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A complete and durable clinical response to high-dose dexamethasone in a patient with scleromyxedema
A complete and durable clinical response to high-dose dexamethasone in a patient with scleromyxedema Keren B. Horn, MD,a Meyer A. Horn, MD,c James Swan, MD,a Seema Singhal, MD,b and Joan Guitart, MDa Chicago, Illinois We report a case of a patient with scleromyxedema limited to the skin with an associated IgG l monoclonal protein treated successfully with high-dose dexamethasone. We encourage the continued investigation of this complex relationship between the clinical presentation of scleromyxedema and its frequently associated paraproteinemia. (J Am Acad Dermatol 2004;51:S120-3.)
W
e describe a patient with scleromyxedema limited to the skin treated successfully with high-dose dexamethasone. The patient had an excellent response with complete resolution of the cutaneous symptoms and disappearance of the associated IgG paraprotein for over 1 year. Although a trace (unmeasurable quantity) monoclonal IgG lambda chain (Reference 0.0) was detected on his most recent immunofixation electrophoresis, he remains in complete clinical remission and is receiving maintenance therapy. Treatment of scleromyxedema is difficult and based largely on anecdotal experience. Reported therapies include melphalan,1 psoralen plus ultraviolet A (PUVA), electron beam,2 systemic steroids, adrenocorticotropic hormone (ACTH), oral retinoids, chlorambucil, 2-chlorodeoxyadenosine, and daily and/or pulse cyclophosphamide.3 Plasmapheresis with concomitant immunosuppression,4 extracorporeal photochemotherapy,5 high-dose intravenous immunoglobulin,6 interferon alfa,7 and autologous stem cell transplantation8 have also been investigated as hopeful therapeutic approaches. Disappointingly, no widely effective therapy, and many of these therapeutic
This supplement is made possible through the generous support of Stiefel Laboratories for the American Academy of Dermatology. From the Departments of Dermatology,a and Hematology/Oncology,b Feinberg School of Medicine, Northwestern University, and the Northwestern Memorial Physicians Group, Northwestern Memorial Hospital.c Funding sources: None. Conflicts of interest: None identified. Reprints not available from authors. Correspondence to: Joan Guitart, MD, 675 N St. Clair St, Suite 19150, Chicago, IL 60611. E-mail: [email protected]. 0190-9622/$30.00 ª 2004 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2004.03.023
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agents are associated with significant morbidity, and mortality.
CASE REPORT In July 2002, a 63-year-old white man presented with a 2-month history of progressive peri-ocular swelling and redness. This was followed by an eruption on all extremities which rapidly progressed to involve his abdomen, chest, back, and buttocks. The patient complained of difficulty walking due to generalized skin stiffness, as well as intermittent fatigue. He denied pruritus or tenderness of the lesions. His review of systems was negative for dysphagia, hoarseness, dyspnea, proximal muscle weakness, memory loss, and seizures. Physical examination revealed widespread and symmetric waxy, firm, flesh-colored to erythematous 2-4 mm papules on bilateral forearms and legs, chest, abdomen, and back. Deep longitudinal furrows and intense erythema of the glabella produced a leonine appearance (Fig 1, A). The papules coalesced on the anterior thighs and forearms into indurated plaques. The skin around the knees (Fig 1, B) and lateral buttocks was sclerotic and thickened. Laboratory evaluation including complete blood count, comprehensive metabolic panel, hepatitis panel, HIV, antinuclear antibody panel, and thyroid function tests were within normal limits. Serum protein electrophoresis revealed a restricted band in the gamma region. Immunofixation confirmed this monoclonal IgG lambda chain measuring 0.5 g/dL (Reference 0.0). Skin biopsies of two waxy papules showed the proliferation of stellate and spindleshaped fibroblasts in the papillary and upper reticular dermis (Fig 1, C). Colloidal iron stain revealed a significant amount of acid mucopolysaccharide in these areas (Fig 1, D).
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Fig 1. A, Face, pretreatment with dexamethasone, July 2002. B, Leg, pretreatment with dexamethasone, July 2002. C, Hematoxylin-eosin stain of biopsy specimen showing the proliferation of stellate and spindle-shaped fibroblasts in the papillary and upper reticular dermis, consistent with scleromyxedema. D, Colloidal iron stain revealed a significant amount of acid mucopolysaccharide.
