International Journal of Rheumatic Diseases 2015; 18: 366–371
APLAR GRAND ROUND CASE
Successful autologous hematopoietic stem cell transplantation for a patient with rapidly progressive localized scleroderma Velu NAIR,1 Ajay SHARMA,2 Sanjeevan SHARMA,2 Satyaranjan DAS,2 Darshan S. BHAKUNI,2 Krishnan NARAYANAN,2 Vivek NAIR3 and Subramanian SHANKAR1 1 Armed Forces Medical College, Pune, 2Army Hospital (Research & Referral), New Delhi, and 3Dr Nair’s Skin Clinic, New Delhi, India
Abstract Autologous hematopoietic stem cell transplant (HSCT) for rapidly progressive disease has not been reported in localized scleroderma. Our patient, a 16-year-old girl had an aggressive variant of localized scleroderma, mixed subtype (linear-generalized) with Parry Romberg syndrome, with no internal organ involvement, that was unresponsive to immunosuppressive therapy and was causing rapid disfigurement. She was administered autologous HSCT in June 2011 and has maintained drug-free remission with excellent functional status at almost 3.5 years of follow-up. Key words: autologous, localised scleroderma, stem cell transplantation.
INTRODUCTION Localized scleroderma, also known as morphoea, comprises a group of distinct conditions that involve the skin and subcutaneous tissues. They range from very small plaques limited only to the skin, to extensive involvement that may cause significant functional and cosmetic deformity, with a variety of extracutaneous features.1 Numerous therapeutic agents have been used for morphea, but there is a paucity of controlled studies.2 An evaluation of the effects of treatment is difficult due to the variable course and tendency of morphea to resolve spontaneously, as well as the lack of standard criteria of disease activity. Almost 50% of cases undergo spontaneous remission or skin softening within 3 years after onset.3 In a few cases the illness may progress relentlessly despite optimal immunosuppression with development
Correspondence: Professor (Internal Medicine) and Consultant Rheumatologist, Subramanian Shankar, Armed Forces Medical College, Pune 411040, India. Email: [email protected]
of new skin lesions, greater subcutaneous tissue and muscle atrophy causing severe dysmorphism and disfigurement. In such patients the course of action is less clearly defined.4 We report one such patient with rapidly progressive localized scleroderma, mixed subtype (linear-generalized) with Parry Romberg syndrome in whom autologous stem cell transplant was successfully performed. We believe this might be the first such case, to the best of our knowledge (PubMed search).
CASE REPORT A 16-year-old girl first became symptomatic in August 2008 with multiple plaque lesions involving the trunk (at 11 years of age). This was followed by linear skin lesions involving the right half of the body that started in the legs and had a caudocephalic spread. The patient noticed thinning of the involved limb. By 2010 it rapidly progressed to also involve the right half of the face, causing facial asymmetry (Fig. 1). There was no history of Raynaud’s phenomenon or any evidence of internal
© 2015 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
Autologous HSCT for progressive localised scleroderma
Figure 1 Right-sided facial involvement with hemiatrophy started in 2010 and rapidly caused asymmetry and disfigurement within 1 year of onset.
