenteral nutrition can now improve the clinical course of patients with severe gastrointestinal tract dysfunction. 1,47 The greatest problem for patients with systemic sclerosis is pulmonary failure. Pulmonary hypertension and interstitial lung disease have emerged as areas in which we need better treatments. Some progress has been made; calcium channel blockers are often used in the treatment of pulmonary hypertension, and continuous intravenous infusion of prostacyclin seems promising. For treating interstitial lung disease, cyclophosphamide is commonly used, especially when radiographic studies reveal a neutrophilic alveolitis. 52
Conclusions In this brief review, we have focused on localized scleroderma and systemic sclerosis and the recent advances in understanding and treating these conditions. Certain new insights in the pathogenesis of fibrosis are exciting, and will help direct future therapeutic approaches. Although treatment of these conditions remains unsatisfactory and only palliative, progress has been made. For localized scleroderma, the use of vitamin D and ultraviolet light therapy appears promising, as does treatment with methotrexate. Interferon-y may halt the progression of the condition and the development of new lesions. For systemic sclerosis, management is focused on controlling systemic complications, and several new drugs and approaches seem worthwhile when the gastrointestinal tract and pulmonary system are involved. Skin involvement and induration appear to respond to some drugs and treatments, but probably not to a clinically relevant extent. Bioengineered skin offers new hope to patients with persistent digital ulcerations.
REFERENCES 1. Medsger TA Jr. Systemic sclerosis. In: Koopman WH, editor. Arthritis & allied conditions. Baltimore: Williams & Wilkins; 1997. p 1433-55. 2. Uitto J, Jimenez S. Fibrotic skin diseases. Clinical presentations, etiologic considerations, and treatment options. Arch Dermatol 1990;126:661-4. 3. Blauvelt A, Falanga V. Idiopathic and L-tryptophan associated eosinophilic fasciitis before and after L-tryptophan contamination. Arch Dermatol 1991; 127:1159-66. 4. Border WA, Noble NA. Transforming growth factor [~in tissue fibrosis. N Eng J Med 1994;331:1286-92. Curr Probl Dermatol, March/April 2000
5. Brunet CL, Sharpe PM, Ferguson MWJ. Inhibition of TGF-[33 (but not TGF-~I or TGF~2) activity prevents normal mouse embryonic palate fusion. Int J Dev Biol 1995;39:345-55. 6. Murata H, Zhou L, Ochoa S, et al. TGF-[33 stimulates and regulates collagen synthesis through TGF-~31 dependent and independent mechanisms. J Invest Dermatol 1997; 108:258-62. 7. Varga J. Recombinant cytokine treatment for scleroderma: can the antifibrotic potential of interferon-gamma be realized clinically? Arch Dermatol 1997;133:637-42. 8. Key G, Becker MH, Baron B, et al. New Ki-67 equivalent murine monoclonal antibodies (MIB1-3) generated against bacterially expressed parts of the Ki-67 cDNA containing three 62 base pair repetitive elements encoding for the Ki-67 epitope. Lab Invest 1993;68:629-36. 9. Artlett CM, Smith B J, Jimenez SA. Identification of fetal DNA and cells in skin lesions from women with systemic sclerosis. N Eng J Med 1998 ;338:1186-91. 10. Kahari VM, Sandberg M, Kalimo H, et al. Identification of fibroblasts responsible for increased collagen production in localized scleroderma by in situ hybridization. J Invest Dermatol 1988;90:664-70. 11. Falanga V, Zhou L, Takagi H, et al. Human dermal fibroblasts derived from single cells are heterogeneous in the mRNA levels of alpha l(I) procollagen and TGF-beta 1. J Invest Dermatol 1995; 105:27-31. 12. Falanga V, Martin TA, Takagi H, et al. Low oxygen tension increases mRNA levels of alpha l(I) procollagen in human dermal fibroblasts. J Cell Physiol 1993;157:408-12. 13. Falanga V, Yufit T. Low oxygen tension increases collagen synthesis through the action of TGF-~I. J Invest Dermatol 1999;112:83(abstract). 14. Falanga V. Localized scleroderma. Med Clin North Am 1989; 73:1143-56. 15. Buechner SA, Winkelmann RK, Lautenschlager S, et al. Localized scleroderma associated with Borrelia burgdorferi infection; clinical, histologic, and immunohistochemical observations. J Am Acad Dermatol 1993;29:190-6. 16. Aberer E, Klade H, Hobisch G. A clinical, histological, and immunohistochemical comparison of acrodermatitis chronica atrophicans and morphea. Am J Dermatopathol 1991;13: 334-41. 