The patient received 3 consecutive weekly cycles each month of oral high-dose dexamethasone 40 mg once daily for four days (total: 160 mg/wk) between September 2002 and December 2002. He had an excellent clinical response with resolution of cutaneous manifestations of disease (Fig 2). All clinical symptomatology including difficulty walking and fatigue completely resolved. Furthermore, there was a decline in paraprotein level from 0.5 to 0.1 g/dL at the end of the 4-month regimen. Adverse effects were not noted. The patient is currently on oral dexamethasone maintenance therapy of 40 mg once daily for
4 days every month. No paraprotein was detected upon repeat electrophoresis in April 2003 and again in October 2003, over one year since presentation. Routine surveillance in January 2004 revealed a trace (unmeasurable quantity) monoclonal IgG lambda chain on immunofixation electrophoresis. There has been no recurrence of cutaneous or systemic manifestations, and the patient has remained free of clinical disease despite this serologic abnormality. He has undergone collection of stem cells for an autologous stem cell transplant with high-dose chemotherapy if the disease recurs in the future.
S122 Horn et al
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Fig 2. A, Face, post-treatment with dexamethasone, September 2003. B, Leg, post-treatment with dexamethasone, September 2003.
DISCUSSION Scleromyxedema was originally described by Dubreuilh9 in 1906 and Reitmann10 in 1908. The generalized papular and sclerodermoid variant of lichen myxedematosus was coined scleromyxedema by Gottron in 1954. Rongioletti and Rebora11 recently divided lichen myxedematosus into two clinical subsets: generalized (scleromyxedema) and localized (papular mucinosis). In contrast to the latter, scleromyxedema presents with greater cutaneous involvement, is associated with systemic involvement, and can be fatal. For this reason, aggressive treatments associated with high morbidity are often necessary. Monoclonal gammopathy is associated with scleromyxedema 83% of the time.12 Progression to multiple myeloma is rare, and the paraprotein is typically considered a monoclonal gammopathy of unknown significance (MGUS). Systemic involvement in scleromyxedema can present as dysphagia, difficulty chewing, hoarseness, dyspnea, risk of aspiration with resultant pneumonia, ectropion, lagophthalmos, proximal muscle weakness, arthralgias, migratory arthritis, carpel tunnel syndrome, memory loss, vertigo, gait problems, hallucinations, seizures, and coma.13 The pathogenesis of scleromyxedema is unknown. Serum from affected patients has been
shown to increase fibroblast proliferation in vitro and to stimulate the production of hyaluronic acid and prostaglandin E by fibroblasts.14,15 Additionally, fibroblasts from patients with scleromyxedema synthesize greater quantities of hyaluronic acid than fibroblasts from normal, unaffected human skin.15 Fibroblasts in these patients may constitutively produce more mucin than do normal fibroblasts. That the M protein may play a role in these aberrant fibroblasts has been proposed; however, in vitro experiments have argued against this causal relationship and against an etiologic role for the paraprotein. In support of this, Harper and Rispler16 demonstrated fibroblast proliferation after removal of the paraprotein. Furthermore, Bata-Csorgo et al17 showed that the IgG fraction of the serum itself had no influence on fibroblast proliferation in vitro. Other possible etiologic factors, which could include a circulating factor in the serum or an inherent defect in the fibroblasts themselves, have not been identified. Treatment of scleromyxedema remains a challenge to clinicians. There is no standard of care and significant toxicities including death have been associated with some of the therapeutic regimens. Rayson et al18 reported a complete response to prednisone therapy with continued clinical remission 24 months after discontinuation. We were able to replicate these results with the use of oral pulse-dose
J AM ACAD DERMATOL VOLUME 51, NUMBER 2
dexamethasone. Dexamethasone is an oral, longacting corticosteroid with nearly 8 times more glucocorticoid potency than prednisone. Pulsed dose therapy is utilized to rapidly suppress inflammatory conditions, hypothetically avoiding the risks associated with long-term steroid use. It is likely that dexamethasone therapy targets both the paraprotein production and the hyperactive fibroblasts through its immunosuppressive19 and anti-fibroblast effects.20 This regimen is commonly used as a protein synthesis suppression agent in the treatment of multiple myeloma. Hence, it made logical sense to utilize it in the treatment of this paraprotein-associated disorder. If our findings are confirmed in future studies, corticosteroid therapy might be considered as a first-line option for scleromyxedema. Alkylating agents, which may have significant toxicities, should be reserved for corticosteroid-refractory disease. As it is difficult to ignore the relationship between the resolution of our patient’s clinical disease and the decline of his monoclonal protein, we feel it is important to continue to investigate the underlying pathophysiology of scleromyxedema in the hopes of finding a consistent, durable, and well-tolerated treatment for this devastating disease.