organ involvement. Investigations including hemogram, acute phase reactants, liver and renal function tests were normal. She tested negative for antinuclear antibodies (ANA) by indirect immunoflourescence and enzyme-linked immunosorbent assay (ELISA) and her autoantibody profile was normal. A clinical diagnosis of localized scleroderma mixed subtype (linear-generalized) with Parry Romberg syndrome was made (Figs 2a,b and 3a).5 A skin biopsy showed increased
collagenization with lymphocyte infiltration consistent with the diagnosis (Fig. 4a,b). The patient was initially seen at another center where local steroid creams were prescribed. This was followed by administration of methotrexate (15 mg/week) with low-dose oral steroids which was ineffective in halting the progress of illness over 6 months of follow-up. Cyclophosphamide pulses were initiated (15 mg/kg every 4 weeks) with increased oral steroids (1 mg/kg) in May 2010 which halted the progress of skin lesions within 1 month of starting the same. A total of six pulses were given with steroids in tapering doses which maintained clinical remission. Cyclophosphamide was, thereafter, stopped and steroids reduced to 10 mg/day. Methotrexate was reintroduced at a dose of 15 mg/ week. The illness relapsed within a month of stopping cyclophosphamide with progression of lesions despite further hike in dose of methotrexate (up to 20 mg/ week) at which point she reported to our center. There was a concern of restarting high-dose steroids and cyclophosphamide again in a young girl when her disease was proving unresponsive to methotrexate. The lesions were progressing rapidly, leading to disfigurement of the face and limbs. Hence it was necessary to
(a)
(b)
(c)
(d)
Figure 2 (a,b) Right-sided linear scleroderma affecting limbs with active plaques. (c,d) The patient now just has limb thinning and fibrosis.
International Journal of Rheumatic Diseases 2015; 18: 366–371
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(a)
(b)
Figure 3 (a) Multiple plaque lesions over trunk and lower back. The lesions show erythema at margins. (b) The same lesions after autologous hematopoietic stem cell transplantation show no activity.
halt the disease progression by inducing disease remission by alternate means. A retrospective analysis of 10 patients with mycophenolate mofetil (MMF) had recently been published in methotrexate-resistant patients which had shown efficacy, hence it was considered as a therapeutic option.6 However, considering the aggressive nature of the illness that was rapidly causing disfigurement, with methotrexate-resistant status and evidence in favor of MMF being confined to just one observational study, autologous hematopoietic stem cell transplant (HSCT) was also considered as a viable
368
alternative.7 We believed that autologous HSCT held the possibility of totally halting disease progression. Detailed discussions were held with the parents and the patient, focusing on: (i) the progressive nature of disease causing disfigurement; (ii) available therapeutic options in form of conventional immunosuppresives (MMF) with their questionable efficacy and attendant adverse effects; (iii) paucity of literature on the best approach in this subgroup of patients; (iv) autologous stem cell transplant as a treatment option with the possibility of inducing remission; and (v) the expertise of our transplant center with over 250 HSCTs having been performed for various disorders, including five in patients with diffuse systemic sclerosis (SSc) (unpublished data). After multiple sessions of counseling and discussions, the parents opted for this experimental mode and due consent was provided. Ethical approval was taken from the hospital ethics committee. Ovarian cryopreservation was done as per protocol.8 Autologous HSCT was performed on 23 June 2011 using non-myeloablative conditioning with injection fludarabine (25 mg/m2 9 6 days, D-10 to D-5), injection cyclophosphamide (60 mg/kg 9 2 days, D-6 to D-5) and equine anti-thymocyte globulin (injection ATGAM Pharmacia Upjohn, 15 mg/kg/day 9 3 days, D-4 to D-2).6 Injection GCSF (Granulocyte colony stimulating factor) 300 lg subcutaneously daily was initiated on D + 1 along with injection acyclovir 5 mg/kg intravenously 8-hourly from D + 1 until engraftment. Cotrimoxazole was given for PCP (Pneumocystis Carinii Pneumonia) prophylaxis. She received irradiated single donor platelets (6 units) and packed red blood cells (2 units) as supportive care. Besides febrile neutropenia which responded to broad-spectrum intravenous antibiotics, she had no peri- or post-transplantation complications. The patient’s menstrual periods resumed within a month of HSCT. At 41 months of follow-up the patient was stable with no progress of lesions (Figs 2c,d, 3b) and all immunosuppressive therapy (IST) was withdrawn post-HSCT. There has been no progress in her skin lesions and facial asymmetry and a repeat skin biopsy shows quiescent lesions (Fig. 4c). She is pursuing her schooling normally with no functional impairment.