17. Asbfink E, Hederstedt B, Hovmark A. The spirochetal etiology of acrodermatitis chronica atrophicans. Acta Derm Venereol (Stockh) 1984;64:506-12. 18. Aberer E, Neumann R, Stanek G. Is localised scleroderma a borrelia infection? Lancet 1985 ;II:278. 19. Raguin G, Boisnic S, Souteyrand P, et al. No evidence for a spirochaetal origin of localized scleroderma. Br J Dermatol 1992; 127:218-20. 20. Lupoli S, Cutler SJ, Stephens CO, et al. Lyme disease and localized scleroderma: no evidence for a common aetiology. Br J Rheumatol 1991;30:154-6. 21. Ross SA, Sanchez JL, Taboas JO. Spirochetal forms in the dermal lesions of morphea and lichen selerosus et atrophicus. Am J Dermatopathol 1990; 12:357-62. 22. Schempp C, et al. Further evidence for Borrelia burgdorferi infection in morphea and lichen sclerosus et atrophicus confirmed by DNA amplification. J Invest Dermatol 1993;100: 717-20. Curr Probl Dermatol, March/April 2000
23. Meis JF, Koopman R, Van Bergen B, et al. No evidence for a relation between Borrelia burgdorferi infection and old lesions of localized scleroderma (morphea). Arch Dermatol 1993; 129:386-7. 24. Falanga V, Medsger TA, Reichlin M, et al. Linear scleroderma; clinical specmam, prognosis, and laboratory abnormalities. Ann Intern Med 1986;104:849-57. 25. Falanga V. Fibrosing syndromes of childhood. In: Advances in Dermatology. St. Louis: Mosby Year Book; 1991; Vol 6. p 145-59. 26. Falanga V, Medsger TA. D-Penicillamine in the treatment of localized scleroderma. Arch Dermatol 1990; 126:609-12. 27. W'ofle B, Hein R, Krieg T, et al. Cyclosporin in localized and systemic scleroderma: a clinical study. Dermatologica 1990;181:215-20. 28. Zarfonetis CJD. Antifibrofic therapy with POTABA. Am J Med Sci 1964;80:550. 29. Neldner KH. Treatment of localized linear scleroderma with phenytoin. Cutis 1978;22:569-72. 30. Neuhofer J, Fritsch P. Treatment of localized scleroderma and lichen sclerosus with etretinate. Acta Derm Venereol (Stockh) 1984;64:171-4. 31. Humbert PG, Dupond JL, Rochefort A, et al. Localized scleroderma: response to 1,25-dihydroxyvitamin D3. Clin Exp Dermatol 1990;15:396-8. 32. Greenberg SA, Falanga V. Localized cutaneous sclerosis. In: Sontheimer RD, Provost TT, editors. Cutaneous manifestations of rheumatic diseases. Philadelphia: Williams & Wilkins; 1996. p. 141-55. 33. Milan MF, Bennett JE. Scleroderma en coup de sabre. Ann Plast Surg 1983;10:364-70. 34. Kerscher M, Meurer M, Sander C, et al. PUVA bath photochemotherapy for localized scleroderma. Evaluation of 17 consecutive patients. Arch Dermatol 1996; 132:1280-2. 35. Hulshof MM, Pavel S, Breedveld FC, et al. Oral calcitriol as a new therapeutic modality for generalized morphea. Arch Dermatol 1994;130:1290-3. 36. Hunzelmann N, Anders S, Fierlbeck G, et al. Double blind placebo controlled study of intralesional IFN-y for the treatment of localized scleroderma. J Am Acad Dermatol 1997; 36:433-5. 37. Seyger MM, van den Hoogen FH, de Boo T, et al. Low-dose methotrexate in the treatment of widespread morphea. J Am Acad Dermatol 1998;39:220-5. 38. Joly P, Bamberger N, Crickx B, et al. Treatment of severe forms of localized scleroderma with oral corticosteroids: follow up study on 17 patients. Arch Dermatol 1994;130:663-4. 39. Peter RU, Ruzicka T, Eckert F. Low-dose cyclosporine A in the treatment of disabling morphea. Arch Dermatol 1991; 127:1420-I. 40. Kerscher M, Meurer M, Sander C, et al. PUVA bath photochemotherapy for localized scleroderma. Arch Dermatol 1996;132:1280-2. 41. Stege H, Berneburg M, Humke S, et al. High-dose UVA 1 radiation therapy for localized scleroderma. J Am Acad Dermatol 1997;36:938-44. 42. Altman RD, Medsger TA Jr, Bloch DA, et al. Predictors of survival in systemic sclerosis (scleroderma). Arthritis Rheum 1991;34:403-13. 101
43. Wigley FM, Wise RA, Seibold RJ, et al. Intravenous iloprost infusion in patients with RP secondary to systemic sclerosis. Ann Intern Meal 1994;120:199-206. 44. Belch JJ, Capell HA, Cooke ED, et al. Oral iloprost as a treatment for Raynaud's syndrome: A double-blind multicentre placebo-controlled study. Ann Rheum Dis 1995;54: 197-200. 45. Falanga V, Margolis D, Alvarez O, et al. Healing of venous ulcers and lack of clinical rejection with an allogeneic cultured human skin equivalent. Arch Dermatol 1998;134:293300. 46. Falanga V, Bucalo B. The use of a durometer to assess skin hardness. J Am Acad Dermatol 1993;29:47-51. 47. Stone JH, Wigley FM. Management of systemic sclerosis: the art and science. Semin Cutan Meal Surg 1998;17:55-64. 48. Clements PJ, Wong WK, Seibold RJ, et al. High-dose vs. low-dose penicillamine in early diffuse systemic sclerosis