REFERENCES 1. Chanda JJ. Melphalan therapy in the treatment of scleromyxedema. Arch Dermatol 1980;116:862-3. 2. Harris AO, Altman AR, Tschen JA, Wolf JE. Scleromyxedema. Int J Dermatol 1989;28:661-7. 3. Godby A, Bergstresser PR, Chaker B, Pandya AG. Fatal scleromyxedema: report of a case and review of the literature. J Am Acad Dermatol 1998;38:289-94. 4. MacFarlane AW, Davenport A, Verbov JL, Goldsmith HJ. Scleromyxedema: successful treatment with plasma exchange and immunosuppression. Br J Dermatol 1987;117:653-7.
Horn et al S123
5. Berkson M, Lazarus GS, Uberti-Benz M, Rook AH. Extracorporeal photochemotherapy: a potentially useful treatment for scleromyxedema. J Am Acad Dermatol 1991;25:724. 6. Lister RK, Jolles S, Whittaker S, Black C, Forgacs I, Cramp M, et al. Scleromyxedema: response to high-dose intravenous immunoglobulin (hdIVIg). J Am Acad Dermatol 2000;43:403-8. 7. Tschen JA, Chang JR. Scleromyxedema: Treatment with interferon alfa. J Am Acad Dermatol 1999;40:303-7. 8. Feasel AM, Donato MS, Duvic M. Complete remission of scleromyxedema following autologous stem cell transplantation. Arch Dermatol 2001;137:1071-2. 9. Dubreiuilh W. Fibromes miliaires folliculaires: sclerodermie consecutive. Ann Dermatol Syph 1906;37:569-72. 10. Reitmann K. Uber eine Eigenartige, der Sklerodermie Nahestehende Affektion. Arch Dermatol Syph 1908;92:417-24. 11. Rongioletti F, Rebora A. Updated classification of papular mucinosis, lichen myxedematosus, and scleromyxedema. J Am Acad Dermatol 2001;44:273-81. 12. Degos R, Civatte J, Clauvel JP, Danon F. Anomalies globuliniques dans les mucinoses cutane´es. Bull Soci Fr Dermatol Syphiligr 1970;77:579. 13. Jackson EM, English JC. Diffuse cutaneous mucinoses. Dermatol Clin 2002;20:493-501. 14. Yaron M, Yaron I, Brenner S. Lichen myxedematosus (Scleromyxedema) serum stimulates hyaluronic acid and prostaglandin production by human fibroblasts. Rheumatalogy 1985;12: 171-5. 15. Ferrarini M, Helfrich DJ, Walker ER, Medsger TA Jr, Whiteside TL. Scleromyxedema serum increases proliferation but not the glycosaminoglycan synthesis of dermal fibroblasts. J Rheumatal 1989;16:837-41. 16. Harper RA, Rispler J. Lichen myxedematosus serum stimulates human skin fibroblast proliferation. Science 1978;199:545-7. 17. Bata-Csorgo Z, Husz S, Foldes M, Korom I, Molnar K, Morvay M, et al. Scleromyxedema. J Am Acad Dermatol 1999;41:343-6. 18. Rayson D, Lust JA, Duncan A, Su WP. Scleromyxedema: a complete response to prednisone. Mayo Clin Proc 1999;74: 481-4. 19. Barnes PJ. Anti-inflammatory actions of glucocorticoids: molecular mechanisms. Clin Sci 1998;94:557-72. 20. Silvestri M, Sabatini F, Scarso L, Cordone A, Dasic G, Rossi GA. Fluticasone propionate downregulates nasal fibroblast functions involved in airway inflammation and remodeling. Int Arch Allergy Immunol 2002;128:51-8.