DISCUSSION Scleroderma is a multisystem disorder characterized by an abnormal immune activation resulting in
International Journal of Rheumatic Diseases 2015; 18: 366–371
Autologous HSCT for progressive localised scleroderma
(a)
(b)
(c)
Figure 4 (a) Hematoxylin and eosin (H&E) stain. Pre-transplant biopsy showing active inflammation and increase in collagen bundles within the underlying papillary dermis. (b) Masson’s Trichrome stain confirming the presence of collagen in the dermis. (c) Post-transplant skin biopsy post-therapy showing dense collagenization in dermis. There is no inflammation or active lesion (H&E 1009).
fibrotic and vascular disease manifestations. Localized scleroderma or morphea is a rare disorder with a annual incidence of 2.7 per 100 000 adult population (female : male, 2.6:1.0).3 An important common feature of morphea is the presence of skin thickening with increased quantities of collagen in the indurative lesion. Linear scleroderma accounts for almost 65% of all morpheas, and is characterized by one or more linear streaks and induration involving the dermis, subcutaneous tissue, muscle and underlying bone.1 It often occurs on the extremities and face or scalp (or all three areas) of children and adolescents and is unilateral in 95% of cases. When associated with hemifacial atrophy, it is termed as Parry Romberg syndrome.1 The disease process can affect not only the cutaneous and soft tissue structures of the limb but also the growth of bony structures. Complications include deformities,
International Journal of Rheumatic Diseases 2015; 18: 366–371
joint contractures and severe limb atrophy which is essentially irreversible. When linear morphea traverses a joint, contractures may develop, which can be severe. Amputation because of a severe flexural deformity has been reported.9 Mixed varieties of morphea account for almost 15% of all cases, as in our patient.5 Of all forms of localized SSc, linear scleroderma usually shows relentless progression and merits aggressive treatment.10 Numerous therapeutic agents have been used for morphea, but controlled studies are sparse. An evaluation of the effects of treatment is difficult due to the variable course and tendency of morphea to resolve spontaneously, as well as the lack of standard criteria of disease activity.5 A significant majority of patients remit in 5 years and the disease seldom recurs. In the linear and deep entities, aggressive treatment may be necessary. Methotrexate is the
369
V. Nair et al.
current treatment of choice in view of maximum experience with open label trials, proven efficacy and better safety profile.2,5 Other drugs like antimalarials and cyclosporin have been used with steroids with suboptimal response.5,7 Exercises, massages, topical therapy and surgical therapy (like tendon lengthening procedures and release of joint contractures) too have a supportive role. Therapy is even less well defined in methotrexate-resistant cases. A retrospective analysis of 10 cases showed MMF to be of some promise (level III evidence).6 Autologous HSCT has been employed as a possible therapeutic strategy for diffuse systemic sclerosis. European Group for Blood and Marrow Transplantation and the European League Against Rheumatism (EBMT/EULAR) Working Party on Autoimmune Diseases database demonstrated that among the 57 SSc patients treated with high-dose cyclophosphamide followed by autologous HSCT a remarkable and rapid improvement of the skin involvement was noted.11 The mortality associated with autologous HSCT in patients with diffuse SSc is in the range of about 10%.12 However, of the 79 pateints who underwent HSCT, 68 had lung involvement while the others had heart or kidney involvement. The profile was quite different from the index case where there was isolated skin involvement. HSCT for rapidly progressive disease involving skin alone has not been reported in localised scleroderma. Our patient had localized scleroderma, mixed subtype (linear-generalized) with Parry Romberg syndrome, with no internal organ involvement, that was unresponsive to IST. She underwent autologous HSCT and has maintained drug-free remission with excellent functional status with no post-transplant complications at 3.5 years of follow-up.