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Curr Probl Dermatol, March/April 2000
Pathogenesis The key pathogenic events of systemic sclerosis are generally thought to be endothelial cell damage and excessive deposition of collagen and other matrix proteins into tissue. 2 The cause of endothelial cell injury remains unknown, and there continues to be speculation that the injury is, at least in part, the result of an immunologic response or a toxic agent. For example, the recent epidemic of eosinophilia myalgia syndrome, which was associated with ingestion of an over-thecounter L-tryptophan preparation, suggests that certain substances can lead to a scleroderma-like illness and fibrosis. 3 There is increasing evidence that certain cytokines, such as transforming growth factor-~3 (TGF-[3) and connective tissue growth factor, might play a fundamental role in the accumulation of collagen in the skin and internal organs. 4 Blocking the action of these peptides (ie, with antibodies, antisense-oligonucleotide approaches) is emerging as a new and potentially useful way to down-regulate the fibrotic response. 5,6 For example, interferons have become a promising therapeutic agent because they can block collagen synthesis and the action of TGF-[3. 7 As also shown by the presence of autoantibodies, immunologic abnormalities are common in systemic Curr Probl Dermatol, March/April 2000
sclerosis. Importantly, the observation that dense lymphocytic infiltration can occur in the skin early during the development of fibrosis points to a key role of the immune system in either initiating or sustaining the fibrotic response. Similarities in clinical observations and laboratory test results between graft versus host disease and scleroderma also suggest the possibility that immunologic responses are an important aspect of the pathogenesis.1 Most recently, fetal cells have been found in the blood and active skin lesions of women with systemic sclerosis, and it has been proposed that microchimerism is involved in the pathogenesis of the disease. One possible scenario is that fetal T cells, as a result of additional factors (environmental, viral), could stimulate fibroblast proliferation and synthetic activity. However, much more needs to be learned regarding this novel and interesting hypothesis. 8,9 Compared with systemic sclerosis, much less investigative work has been devoted to studying the pathogenesis of localized scleroderma. It is likely, however, that certain principles regarding excessive collagen deposition are operative in both conditions. Increased expression of type I procollagen has been demonstrated by in situ hybridization in the involved skin. 1° Observations have recently provided considerable evidence that dermal fibroblasts constitute a heterogeneous population of cells. It has been hypothesized that, as in the process of wound repair, the pathogenesis of scleroderma is characterized by the emergence of fibroblast clones having a higher synthetic phenotype. 11 There is also evidence that low oxygen tension, an established feature of sclerodermatous skin, stimulates the synthesis of collagen and TGF-131.12,13 It has been suggested that localized scleroderma may be linked to infection with Borrelia burgdorferi or Borrelia-like organisms. Much of this evidence is indirect. For example, in both its inflammatory and atrophic stages, acrodermatitis chronica atrophicans (ACA), a disease associated with tick bites, may mimic linear scleroderma (Figure 1). 2 Moreover, ACA might coexist with localized scleroderma and with lichen sclerosus.14'15 Clinically, ACA involves the acral areas of the body, is seen in elderly patients, and gives the skin a livid discoloration that is not well demarcated. ACA 95
TABLE M a i n clinical and l a b o r a t o r y manifestations of systemic sclerosis and localized scleroderma
Clinical variant Raynaud's phenomenon Symmetric induration Sclerodactyly Systemic involvement Skin biopsy results consistent with "scleroderma" ANA Anticentromere antibodies Antitopoisomerase I antibodies Antibodies to single-stranded DNA Antihistone antibodies Eosinophilia Spontaneous remission
Systemic sclerosis
Localized scleroderma
Limited Diffuse
Morphea Generalized morpheaLinear scleroderma
++ ++ ++ + ++
++
++ + + ~
+ + + + ++
-
++, almost always; +, frequently; ~-, sometimes; -, rarely.
