New Interest Spurs Progress in Treatment of Systemic Sclerosis

NEW YORK – Management of systemic sclerosis is likely to improve as soon as an ongoing convergence of mechanistic insights, improved understanding of clinical trial design, and interest by industry results in new treatments, according to Dr. Robert F. Spiera.

Of particular note are recent trials, with both positive and negative results, of tyrosine kinase inhibitors (TKIs) and autologous stem cell transplantation, he said at a rheumatology meeting sponsored by New York University.

Even while awaiting a big breakthrough in treatment, "we can now do a lot for our patients with scleroderma," said Dr. Spiera, director of the Scleroderma and Vasculitis Center at the Hospital for Special Surgery in New York.

Therapy for systemic sclerosis (SSc) falls into two categories: treatment of organ-specific complications and disease modification. Major advances have been made in treating organ-specific complications affecting the gastrointestinal system, kidneys, heart and lungs, and musculoskeletal organs, according to Dr. Spiera. Many agents are available to manage symptoms of Raynaud’s phenomenon.

While there are no proven disease-modifying therapies as yet, the search for such therapies in scleroderma has intensified. Immunosuppressive therapy is one approach, and limited success has been achieved with cyclophosphamide. There have been several recent reports investigating immunoablative therapy combined with bone marrow transplantation.

In the ASSIST (American Scleroderma Stem Cell vs. Immune Suppression) Trial, an open-label, randomized, controlled phase II trial, 10 patients received hemopoietic stem-cell transplantation (HSCT) plus 200 mg/kg of intravenous cyclophosphamide and 6.5 mg/kg of IV rabbit antithymocyte globulin. The 9 control patients received 1.0 g/m² of IV cyclophosphamide once a month for 6 months. The authors reported that all 10 HSCT patients improved at or before follow-up at 12 months, compared with none of the 9 treated only with cyclophosphamide (odds ratio, 110; P = .00001) (Lancet 2011;378:498-506). Of the 9 controls, 8 had disease progression, compared with none of those treated by HSCT (P = .0001), and 7 controls eventually underwent HSCT. The outcomes were considered to be an improvement, defined as a decrease in the modified Rodnan skin scores (mRSS) of more than 25% or an increase in forced vital capacity (FVC) of more than 10%.

"These results surprised a lot of people in the scleroderma community," commented Dr. Spiera. He noted that some of the inclusion criteria could be subject to challenge, as they potentially allowed for enrollment of patients with relatively mild disease. He also noted that it was a single-center study, which limits the generalizability of the results, as the morbidity of the intervention is likely center- and experience-dependent.

Another single-center study from Germany reported the outcomes of autologous stem cell transplantation in 26 patients with SSc. Patients received cyclophosphamide and granulocyte colony-stimulating factor for mobilization and cyclophosphamide plus antithymocyte globulin for conditioning before retransfusion of CD34-selected stem cells. Six months after transplantation, 91% of patients improved, as measured by a reduction in the mRSS of 25% or more (Rheumatol. 2012;39:269-75). However, 3 patients died between the mobilization and conditioning treatment, 2 due to severe disease progression and 1 whose death was thought to be treatment related. Seven patients relapsed during 4.4 years of follow-up. Progression-free survival was 74%. During follow-up, 4 patients died, mostly due to pulmonary or cardiac complications of SSc.

More definitive evidence regarding scleroderma may be forthcoming from the ongoing National Institutes of Health SCOT (Scleroderma: Cyclophosphamide or Transplantation) trial. The study will compare the potential benefits of autologous stem cell transplant with those of cyclophosphamide (12 IV treatments at monthly intervals). A composite end point will include mortality, organ failure, change in FVC of more than 10%, change in mRSS of more than 25%, and the Scleroderma Health Assessment Questionnaire (SHAQ). Enrollment in SCOT was completed in May 2011, and randomization continued until Oct. 1, 2011.