Questions 1 About localized scleroderma, it can be said that a b c d
there is absence of internal organ involvement outcome depends upon type and extent of lesion it is seldom associated with significant morbidity circumscribed (plaque) morphea is the commonest variety in childhood e is less common than systemic sclerosis 2 Extracutaneous manifestations of localized scleroderma a can be seen in almost 10% of all cases b arthritis is the commonest manifestation
370
c arthritis is commonly associated with pansclerotic morphea d has almost 70% association with anti-centromere and anti-topoisomerase autoantibodies e Raynaud’s phenomenon is never encountered and is a distinguishing feature between localized scleroderma and systemic sclerosis. 3 About treatment for localized scleroderma a plaque morphea often requires systemic steroids and methotrexate b drug of choice for linear scleroderma is mycophenolate mofetil c recovery is best with linear scleroderma d vitamin D should be routinely added for all patients e intralesional interferon can be given in methotrexate-refractory cases. 4 All except one are considered criteria for offering patients with scleroderma for autologous HSCT a having progressive disease b unresponsive to conventional treatments c autologous HSCT should be undertaken before irreversible organ damage d patients with irreversible organ damage
Answers 1 B. Localized scleroderma, although uncommon, is almost 10 times more common than systemic sclerosis. The linear form is the commonest variety in childhood and can be associated with significant morbidity. The outcome does depend upon the type and extent of lesions. Increasingly, it is becoming evident that localized scleroderma is associated with a variety of extracutaneous manifestations. 2 B. Extracutaneous manifestations are seen in 25% of all cases. The commonest manifestation is arthritis accounting for half of all extracutaneous manifestations. It is most commonly associated with linear scleroderma. No association has been described with anti-centromere and anti-topoisomerase autoantibodies which are seen in less than 2% of cases. Raynaud’s phenomenon can be seen in 3% of patients. 3 C. Plaque morphea seldom requires any therapy except topical steroids and has a good prognosis. Linear scleroderma is often the most difficult to treat
International Journal of Rheumatic Diseases 2015; 18: 366–371
Autologous HSCT for progressive localised scleroderma
and the drug of choice is methotrexate (15 mg/m2/ week) with oral prednisolone for the first 3 months. This is associated with a high response rate with new lesions occurring in just 6.5% and relapse in another 12.5%. Among refractory cases, mycophenolate mofetil has been used with success. Recovery is best seen with plaque morphea and generalized scleroderma. Linear scleroderma invariably leaves behind muscle atrophy, scarring and growth defects. The only study in vitamin D showed that it was no better than placebo. There is no role of intralesional interferon. 4 D. Autologous HSCT has been performed in over 2000 patients worldwide for various autoimmune disorders including scleroderma. With passing years and improved expertise the transplant-related mortality has decreased and is in the range of 7 3% at 3 years of transplant. The mechanism of action is not fully understood but studies have shown that initial immune suppression with subsequent increased regulatory T-cell activity helps in disease control. The best results have been achieved in patients with progressive disease where irreversible organ damage has not yet occurred.
CONFLICTS OF INTEREST None.
REFERENCES 1 Laxer RM, Zulian F (2006) Localized scleroderma. Curr Opin Rheumatol 18, 606–13.
International Journal of Rheumatic Diseases 2015; 18: 366–371
2 Zwischenberger BA, Jacobe HT (2011) A systematic review of morphea treatments and therapeutic algorithm. J Am Acad Dermatol 65, 925–41. 3 Peterson LS, Nelson AM, Su WPD, Mason TG, O’Fallon WM, Gabriel SE (1995) The epidemiology of morphea (localized scleroderma) in Olmsted County 1960–1993 [abstract]. Arthritis Rheum 38(Suppl), S333. 4 Torok KS (2012) Pediatric scleroderma: systemic or localized forms. Pediatr Clin North Am 59, 381–405. 5 Zulian F, Athreya BH, Laxer R et al. (2006) Juvenile localized scleroderma: clinical and epidemiological features in 750 children. An international study. Rheumatology 45, 614–20. 6 Martini G, Ramanan AV, Falcini F, Girschick H, Goldsmith DP, Zulian F (2009) Successful treatment of severe or methotrexate-resistant juvenile localized scleroderma with mycophenolate mofetil. Rheumatology 48, 1410–3. 7 Nair V (2008) Haematopoietic stem cell transplantation in autoimmune diseases. Indian J Rheumatol 3, 101–9. 8 Song Y, Sharp R, Lu F, Hassan M (2010) The future potential of cryopreservation for assisted reproduction. Cryobiology 60(Suppl 3), S60–5. 9 Kornreich HK, King KK, Bernstein BH, Singsen BH, Hanson V (1977) Scleroderma in childhood. Arthritis Rheum 20, 343–50. 10 Saxon Daniels S, Jacobe HT (2010) An evaluation of longterm outcomes in adults with pediatric onset morphea. Arch Dermatol 146, 1044–5. 11 Farge D, Passweg JM, van Laar J, Marjanovic Z, Besenthal C, Finke J (2004) Autologous stem cell transplantation in the treatment of systemic sclerosis: report from the EBMT/ EULAR Registry. Ann Rheum Dis 63, 974–81. 12 van Laar JM, Farge D, Sont JK et al. (2014) EBMT/EULAR Scleroderma Study Group. Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA 311, 2490–8.