and linear scleroderma cannot always be separated on the basis of histopathologic results. 16 It has been proposed that ACA is the result of infection with B burgdorferi. 17The possibility that this organism is also be the causal agent of morphea has been proposed by several authors. In one study, antibodies to B burgdorferi were found in 5 of 10 patients with morphea. 18 Other studies of patients with localized scleroderma have found no evidence of Borrelia infection; these conclusions were based on the results of histopathologic studies, cultures, and response to 1- to 2-week courses of systemic antibiotic treatment. 192° However, spirochetal forms have been detected in the dermis of 45% and 40% of patients with active lichen sclerosus et atrophicus (LSA) and morphea, respectively, but not in patients with older, nonactive lesions. 21 Variable results have also been obtained when testing for the presence of B burgdorferi in localized scleroderma by the polymerase chain reaction. 22,23 In summary, it remains unclear whether B burgdorferi infection plays a role in the pathogenesis of localized scleroderma.
Localized Scleroderma There are 3 main variants of localized scleroderma (TABLE). 14 Patches of morphea are said to have a violaceous border when active, but this is quite variable. Generalized morphea is characterized by the tendency for patches to become confluent. Patients with linear scleroderma lesions on the extremities are at risk for contractures, and thus can benefit from early intervention with physical therapy. On the face, linear lesions 96
(en coup de sabre) are often atrophic. Pigment changes are the rule in localized scleroderma. Atrophoderma of Pasini and Pierini, probably an aborted form of localized scleroderma, is characterized by the presence of hyperpigmented, slightly atrophic patches. Up to 50% of patients with active generalized morphea or linear scleroderma will have eosinophilia in their peripheral circulation. 14,24 Over the last several years, important predictors of prognosis--antinuclear antibodies (ANAs), anti-single-stranded DNA antibodies, and antihistone antibodies--have been described. The presence of ANAs suggests a longer disease course, generally yearsY Antibodies to singlestranded DNA are found in patients with extensive disease involving either a major portion of the skin or extending into the subcutaneous tissues. 14 The presence of antihistone antibodies also seems to correlate with more extensive disease.