Another avenue of active research is the search for antifibrotic therapy. The TKI imatinib is one agent undergoing active scrutiny. According to Dr. Spiera, there are good preclinical data available for imatinib, including reports that imatinib treatment in a mouse model of SSc reduced dermal thickening and prevented the differentiation of resting fibroblasts into myofibroblasts, perhaps by blocking noncanonical transforming growth factor-beta (TGF-beta) pathways and platelet-derived growth factor receptor (PDGFR) signaling (Arthritis Rheum. 2009;60:219-24; Oncogene 2009;28:1285-97).

Clinical findings for the treatment of SSc with imatinib have been mixed. In the largest and longest-observed cohort, Dr. Spiera conducted a prospective, phase IIa, open-label, single-arm clinical trial of 30 patients with diffuse cutaneous SSc of less than 4 years’ duration treated with imatinib 400 mg daily. Patients with both early and late disease were included, and about three-quarters had previously received other treatments, including corticosteroids (46.7%), methotrexate (30.0%), mycophenolate mofetil (20.0%), and autologous stem cell transplantation (3.3%). Twenty-four patients completed 12 months of therapy (Ann. Rheum. Dis. 2011;70:1003-9). Improvements in skin thickening and FVC were observed. The mRSS decreased by 22.4% at 12 months (P = .001), and changes were noted 6 months after initiation of therapy. Patients with early disease (less than 18 months) improved the most. FVC improved by 6.4% predicted (P = .008), and diffusion capacity remained stable. Dr. Spiera questioned the clinical significance of the change in FVC, since not all the patients had interstitial lung disease at baseline.

Treatment with imatinib was tolerated by most patients. Adverse events – including edema, nausea, and myalgias – were common (n = 171), although most (98%) were mild to moderate. There were 24 serious adverse events, and 2 were attributed to imatinib.

Steps were taken to improve tolerability. In 83% of patients, the imatinib dose was adjusted due to myalgia; edema and effusions; gastrointestinal complaints; or other illness. About 60% of patients who developed edema were given furosemide, which proved helpful.

These results stand in contrast to those of another group of investigators who set out to do a 6-month, randomized, double-blind, placebo-controlled proof-of-concept pilot study of imatinib in patients with active diffuse cutaneous SSc (Arthritis Rheum. 2011;63:3547-51). A 4:1 randomization strategy was used, stratifying patients according to current use of methotrexate. Imatinib 200 mg was given twice daily. The goal of the study was to enroll 20 patients. However, the study was discontinued after 10 patients were enrolled (9 who received imatinib and 1 placebo) due to poor tolerability and high rates of adverse events. These events were similar to those reported by Dr. Spiera: edema, fluid retention, fatigue, nausea, cramps/myalgias, and diarrhea, but also alopecia and anemia. According to the authors, the side effects occurred even when the imatinib dose was reduced to 200 mg daily. Two patients were hospitalized because of medication side effects.

No differences were found in any measures of efficacy (that is, changes in mRSS, physician’s global assessment, patient’s global assessment, or HAQ scores), but this was attributed to the small number of patients who actually completed the study.

"I think we are going to see more about [TKIs] for systemic sclerosis," said Dr. Spiera. He noted that clinical trials were underway for other TKIs, such as dasatinib and nilotinib. The TKI BIBF 1120 was shown in a phase II, randomized, placebo-controlled trial to slow down the rate of decline of FVC in patients with idiopathic pulmonary fibrosis (N. Engl. J. Med. 2011;365:1079-87).

While Dr. Spiera called for more randomized controlled trials, he also highlighted some of the challenges faced by those conducting clinical trials in scleroderma. These include the difficulty of recruiting patients with such an uncommon disease, the variety in disease phenotypes, the variable natural history, uncertainty as to what are the most relevant and valid outcome measures, and the ethical ramifications of randomizing patients to placebo.

Dr. Spiera listed research support from BMS, Boehringer Ingelheim, Novartis, Roche/Genentech, and United Therapeutics.