371
APLAR GRAND ROUND CASE
Successful autologous hematopoietic stem cell transplantation for a patient with rapidly progressive localized scleroderma Velu NAIR,1 Ajay SHARMA,2 Sanjeevan SHARMA,2 Satyaranjan DAS,2 Darshan S. BHAKUNI,2 Krishnan NARAYANAN,2 Vivek NAIR3 and Subramanian SHANKAR1 1 Armed Forces Medical College, Pune, 2Army Hospital (Research & Referral), New Delhi, and 3Dr Nair’s Skin Clinic, New Delhi, India
Abstract Autologous hematopoietic stem cell transplant (HSCT) for rapidly progressive disease has not been reported in localized scleroderma. Our patient, a 16-year-old girl had an aggressive variant of localized scleroderma, mixed subtype (linear-generalized) with Parry Romberg syndrome, with no internal organ involvement, that was unresponsive to immunosuppressive therapy and was causing rapid disfigurement. She was administered autologous HSCT in June 2011 and has maintained drug-free remission with excellent functional status at almost 3.5 years of follow-up. Key words: autologous, localised scleroderma, stem cell transplantation.
INTRODUCTION Localized scleroderma, also known as morphoea, comprises a group of distinct conditions that involve the skin and subcutaneous tissues. They range from very small plaques limited only to the skin, to extensive involvement that may cause significant functional and cosmetic deformity, with a variety of extracutaneous features.1 Numerous therapeutic agents have been used for morphea, but there is a paucity of controlled studies.2 An evaluation of the effects of treatment is difficult due to the variable course and tendency of morphea to resolve spontaneously, as well as the lack of standard criteria of disease activity. Almost 50% of cases undergo spontaneous remission or skin softening within 3 years after onset.3 In a few cases the illness may progress relentlessly despite optimal immunosuppression with development
Correspondence: Professor (Internal Medicine) and Consultant Rheumatologist, Subramanian Shankar, Armed Forces Medical College, Pune 411040, India. Email: [email protected]
of new skin lesions, greater subcutaneous tissue and muscle atrophy causing severe dysmorphism and disfigurement. In such patients the course of action is less clearly defined.4 We report one such patient with rapidly progressive localized scleroderma, mixed subtype (linear-generalized) with Parry Romberg syndrome in whom autologous stem cell transplant was successfully performed. We believe this might be the first such case, to the best of our knowledge (PubMed search).