Management Consistently effective therapy for localized scleroderma does not exist yet, and commonly used agents have not been tested in randomized and controlled clinical trials. There have been obstacles to proper trials in localized scleroderma. One problem is that enrolling enough patients with localized scleroderma to evaluate the efficacy of old or new treatments would require substantial collaboration and organizational efforts among many referral centers. The second is that the clinical manifestations of localized scleroderma are quite heterogeneous; stratification according to different clinical variants may be necessary and might further dilute the population being studied. Some of the therapies used with reported improvement in the cutaneous lesions or joint contractures include the following: D-penicillamine,26 cyclosporine,27 aminobenzoate potassium, 28 phenytoin, 29 etretinate,3° 1,25 dihydroxyvitamin D3,31 antimalarial medications, 32 corticosteroids, 32 surgical grafting and transplantation, 33 and psoralen plus ultraviolet A (PUVA) baths. 31 When justified by the severity of localized scleroderma, D-penicillamine has been found to be effective in a retrospective study of selected patients. 34 However, the nephrotic syndrome and bone marrow suppression are common adverse effects of D-penicillamine. Vitamin D 3 has recently been proposed as an effective therapy for localized scleroderma. This vitamin might play a role in fibroblast differentiation and has immunologic effects. Although topical vitamin D, (for Curr Probl Dermatol, March/April 2 0 0 0
treating psoriasis) has been used in the treatment of limited morphea plaques, the oral calcitriol form has been used to treat more extensive disease. The dosage of oral calcitriol is 0.5 to 0.75 gg/day. In one report, 2 patients with widespread morphea had a remarkable response to this therapy. 35 In our experience, oral calcitriol is also useful in the management of en coup de sabre resistant to treatment with plaquenyl, our firstline drug. 32 A double-blind, placebo-controlled multicenter trial of interferon-,/in the treatment of localized scleroderma was recently completed. Although no therapeutic response was observed in the existing lesions, the number of new lesions in the interferon-7 group was lower than in the placebo group. 36 In another recent report, methotrexate was helpful in softening the lesions of morphea and generalized morphea, as determined clinically and by the use of a durometer. 37 This therapy holds considerable promise, and there is now some interest in initiating a double-blind trial to test its efficacy. Other immunologic approaches to treating localized scleroderma have been tried. In 13 of 17 patients with localized scleroderma, it was found that systemic (oral) steroids improved the lesions when given at 0.5 to 1.0 mg/kg over 6 weeks. 38 We have often used even smaller doses of oral prednisone (0.25 mg/kg) in treating active and extensive generalized morphea or rapidly disfiguring linear scleroderma and en coup de sabre. In our experience, oral prednisone seems to be most helpful in the first few months of therapy, and we generally use it in combination with plaquenyl. 32 Not surprisingly, there have also been some anecdotal reports of the successful use of cyclosporine in the treatment of disabling morphea. 39 It remains to be seen whether this immunosuppressive agent, particularly if used at low (safer) doses, can bring about remissions in difficult cases. A rather exciting development in the management of localized scleroderma is the increasing use of ultraviolet light therapy. Although no controlled trials have been done, reports detailing this therapy are promising. PUVA baths have been reported to be successful. In a recent report, a PUVA bath improved 13 of 17 patients. 4° Perhaps more exciting and novel is the use of narrow-band UVA. In a recent report of 17 patients, high doses of narrow-band UVA (130 J/cm 2) were found to be superior to lower doses (20 J/cm2). Narrow-band UVA may act by stimulating the production of interstitial collagenase. 41 Curr Probl Dermatol, March/April 2000
FIG 1. The atrophic stage of linear scleroderma in the ankle.
Systemic Sclerosis Systemic sclerosis involves internal organs and is often life-threatening. It is generally preceded by the development of Raynaud's phenomenon and eventually leads to cutaneous induration and internal organ involvement from excessive collagen deposition. This condition is up to 15 times more common in women than in men, and it generally occurs in people aged 30 to 50 years. 1 There is a rather substantial uniformity in the ways in which systemic sclerosis presents clinically. Common clinical features include Raynaud's phenomenon, early induration of digits (sclerodactyly) and face, and esophageal symptoms. Many investigators and clinicians separate systemic sclerosis into 2 clinical variants: (1) limited disease and (2) diffuse disease. 1 In the latter, truncal skin or proximal portions of the extremities are involved, and patients have a worse prognosis. Some patients with limited cutaneous disease have the CREST syndrome (C, calcinosis; R, Raynaud's phenomenon; E, esophageal involvement; S, sclerodactyly; T, telangiectasia). Changes in skin pigmentation are almost the rule in systemic sclerosis, and hyperpigmentation can be diffuse or concentrated in areas of pressure, such as the patient's belt line. The most commonly affected internal organs are the esophagus, lungs, heart, and kidney. Since angiotensin converting enzyme inhibitors became available, hypertensive renal crisis has become less common, and death from fulminant renal failure is unusual. However, lung involvement has now emerged as a major cause of fatal 97
1:1133. Bioengineered skin Graftskin [Organogenesis (Canton, MA)] after it has been meshed and just before application to an ulcer. 1:1132. Ulcers near the tip of the digits.