NEW YORK – Management of systemic sclerosis is likely to improve as soon as an ongoing convergence of mechanistic insights, improved understanding of clinical trial design, and interest by industry results in new treatments, according to Dr. Robert F. Spiera.

Of particular note are recent trials, with both positive and negative results, of tyrosine kinase inhibitors (TKIs) and autologous stem cell transplantation, he said at a rheumatology meeting sponsored by New York University.

Even while awaiting a big breakthrough in treatment, "we can now do a lot for our patients with scleroderma," said Dr. Spiera, director of the Scleroderma and Vasculitis Center at the Hospital for Special Surgery in New York.

Therapy for systemic sclerosis (SSc) falls into two categories: treatment of organ-specific complications and disease modification. Major advances have been made in treating organ-specific complications affecting the gastrointestinal system, kidneys, heart and lungs, and musculoskeletal organs, according to Dr. Spiera. Many agents are available to manage symptoms of Raynaud’s phenomenon.

While there are no proven disease-modifying therapies as yet, the search for such therapies in scleroderma has intensified. Immunosuppressive therapy is one approach, and limited success has been achieved with cyclophosphamide. There have been several recent reports investigating immunoablative therapy combined with bone marrow transplantation.

In the ASSIST (American Scleroderma Stem Cell vs. Immune Suppression) Trial, an open-label, randomized, controlled phase II trial, 10 patients received hemopoietic stem-cell transplantation (HSCT) plus 200 mg/kg of intravenous cyclophosphamide and 6.5 mg/kg of IV rabbit antithymocyte globulin. The 9 control patients received 1.0 g/m² of IV cyclophosphamide once a month for 6 months. The authors reported that all 10 HSCT patients improved at or before follow-up at 12 months, compared with none of the 9 treated only with cyclophosphamide (odds ratio, 110; P = .00001) (Lancet 2011;378:498-506). Of the 9 controls, 8 had disease progression, compared with none of those treated by HSCT (P = .0001), and 7 controls eventually underwent HSCT. The outcomes were considered to be an improvement, defined as a decrease in the modified Rodnan skin scores (mRSS) of more than 25% or an increase in forced vital capacity (FVC) of more than 10%.

"These results surprised a lot of people in the scleroderma community," commented Dr. Spiera. He noted that some of the inclusion criteria could be subject to challenge, as they potentially allowed for enrollment of patients with relatively mild disease. He also noted that it was a single-center study, which limits the generalizability of the results, as the morbidity of the intervention is likely center- and experience-dependent.

Another single-center study from Germany reported the outcomes of autologous stem cell transplantation in 26 patients with SSc. Patients received cyclophosphamide and granulocyte colony-stimulating factor for mobilization and cyclophosphamide plus antithymocyte globulin for conditioning before retransfusion of CD34-selected stem cells. Six months after transplantation, 91% of patients improved, as measured by a reduction in the mRSS of 25% or more (Rheumatol. 2012;39:269-75). However, 3 patients died between the mobilization and conditioning treatment, 2 due to severe disease progression and 1 whose death was thought to be treatment related. Seven patients relapsed during 4.4 years of follow-up. Progression-free survival was 74%. During follow-up, 4 patients died, mostly due to pulmonary or cardiac complications of SSc.

More definitive evidence regarding scleroderma may be forthcoming from the ongoing National Institutes of Health SCOT (Scleroderma: Cyclophosphamide or Transplantation) trial. The study will compare the potential benefits of autologous stem cell transplant with those of cyclophosphamide (12 IV treatments at monthly intervals). A composite end point will include mortality, organ failure, change in FVC of more than 10%, change in mRSS of more than 25%, and the Scleroderma Health Assessment Questionnaire (SHAQ). Enrollment in SCOT was completed in May 2011, and randomization continued until Oct. 1, 2011.