CASE REPORT A 16-year-old girl first became symptomatic in August 2008 with multiple plaque lesions involving the trunk (at 11 years of age). This was followed by linear skin lesions involving the right half of the body that started in the legs and had a caudocephalic spread. The patient noticed thinning of the involved limb. By 2010 it rapidly progressed to also involve the right half of the face, causing facial asymmetry (Fig. 1). There was no history of Raynaud’s phenomenon or any evidence of internal
© 2015 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
Autologous HSCT for progressive localised scleroderma
Figure 1 Right-sided facial involvement with hemiatrophy started in 2010 and rapidly caused asymmetry and disfigurement within 1 year of onset.
organ involvement. Investigations including hemogram, acute phase reactants, liver and renal function tests were normal. She tested negative for antinuclear antibodies (ANA) by indirect immunoflourescence and enzyme-linked immunosorbent assay (ELISA) and her autoantibody profile was normal. A clinical diagnosis of localized scleroderma mixed subtype (linear-generalized) with Parry Romberg syndrome was made (Figs 2a,b and 3a).5 A skin biopsy showed increased
collagenization with lymphocyte infiltration consistent with the diagnosis (Fig. 4a,b). The patient was initially seen at another center where local steroid creams were prescribed. This was followed by administration of methotrexate (15 mg/week) with low-dose oral steroids which was ineffective in halting the progress of illness over 6 months of follow-up. Cyclophosphamide pulses were initiated (15 mg/kg every 4 weeks) with increased oral steroids (1 mg/kg) in May 2010 which halted the progress of skin lesions within 1 month of starting the same. A total of six pulses were given with steroids in tapering doses which maintained clinical remission. Cyclophosphamide was, thereafter, stopped and steroids reduced to 10 mg/day. Methotrexate was reintroduced at a dose of 15 mg/ week. The illness relapsed within a month of stopping cyclophosphamide with progression of lesions despite further hike in dose of methotrexate (up to 20 mg/ week) at which point she reported to our center. There was a concern of restarting high-dose steroids and cyclophosphamide again in a young girl when her disease was proving unresponsive to methotrexate. The lesions were progressing rapidly, leading to disfigurement of the face and limbs. Hence it was necessary to
(a)
(b)
(c)
(d)
Figure 2 (a,b) Right-sided linear scleroderma affecting limbs with active plaques. (c,d) The patient now just has limb thinning and fibrosis.
International Journal of Rheumatic Diseases 2015; 18: 366–371
367
V. Nair et al.
(a)
(b)
Figure 3 (a) Multiple plaque lesions over trunk and lower back. The lesions show erythema at margins. (b) The same lesions after autologous hematopoietic stem cell transplantation show no activity.
halt the disease progression by inducing disease remission by alternate means. A retrospective analysis of 10 patients with mycophenolate mofetil (MMF) had recently been published in methotrexate-resistant patients which had shown efficacy, hence it was considered as a therapeutic option.6 However, considering the aggressive nature of the illness that was rapidly causing disfigurement, with methotrexate-resistant status and evidence in favor of MMF being confined to just one observational study, autologous hematopoietic stem cell transplant (HSCT) was also considered as a viable
368
alternative.7 We believed that autologous HSCT held the possibility of totally halting disease progression. Detailed discussions were held with the parents and the patient, focusing on: (i) the progressive nature of disease causing disfigurement; (ii) available therapeutic options in form of conventional immunosuppresives (MMF) with their questionable efficacy and attendant adverse effects; (iii) paucity of literature on the best approach in this subgroup of patients; (iv) autologous stem cell transplant as a treatment option with the possibility of inducing remission; and (v) the expertise of our transplant center with over 250 HSCTs having been performed for various disorders, including five in patients with diffuse systemic sclerosis (SSc) (unpublished data). After multiple sessions of counseling and discussions, the parents opted for this experimental mode and due consent was provided. Ethical approval was taken from the hospital ethics committee. Ovarian cryopreservation was done as per protocol.8 Autologous HSCT was performed on 23 June 2011 using non-myeloablative conditioning with injection fludarabine (25 mg/m2 9 6 days, D-10 to D-5), injection cyclophosphamide (60 mg/kg 9 2 days, D-6 to D-5) and equine anti-thymocyte globulin (injection ATGAM Pharmacia Upjohn, 15 mg/kg/day 9 3 days, D-4 to D-2).6 Injection GCSF (Granulocyte colony stimulating factor) 300 lg subcutaneously daily was initiated on D + 1 along with injection acyclovir 5 mg/kg intravenously 8-hourly from D + 1 until engraftment. Cotrimoxazole was given for PCP (Pneumocystis Carinii Pneumonia) prophylaxis. She received irradiated single donor platelets (6 units) and packed red blood cells (2 units) as supportive care. Besides febrile neutropenia which responded to broad-spectrum intravenous antibiotics, she had no peri- or post-transplantation complications. The patient’s menstrual periods resumed within a month of HSCT. At 41 months of follow-up the patient was stable with no progress of lesions (Figs 2c,d, 3b) and all immunosuppressive therapy (IST) was withdrawn post-HSCT. There has been no progress in her skin lesions and facial asymmetry and a repeat skin biopsy shows quiescent lesions (Fig. 4c). She is pursuing her schooling normally with no functional impairment.