outcome. Pulmonary hypertension is a dreaded complication of systemic sclerosis, and is more common in patients with limited disease. Pulmonary interstitial disease can be rapidly progressive.1 Most patients with systemic sclerosis have elevated ANA titers as shown by indirect immunofluorescence. 3-6 The antinucleolar pattern is most specific for systemic sclerosis. The antitopoisomerase I antibody (Scl 70) is more commonly detected in diffuse disease and is associated with a worse prognosis. Anticentromere antibodies are more common in patients with limited disease. Autoantibodies to RNA polymerases I and III can be exclusive of both anticentromere and antitopoisomerase I (10% of cases). 1
Management Systemic sclerosis remains a condition in which the clinician can provide treatment of only specific symptoms and complications. A true disease-modifying agent or approach has yet to be found. Contrary to what is commonly thought, many patients do quite well with supportive care. At presentation, certain factors are predictive of a poor outcome: male sex, black race, diffuse disease, proteinuria, and evidence of lung, cardiac, or renal involvement at presentation. 42 Here we will focus on recent advances in therapeutic modalities for different complications of systemic sclerosis.
Raynaud's Phenomenon The most important approach is to instruct patients to avoid cold exposure and to discontinue the use of 98
tobacco products. Calcium channel blockers, such as sustained-release preparations of nifedipine, are firstline pharmacologic agents for the treatment of Raynaud's phenomenon. In difficult situations, one can combine calcium channel blockers with other drugs such as prazosin and reserpine. Pentoxifylline has been tried but its effectiveness has not been shown. Topical nitrates are often used, but they may actually divert blood flow from areas of ischemia. Intravenous prostaglandin E 1 can be useful in cases in which the condition is refractory to treatment. 43 An oral preparation of the prostacyclin analog iloprost has given mixed results in double-blind randomized trials. 44 Repeated nerve blocks are necessary in a minority of patients with severe Raynaud's phenomenon. Conditioning measures are probably a useful approach but they require substantial compliance and effort.
Cutaneous Ulcers Cutaneous ulcers can remain unhealed for months or years. Ulcers on or near the tip of the digits are probably the result of ischemia (Figure 2), whereas those on the interphalangeal joints axe more likely to persist because of continued trauma. Regardless of ulcer location, however, approaches to increase blood flow (see Raynaud's Phenomenon section) are usually indicated. Calcium channel blockers (nifedipine) have proved useful in this regard, but care must be taken not to decrease systemic blood pressure so much as to diminish perfusion in the already compromised digital vessels. Occlusive dressings can relieve ulcer pain and speed up Curr Probl Dermatol, March/April 2000
FIG 4. A persistent digital ulcer being treated with bioengineered skin (Graftskin or Apligraf, meshed at a 1.5:1 ratio). Immediate pain relief and complete healing resulted after 2 weeks of application.
debridement but have proved difficult for patients to apply by themselves. Bioengineered skin holds considerable promise as a way to stimulate ulcer healing. Laboratory-grown living skin [Graftskin (Organogenesis, Canton, MA)], approved for use in the treatment of ulcers of the lower extremities,45 is a new and attractive way to treat scleroderma ulcers (Figure 3). Our own experience suggests that bioengineered skin relieves pain dramatically and stimulates ulcer healing (Figure 4). The use of topical nitrates to heal ulcers has been disappointing. As with Raynaud's phenomenon, improvement of ulcers can be expected by stopping cigarette smoking. Sympathetic blocks are unlikely to be effective in improving blood flow sufficiently to heal intractable ulcers. Little can be done for ulcers caused by calcinosis other than removing as much of the calcium deposit as possible, then gaffing. Some pharmacologic approaches are interesting, as described in the following sections.
Skin Involvement Conclusions regarding the effectiveness of therapeutic interventions for skin involvement and fibrosis in systemic sclerosis have been made mostly with a clinical scoring system that assesses skin induration. We have recently shown that the durometer, a simple device to measure induration of skin, might be useful as an Curr Probl Dermatol, March/April 2000
FIG 5, Cutaneous ulcers complicated by substantial calcinosis. The white material on the third finger represents calcium deposits. The pain was severe, but seemed to improve with giving low-dose warfarin.