Another avenue of active research is the search for antifibrotic therapy. The TKI imatinib is one agent undergoing active scrutiny. According to Dr. Spiera, there are good preclinical data available for imatinib, including reports that imatinib treatment in a mouse model of SSc reduced dermal thickening and prevented the differentiation of resting fibroblasts into myofibroblasts, perhaps by blocking noncanonical transforming growth factor-beta (TGF-beta) pathways and platelet-derived growth factor receptor (PDGFR) signaling (Arthritis Rheum. 2009;60:219-24; Oncogene 2009;28:1285-97).

Clinical findings for the treatment of SSc with imatinib have been mixed. In the largest and longest-observed cohort, Dr. Spiera conducted a prospective, phase IIa, open-label, single-arm clinical trial of 30 patients with diffuse cutaneous SSc of less than 4 years’ duration treated with imatinib 400 mg daily. Patients with both early and late disease were included, and about three-quarters had previously received other treatments, including corticosteroids (46.7%), methotrexate (30.0%), mycophenolate mofetil (20.0%), and autologous stem cell transplantation (3.3%). Twenty-four patients completed 12 months of therapy (Ann. Rheum. Dis. 2011;70:1003-9). Improvements in skin thickening and FVC were observed. The mRSS decreased by 22.4% at 12 months (P = .001), and changes were noted 6 months after initiation of therapy. Patients with early disease (less than 18 months) improved the most. FVC improved by 6.4% predicted (P = .008), and diffusion capacity remained stable. Dr. Spiera questioned the clinical significance of the change in FVC, since not all the patients had interstitial lung disease at baseline.

Treatment with imatinib was tolerated by most patients. Adverse events – including edema, nausea, and myalgias – were common (n = 171), although most (98%) were mild to moderate. There were 24 serious adverse events, and 2 were attributed to imatinib.

Steps were taken to improve tolerability. In 83% of patients, the imatinib dose was adjusted due to myalgia; edema and effusions; gastrointestinal complaints; or other illness. About 60% of patients who developed edema were given furosemide, which proved helpful.

These results stand in contrast to those of another group of investigators who set out to do a 6-month, randomized, double-blind, placebo-controlled proof-of-concept pilot study of imatinib in patients with active diffuse cutaneous SSc (Arthritis Rheum. 2011;63:3547-51). A 4:1 randomization strategy was used, stratifying patients according to current use of methotrexate. Imatinib 200 mg was given twice daily. The goal of the study was to enroll 20 patients. However, the study was discontinued after 10 patients were enrolled (9 who received imatinib and 1 placebo) due to poor tolerability and high rates of adverse events. These events were similar to those reported by Dr. Spiera: edema, fluid retention, fatigue, nausea, cramps/myalgias, and diarrhea, but also alopecia and anemia. According to the authors, the side effects occurred even when the imatinib dose was reduced to 200 mg daily. Two patients were hospitalized because of medication side effects.

No differences were found in any measures of efficacy (that is, changes in mRSS, physician’s global assessment, patient’s global assessment, or HAQ scores), but this was attributed to the small number of patients who actually completed the study.

"I think we are going to see more about [TKIs] for systemic sclerosis," said Dr. Spiera. He noted that clinical trials were underway for other TKIs, such as dasatinib and nilotinib. The TKI BIBF 1120 was shown in a phase II, randomized, placebo-controlled trial to slow down the rate of decline of FVC in patients with idiopathic pulmonary fibrosis (N. Engl. J. Med. 2011;365:1079-87).

While Dr. Spiera called for more randomized controlled trials, he also highlighted some of the challenges faced by those conducting clinical trials in scleroderma. These include the difficulty of recruiting patients with such an uncommon disease, the variety in disease phenotypes, the variable natural history, uncertainty as to what are the most relevant and valid outcome measures, and the ethical ramifications of randomizing patients to placebo.

Dr. Spiera listed research support from BMS, Boehringer Ingelheim, Novartis, Roche/Genentech, and United Therapeutics.