W
e describe a patient with scleromyxedema limited to the skin treated successfully with high-dose dexamethasone. The patient had an excellent response with complete resolution of the cutaneous symptoms and disappearance of the associated IgG paraprotein for over 1 year. Although a trace (unmeasurable quantity) monoclonal IgG lambda chain (Reference 0.0) was detected on his most recent immunofixation electrophoresis, he remains in complete clinical remission and is receiving maintenance therapy. Treatment of scleromyxedema is difficult and based largely on anecdotal experience. Reported therapies include melphalan,1 psoralen plus ultraviolet A (PUVA), electron beam,2 systemic steroids, adrenocorticotropic hormone (ACTH), oral retinoids, chlorambucil, 2-chlorodeoxyadenosine, and daily and/or pulse cyclophosphamide.3 Plasmapheresis with concomitant immunosuppression,4 extracorporeal photochemotherapy,5 high-dose intravenous immunoglobulin,6 interferon alfa,7 and autologous stem cell transplantation8 have also been investigated as hopeful therapeutic approaches. Disappointingly, no widely effective therapy, and many of these therapeutic
This supplement is made possible through the generous support of Stiefel Laboratories for the American Academy of Dermatology. From the Departments of Dermatology,a and Hematology/Oncology,b Feinberg School of Medicine, Northwestern University, and the Northwestern Memorial Physicians Group, Northwestern Memorial Hospital.c Funding sources: None. Conflicts of interest: None identified. Reprints not available from authors. Correspondence to: Joan Guitart, MD, 675 N St. Clair St, Suite 19150, Chicago, IL 60611. E-mail: [email protected]. 0190-9622/$30.00 ª 2004 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2004.03.023
S120
agents are associated with significant morbidity, and mortality.
CASE REPORT In July 2002, a 63-year-old white man presented with a 2-month history of progressive peri-ocular swelling and redness. This was followed by an eruption on all extremities which rapidly progressed to involve his abdomen, chest, back, and buttocks. The patient complained of difficulty walking due to generalized skin stiffness, as well as intermittent fatigue. He denied pruritus or tenderness of the lesions. His review of systems was negative for dysphagia, hoarseness, dyspnea, proximal muscle weakness, memory loss, and seizures. Physical examination revealed widespread and symmetric waxy, firm, flesh-colored to erythematous 2-4 mm papules on bilateral forearms and legs, chest, abdomen, and back. Deep longitudinal furrows and intense erythema of the glabella produced a leonine appearance (Fig 1, A). The papules coalesced on the anterior thighs and forearms into indurated plaques. The skin around the knees (Fig 1, B) and lateral buttocks was sclerotic and thickened. Laboratory evaluation including complete blood count, comprehensive metabolic panel, hepatitis panel, HIV, antinuclear antibody panel, and thyroid function tests were within normal limits. Serum protein electrophoresis revealed a restricted band in the gamma region. Immunofixation confirmed this monoclonal IgG lambda chain measuring 0.5 g/dL (Reference 0.0). Skin biopsies of two waxy papules showed the proliferation of stellate and spindleshaped fibroblasts in the papillary and upper reticular dermis (Fig 1, C). Colloidal iron stain revealed a significant amount of acid mucopolysaccharide in these areas (Fig 1, D).
J AM ACAD DERMATOL VOLUME 51, NUMBER 2
Horn et al S121
Fig 1. A, Face, pretreatment with dexamethasone, July 2002. B, Leg, pretreatment with dexamethasone, July 2002. C, Hematoxylin-eosin stain of biopsy specimen showing the proliferation of stellate and spindle-shaped fibroblasts in the papillary and upper reticular dermis, consistent with scleromyxedema. D, Colloidal iron stain revealed a significant amount of acid mucopolysaccharide.