DISCUSSION Scleroderma is a multisystem disorder characterized by an abnormal immune activation resulting in
International Journal of Rheumatic Diseases 2015; 18: 366–371
Autologous HSCT for progressive localised scleroderma
(a)
(b)
(c)
Figure 4 (a) Hematoxylin and eosin (H&E) stain. Pre-transplant biopsy showing active inflammation and increase in collagen bundles within the underlying papillary dermis. (b) Masson’s Trichrome stain confirming the presence of collagen in the dermis. (c) Post-transplant skin biopsy post-therapy showing dense collagenization in dermis. There is no inflammation or active lesion (H&E 1009).
fibrotic and vascular disease manifestations. Localized scleroderma or morphea is a rare disorder with a annual incidence of 2.7 per 100 000 adult population (female : male, 2.6:1.0).3 An important common feature of morphea is the presence of skin thickening with increased quantities of collagen in the indurative lesion. Linear scleroderma accounts for almost 65% of all morpheas, and is characterized by one or more linear streaks and induration involving the dermis, subcutaneous tissue, muscle and underlying bone.1 It often occurs on the extremities and face or scalp (or all three areas) of children and adolescents and is unilateral in 95% of cases. When associated with hemifacial atrophy, it is termed as Parry Romberg syndrome.1 The disease process can affect not only the cutaneous and soft tissue structures of the limb but also the growth of bony structures. Complications include deformities,
International Journal of Rheumatic Diseases 2015; 18: 366–371
joint contractures and severe limb atrophy which is essentially irreversible. When linear morphea traverses a joint, contractures may develop, which can be severe. Amputation because of a severe flexural deformity has been reported.9 Mixed varieties of morphea account for almost 15% of all cases, as in our patient.5 Of all forms of localized SSc, linear scleroderma usually shows relentless progression and merits aggressive treatment.10 Numerous therapeutic agents have been used for morphea, but controlled studies are sparse. An evaluation of the effects of treatment is difficult due to the variable course and tendency of morphea to resolve spontaneously, as well as the lack of standard criteria of disease activity.5 A significant majority of patients remit in 5 years and the disease seldom recurs. In the linear and deep entities, aggressive treatment may be necessary. Methotrexate is the
369
V. Nair et al.
current treatment of choice in view of maximum experience with open label trials, proven efficacy and better safety profile.2,5 Other drugs like antimalarials and cyclosporin have been used with steroids with suboptimal response.5,7 Exercises, massages, topical therapy and surgical therapy (like tendon lengthening procedures and release of joint contractures) too have a supportive role. Therapy is even less well defined in methotrexate-resistant cases. A retrospective analysis of 10 cases showed MMF to be of some promise (level III evidence).6 Autologous HSCT has been employed as a possible therapeutic strategy for diffuse systemic sclerosis. European Group for Blood and Marrow Transplantation and the European League Against Rheumatism (EBMT/EULAR) Working Party on Autoimmune Diseases database demonstrated that among the 57 SSc patients treated with high-dose cyclophosphamide followed by autologous HSCT a remarkable and rapid improvement of the skin involvement was noted.11 The mortality associated with autologous HSCT in patients with diffuse SSc is in the range of about 10%.12 However, of the 79 pateints who underwent HSCT, 68 had lung involvement while the others had heart or kidney involvement. The profile was quite different from the index case where there was isolated skin involvement. HSCT for rapidly progressive disease involving skin alone has not been reported in localised scleroderma. Our patient had localized scleroderma, mixed subtype (linear-generalized) with Parry Romberg syndrome, with no internal organ involvement, that was unresponsive to IST. She underwent autologous HSCT and has maintained drug-free remission with excellent functional status with no post-transplant complications at 3.5 years of follow-up.