NEW YORK – Management of systemic sclerosis is likely to improve as soon as an ongoing convergence of mechanistic insights, improved understanding of clinical trial design, and interest by industry results in new treatments, according to Dr. Robert F. Spiera.

Of particular note are recent trials, with both positive and negative results, of tyrosine kinase inhibitors (TKIs) and autologous stem cell transplantation, he said at a rheumatology meeting sponsored by New York University.

Even while awaiting a big breakthrough in treatment, "we can now do a lot for our patients with scleroderma," said Dr. Spiera, director of the Scleroderma and Vasculitis Center at the Hospital for Special Surgery in New York.

Therapy for systemic sclerosis (SSc) falls into two categories: treatment of organ-specific complications and disease modification. Major advances have been made in treating organ-specific complications affecting the gastrointestinal system, kidneys, heart and lungs, and musculoskeletal organs, according to Dr. Spiera. Many agents are available to manage symptoms of Raynaud’s phenomenon.

While there are no proven disease-modifying therapies as yet, the search for such therapies in scleroderma has intensified. Immunosuppressive therapy is one approach, and limited success has been achieved with cyclophosphamide. There have been several recent reports investigating immunoablative therapy combined with bone marrow transplantation.

In the ASSIST (American Scleroderma Stem Cell vs. Immune Suppression) Trial, an open-label, randomized, controlled phase II trial, 10 patients received hemopoietic stem-cell transplantation (HSCT) plus 200 mg/kg of intravenous cyclophosphamide and 6.5 mg/kg of IV rabbit antithymocyte globulin. The 9 control patients received 1.0 g/m² of IV cyclophosphamide once a month for 6 months. The authors reported that all 10 HSCT patients improved at or before follow-up at 12 months, compared with none of the 9 treated only with cyclophosphamide (odds ratio, 110; P = .00001) (Lancet 2011;378:498-506). Of the 9 controls, 8 had disease progression, compared with none of those treated by HSCT (P = .0001), and 7 controls eventually underwent HSCT. The outcomes were considered to be an improvement, defined as a decrease in the modified Rodnan skin scores (mRSS) of more than 25% or an increase in forced vital capacity (FVC) of more than 10%.

"These results surprised a lot of people in the scleroderma community," commented Dr. Spiera. He noted that some of the inclusion criteria could be subject to challenge, as they potentially allowed for enrollment of patients with relatively mild disease. He also noted that it was a single-center study, which limits the generalizability of the results, as the morbidity of the intervention is likely center- and experience-dependent.

Another single-center study from Germany reported the outcomes of autologous stem cell transplantation in 26 patients with SSc. Patients received cyclophosphamide and granulocyte colony-stimulating factor for mobilization and cyclophosphamide plus antithymocyte globulin for conditioning before retransfusion of CD34-selected stem cells. Six months after transplantation, 91% of patients improved, as measured by a reduction in the mRSS of 25% or more (Rheumatol. 2012;39:269-75). However, 3 patients died between the mobilization and conditioning treatment, 2 due to severe disease progression and 1 whose death was thought to be treatment related. Seven patients relapsed during 4.4 years of follow-up. Progression-free survival was 74%. During follow-up, 4 patients died, mostly due to pulmonary or cardiac complications of SSc.

More definitive evidence regarding scleroderma may be forthcoming from the ongoing National Institutes of Health SCOT (Scleroderma: Cyclophosphamide or Transplantation) trial. The study will compare the potential benefits of autologous stem cell transplant with those of cyclophosphamide (12 IV treatments at monthly intervals). A composite end point will include mortality, organ failure, change in FVC of more than 10%, change in mRSS of more than 25%, and the Scleroderma Health Assessment Questionnaire (SHAQ). Enrollment in SCOT was completed in May 2011, and randomization continued until Oct. 1, 2011.