The patient received 3 consecutive weekly cycles each month of oral high-dose dexamethasone 40 mg once daily for four days (total: 160 mg/wk) between September 2002 and December 2002. He had an excellent clinical response with resolution of cutaneous manifestations of disease (Fig 2). All clinical symptomatology including difficulty walking and fatigue completely resolved. Furthermore, there was a decline in paraprotein level from 0.5 to 0.1 g/dL at the end of the 4-month regimen. Adverse effects were not noted. The patient is currently on oral dexamethasone maintenance therapy of 40 mg once daily for
4 days every month. No paraprotein was detected upon repeat electrophoresis in April 2003 and again in October 2003, over one year since presentation. Routine surveillance in January 2004 revealed a trace (unmeasurable quantity) monoclonal IgG lambda chain on immunofixation electrophoresis. There has been no recurrence of cutaneous or systemic manifestations, and the patient has remained free of clinical disease despite this serologic abnormality. He has undergone collection of stem cells for an autologous stem cell transplant with high-dose chemotherapy if the disease recurs in the future.
S122 Horn et al
J AM ACAD DERMATOL AUGUST 2004
Fig 2. A, Face, post-treatment with dexamethasone, September 2003. B, Leg, post-treatment with dexamethasone, September 2003.
DISCUSSION Scleromyxedema was originally described by Dubreuilh9 in 1906 and Reitmann10 in 1908. The generalized papular and sclerodermoid variant of lichen myxedematosus was coined scleromyxedema by Gottron in 1954. Rongioletti and Rebora11 recently divided lichen myxedematosus into two clinical subsets: generalized (scleromyxedema) and localized (papular mucinosis). In contrast to the latter, scleromyxedema presents with greater cutaneous involvement, is associated with systemic involvement, and can be fatal. For this reason, aggressive treatments associated with high morbidity are often necessary. Monoclonal gammopathy is associated with scleromyxedema 83% of the time.12 Progression to multiple myeloma is rare, and the paraprotein is typically considered a monoclonal gammopathy of unknown significance (MGUS). Systemic involvement in scleromyxedema can present as dysphagia, difficulty chewing, hoarseness, dyspnea, risk of aspiration with resultant pneumonia, ectropion, lagophthalmos, proximal muscle weakness, arthralgias, migratory arthritis, carpel tunnel syndrome, memory loss, vertigo, gait problems, hallucinations, seizures, and coma.13 The pathogenesis of scleromyxedema is unknown. Serum from affected patients has been
shown to increase fibroblast proliferation in vitro and to stimulate the production of hyaluronic acid and prostaglandin E by fibroblasts.14,15 Additionally, fibroblasts from patients with scleromyxedema synthesize greater quantities of hyaluronic acid than fibroblasts from normal, unaffected human skin.15 Fibroblasts in these patients may constitutively produce more mucin than do normal fibroblasts. That the M protein may play a role in these aberrant fibroblasts has been proposed; however, in vitro experiments have argued against this causal relationship and against an etiologic role for the paraprotein. In support of this, Harper and Rispler16 demonstrated fibroblast proliferation after removal of the paraprotein. Furthermore, Bata-Csorgo et al17 showed that the IgG fraction of the serum itself had no influence on fibroblast proliferation in vitro. Other possible etiologic factors, which could include a circulating factor in the serum or an inherent defect in the fibroblasts themselves, have not been identified. Treatment of scleromyxedema remains a challenge to clinicians. There is no standard of care and significant toxicities including death have been associated with some of the therapeutic regimens. Rayson et al18 reported a complete response to prednisone therapy with continued clinical remission 24 months after discontinuation. We were able to replicate these results with the use of oral pulse-dose
J AM ACAD DERMATOL VOLUME 51, NUMBER 2
dexamethasone. Dexamethasone is an oral, longacting corticosteroid with nearly 8 times more glucocorticoid potency than prednisone. Pulsed dose therapy is utilized to rapidly suppress inflammatory conditions, hypothetically avoiding the risks associated with long-term steroid use. It is likely that dexamethasone therapy targets both the paraprotein production and the hyperactive fibroblasts through its immunosuppressive19 and anti-fibroblast effects.20 This regimen is commonly used as a protein synthesis suppression agent in the treatment of multiple myeloma. Hence, it made logical sense to utilize it in the treatment of this paraprotein-associated disorder. If our findings are confirmed in future studies, corticosteroid therapy might be considered as a first-line option for scleromyxedema. Alkylating agents, which may have significant toxicities, should be reserved for corticosteroid-refractory disease. As it is difficult to ignore the relationship between the resolution of our patient’s clinical disease and the decline of his monoclonal protein, we feel it is important to continue to investigate the underlying pathophysiology of scleromyxedema in the hopes of finding a consistent, durable, and well-tolerated treatment for this devastating disease.