Questions 1 About localized scleroderma, it can be said that a b c d
there is absence of internal organ involvement outcome depends upon type and extent of lesion it is seldom associated with significant morbidity circumscribed (plaque) morphea is the commonest variety in childhood e is less common than systemic sclerosis 2 Extracutaneous manifestations of localized scleroderma a can be seen in almost 10% of all cases b arthritis is the commonest manifestation
370
c arthritis is commonly associated with pansclerotic morphea d has almost 70% association with anti-centromere and anti-topoisomerase autoantibodies e Raynaud’s phenomenon is never encountered and is a distinguishing feature between localized scleroderma and systemic sclerosis. 3 About treatment for localized scleroderma a plaque morphea often requires systemic steroids and methotrexate b drug of choice for linear scleroderma is mycophenolate mofetil c recovery is best with linear scleroderma d vitamin D should be routinely added for all patients e intralesional interferon can be given in methotrexate-refractory cases. 4 All except one are considered criteria for offering patients with scleroderma for autologous HSCT a having progressive disease b unresponsive to conventional treatments c autologous HSCT should be undertaken before irreversible organ damage d patients with irreversible organ damage
Answers 1 B. Localized scleroderma, although uncommon, is almost 10 times more common than systemic sclerosis. The linear form is the commonest variety in childhood and can be associated with significant morbidity. The outcome does depend upon the type and extent of lesions. Increasingly, it is becoming evident that localized scleroderma is associated with a variety of extracutaneous manifestations. 2 B. Extracutaneous manifestations are seen in 25% of all cases. The commonest manifestation is arthritis accounting for half of all extracutaneous manifestations. It is most commonly associated with linear scleroderma. No association has been described with anti-centromere and anti-topoisomerase autoantibodies which are seen in less than 2% of cases. Raynaud’s phenomenon can be seen in 3% of patients. 3 C. Plaque morphea seldom requires any therapy except topical steroids and has a good prognosis. Linear scleroderma is often the most difficult to treat
International Journal of Rheumatic Diseases 2015; 18: 366–371
Autologous HSCT for progressive localised scleroderma
and the drug of choice is methotrexate (15 mg/m2/ week) with oral prednisolone for the first 3 months. This is associated with a high response rate with new lesions occurring in just 6.5% and relapse in another 12.5%. Among refractory cases, mycophenolate mofetil has been used with success. Recovery is best seen with plaque morphea and generalized scleroderma. Linear scleroderma invariably leaves behind muscle atrophy, scarring and growth defects. The only study in vitamin D showed that it was no better than placebo. There is no role of intralesional interferon. 4 D. Autologous HSCT has been performed in over 2000 patients worldwide for various autoimmune disorders including scleroderma. With passing years and improved expertise the transplant-related mortality has decreased and is in the range of 7 3% at 3 years of transplant. The mechanism of action is not fully understood but studies have shown that initial immune suppression with subsequent increased regulatory T-cell activity helps in disease control. The best results have been achieved in patients with progressive disease where irreversible organ damage has not yet occurred.
CONFLICTS OF INTEREST None.
REFERENCES 1 Laxer RM, Zulian F (2006) Localized scleroderma. Curr Opin Rheumatol 18, 606–13.
International Journal of Rheumatic Diseases 2015; 18: 366–371
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