adjunctive method for assessing skin involvement in systemic sclerosis. 46 No therapeutic approach has convincingly shown that one can alter the clinical course of cutaneous fibrosis. Most therapies have been based on either the notion that the inflammatory component of the disease plays a fundamental role in pathogenesis, or that fibroblast activation and increased collagen deposition must be the therapeutic target. Clinical trials have at least told us what does not work. 1,47 For many years, on the basis of retrospective evidence, D-penicillamine was used to both control inflammation and to interfere with the formation and crosslinking of collagen. 47 In a recent multicenter prospective trial of 143 patients with diffuse disease, high dosage (750 to 1,000 rag/day) versus low dosage (62.5 mg/day) of D-penicillamine were tested. The results of this trial cast considerable doubt on the effectiveness of D-penicillamine, 48 although it remains possible that a few selected patients will respond favorably to this treatment. Interferonqx and interferon-7 have been tested in small trials. These agents appear to have little or no effectiveness. Relaxin, which can promote collagenase activity, has recently undergone testing in a phase II trial. Low-dosage relaxin (25 gg/kg/day) decreased skin scores when compared with high-dosage (100 99
gg/kg/day) or placebo. Further studies are needed with relaxin. No other outcome measures, including internal organ involvement, were improved by relaxin. 49 Some interventions have been based mainly on the notion that the inflammatory or immunologic component of systemic sclerosis is a key player in the pathogenesis and progression of the disease. Photophoresis has led to an improvement in skin scores after 6 months o f therapy) ° However, the results are not impressive, and further work should be done to test this interesting approach. Systemic corticosteroids given as monthly injections of dexamethasone (100 mg) have led to a decrease in skin scores. 47 However, there have also been reports that corticosteroids may hasten or bring on renal crisis. Methotrexate is an interesting therapeutic possibility that should be pursued further. The results of a small, randomized trial of 29 patients suggests that 15 mg of methotrexate per week might lead .to improvement in some variables, including skin scores. 51 Cyclosporine has not been tested extensively, perhaps because of the renal dysfunction associated with this agent. The alkylating agent chlorambucil has proved to be largely ineffective, as have 5-fluorouracil and ketotifen. 47 In addition to cutaneous fibrosis and digital ulceration, there are other complications related to skin in systemic sclerosis. Dryness, pruritus, hyperpigmentation, are all common. Colchicine has been empirically found to decrease pruritus; the mechanism of action is unknown. PUVA therapy can be used to decrease pruritus in patients in whom colchicine or topical steroids are not effective. Calcinosis is a difficult problem to deal with. Some calcium deposits are associated with ulcerations, which may be quite inflamed and painful (Figure 5). The use of diltiazam and low-dose warfarin in the treatment of calcinosis is controversial. 1,47 However, given that little can be done for calcinosis other than surgical removal, one tends to try these therapies. Lasers are an effective treatment of cutaneous telengiectasia.
Internal Organ Involvement Encouraging results have been obtained in the last few years in managing complications. For example, much progress has been made in the management and prevention of renal crisis. In large part, this is the result of the development and use of angiotensin converting enzyme inhibitors. Some clinicians use these antihypertensive agents in all patients with diffuse disease. Proton pump inhibitors are now the therapy of choice 100
to treat esophageal symptoms. To increase gastric motility, cisapride is generally used; and often empirically. Cisapride can also improve small bowel hypomotility. Advances in total parenteral nutrition can now improve the clinical course of patients with severe gastrointestinal tract dysfunction. 1,47 The greatest problem for patients with systemic sclerosis is pulmonary failure. Pulmonary hypertension and interstitial lung disease have emerged as areas in which we need better treatments. Some progress has been made; calcium channel blockers are often used in the treatment of pulmonary hypertension, and continuous intravenous infusion of prostacyclin seems promising. For treating interstitial lung disease, cyclophosphamide is commonly used, especially when radiographic studies reveal a neutrophilic alveolitis. 52
Conclusions In this brief review, we have focused on localized scleroderma and systemic sclerosis and the recent advances in understanding and treating these conditions. Certain new insights in the pathogenesis of fibrosis are exciting, and will help direct future therapeutic approaches. Although treatment of these conditions remains unsatisfactory and only palliative, progress has been made. For localized scleroderma, the use of vitamin D and ultraviolet light therapy appears promising, as does treatment with methotrexate. Interferon-y may halt the progression of the condition and the development of new lesions. For systemic sclerosis, management is focused on controlling systemic complications, and several new drugs and approaches seem worthwhile when the gastrointestinal tract and pulmonary system are involved. Skin involvement and induration appear to respond to some drugs and treatments, but probably not to a clinically relevant extent. Bioengineered skin offers new hope to patients with persistent digital ulcerations.
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