REFERENCES 1. Chanda JJ. Melphalan therapy in the treatment of scleromyxedema. Arch Dermatol 1980;116:862-3. 2. Harris AO, Altman AR, Tschen JA, Wolf JE. Scleromyxedema. Int J Dermatol 1989;28:661-7. 3. Godby A, Bergstresser PR, Chaker B, Pandya AG. Fatal scleromyxedema: report of a case and review of the literature. J Am Acad Dermatol 1998;38:289-94. 4. MacFarlane AW, Davenport A, Verbov JL, Goldsmith HJ. Scleromyxedema: successful treatment with plasma exchange and immunosuppression. Br J Dermatol 1987;117:653-7.
Horn et al S123
5. Berkson M, Lazarus GS, Uberti-Benz M, Rook AH. Extracorporeal photochemotherapy: a potentially useful treatment for scleromyxedema. J Am Acad Dermatol 1991;25:724. 6. Lister RK, Jolles S, Whittaker S, Black C, Forgacs I, Cramp M, et al. Scleromyxedema: response to high-dose intravenous immunoglobulin (hdIVIg). J Am Acad Dermatol 2000;43:403-8. 7. Tschen JA, Chang JR. Scleromyxedema: Treatment with interferon alfa. J Am Acad Dermatol 1999;40:303-7. 8. Feasel AM, Donato MS, Duvic M. Complete remission of scleromyxedema following autologous stem cell transplantation. Arch Dermatol 2001;137:1071-2. 9. Dubreiuilh W. Fibromes miliaires folliculaires: sclerodermie consecutive. Ann Dermatol Syph 1906;37:569-72. 10. Reitmann K. Uber eine Eigenartige, der Sklerodermie Nahestehende Affektion. Arch Dermatol Syph 1908;92:417-24. 11. Rongioletti F, Rebora A. Updated classification of papular mucinosis, lichen myxedematosus, and scleromyxedema. J Am Acad Dermatol 2001;44:273-81. 12. Degos R, Civatte J, Clauvel JP, Danon F. Anomalies globuliniques dans les mucinoses cutane´es. Bull Soci Fr Dermatol Syphiligr 1970;77:579. 13. Jackson EM, English JC. Diffuse cutaneous mucinoses. Dermatol Clin 2002;20:493-501. 14. Yaron M, Yaron I, Brenner S. Lichen myxedematosus (Scleromyxedema) serum stimulates hyaluronic acid and prostaglandin production by human fibroblasts. Rheumatalogy 1985;12: 171-5. 15. Ferrarini M, Helfrich DJ, Walker ER, Medsger TA Jr, Whiteside TL. Scleromyxedema serum increases proliferation but not the glycosaminoglycan synthesis of dermal fibroblasts. J Rheumatal 1989;16:837-41. 16. Harper RA, Rispler J. Lichen myxedematosus serum stimulates human skin fibroblast proliferation. Science 1978;199:545-7. 17. Bata-Csorgo Z, Husz S, Foldes M, Korom I, Molnar K, Morvay M, et al. Scleromyxedema. J Am Acad Dermatol 1999;41:343-6. 18. Rayson D, Lust JA, Duncan A, Su WP. Scleromyxedema: a complete response to prednisone. Mayo Clin Proc 1999;74: 481-4. 19. Barnes PJ. Anti-inflammatory actions of glucocorticoids: molecular mechanisms. Clin Sci 1998;94:557-72. 20. Silvestri M, Sabatini F, Scarso L, Cordone A, Dasic G, Rossi GA. Fluticasone propionate downregulates nasal fibroblast functions involved in airway inflammation and remodeling. Int Arch Allergy Immunol 2002;128:51-8.