Another avenue of active research is the search for antifibrotic therapy. The TKI imatinib is one agent undergoing active scrutiny. According to Dr. Spiera, there are good preclinical data available for imatinib, including reports that imatinib treatment in a mouse model of SSc reduced dermal thickening and prevented the differentiation of resting fibroblasts into myofibroblasts, perhaps by blocking noncanonical transforming growth factor-beta (TGF-beta) pathways and platelet-derived growth factor receptor (PDGFR) signaling (Arthritis Rheum. 2009;60:219-24; Oncogene 2009;28:1285-97).

Clinical findings for the treatment of SSc with imatinib have been mixed. In the largest and longest-observed cohort, Dr. Spiera conducted a prospective, phase IIa, open-label, single-arm clinical trial of 30 patients with diffuse cutaneous SSc of less than 4 years’ duration treated with imatinib 400 mg daily. Patients with both early and late disease were included, and about three-quarters had previously received other treatments, including corticosteroids (46.7%), methotrexate (30.0%), mycophenolate mofetil (20.0%), and autologous stem cell transplantation (3.3%). Twenty-four patients completed 12 months of therapy (Ann. Rheum. Dis. 2011;70:1003-9). Improvements in skin thickening and FVC were observed. The mRSS decreased by 22.4% at 12 months (P = .001), and changes were noted 6 months after initiation of therapy. Patients with early disease (less than 18 months) improved the most. FVC improved by 6.4% predicted (P = .008), and diffusion capacity remained stable. Dr. Spiera questioned the clinical significance of the change in FVC, since not all the patients had interstitial lung disease at baseline.

Treatment with imatinib was tolerated by most patients. Adverse events – including edema, nausea, and myalgias – were common (n = 171), although most (98%) were mild to moderate. There were 24 serious adverse events, and 2 were attributed to imatinib.

Steps were taken to improve tolerability. In 83% of patients, the imatinib dose was adjusted due to myalgia; edema and effusions; gastrointestinal complaints; or other illness. About 60% of patients who developed edema were given furosemide, which proved helpful.

These results stand in contrast to those of another group of investigators who set out to do a 6-month, randomized, double-blind, placebo-controlled proof-of-concept pilot study of imatinib in patients with active diffuse cutaneous SSc (Arthritis Rheum. 2011;63:3547-51). A 4:1 randomization strategy was used, stratifying patients according to current use of methotrexate. Imatinib 200 mg was given twice daily. The goal of the study was to enroll 20 patients. However, the study was discontinued after 10 patients were enrolled (9 who received imatinib and 1 placebo) due to poor tolerability and high rates of adverse events. These events were similar to those reported by Dr. Spiera: edema, fluid retention, fatigue, nausea, cramps/myalgias, and diarrhea, but also alopecia and anemia. According to the authors, the side effects occurred even when the imatinib dose was reduced to 200 mg daily. Two patients were hospitalized because of medication side effects.

No differences were found in any measures of efficacy (that is, changes in mRSS, physician’s global assessment, patient’s global assessment, or HAQ scores), but this was attributed to the small number of patients who actually completed the study.

"I think we are going to see more about [TKIs] for systemic sclerosis," said Dr. Spiera. He noted that clinical trials were underway for other TKIs, such as dasatinib and nilotinib. The TKI BIBF 1120 was shown in a phase II, randomized, placebo-controlled trial to slow down the rate of decline of FVC in patients with idiopathic pulmonary fibrosis (N. Engl. J. Med. 2011;365:1079-87).

While Dr. Spiera called for more randomized controlled trials, he also highlighted some of the challenges faced by those conducting clinical trials in scleroderma. These include the difficulty of recruiting patients with such an uncommon disease, the variety in disease phenotypes, the variable natural history, uncertainty as to what are the most relevant and valid outcome measures, and the ethical ramifications of randomizing patients to placebo.

Dr. Spiera listed research support from BMS, Boehringer Ingelheim, Novartis, Roche/Genentech, and United Therapeutics.