Arthritis Drug Shows Promise for Severe Vasculitis

SORRENTO, ITALY — Rituximab may provide a therapeutic option for patients with refractory, potentially life-threatening autoimmune vasculitic conditions that do not respond to conventional therapies or when dose-limiting toxicity occurs, Dr. Dario Roccatello said at the Fifth International Congress on Autoimmunity.

Although prognosis in the once rapidly fatal systemic vasculitides improved following the introduction of treatment with corticosteroids and cyclophosphamide, approximately one-fourth of patients cannot tolerate the associated side effects, and many relapse. Recent interest in the long-term management of these disorders therefore has centered on cyclophosphamide-sparing approaches, Dr. Roccatello said.

He reported on eight patients with systemic vasculitis who have been treated with this B cell-depleting agent. Their diagnoses included systemic micropolyangiitis, Wegener's granulomatosis, and Churg-Strauss syndrome. Six had kidney involvement, and necrotizing glomerulonephritis was present in four who underwent renal biopsy.

Intravenous rituximab was given in doses of 375 mg/m

Levels of the antineutrophil cytoplasmic antibodies (ANCA) that characterize these vasculitides decreased by fivefold following rituximab treatment, and one patient became ANCA-negative by week 4, said Dr. Roccatello of the University of Turin (Italy).

Treatment also resulted in significant decreases in pain and disease activity scores as measured on visual analog scales, with statistically significant decreases seen in levels of erythrocyte sedimentation rate (ESR), serum creatinine levels, proteinuria, and hematuria.

Weakness, paresthesias, arthralgias, and fever also resolved in the majority of patients.

One of the patients was a 38-year-old man who had involvement of the left carotid artery and elevations of ESR, C-reactive protein, and rheumatoid factor (RF). He was antibody positive for phospholipids and perinuclear ANCA (p-ANCA), and had symptoms including hematuria, fever, severe weakness, and paresthesia.

Initially he was treated with anticoagulants, gabapentin, and high-dose immunoglobulins, but after 2 months he had further elevations of p-ANCA and RF, as well as worsening neuropathy, and was treated with three steroid pulses and mycophenolate mofetil. One month later, he developed a leukocytic vasculitis with motor disability and underwent plasma exchange. Methotrexate was substituted for the mycophenolate mofetil, which he was not tolerating.

The patient continued to experience severe neuropathy until given rituximab. Subsequent nerve conduction studies showed resolution of the neuropathic symptoms, with amelioration in velocity, amplitude, and latency, Dr. Roccatello said.

A second patient was a 61-year-old woman who had been treated for necrotizing glomerulonephritis with corticosteroids and cylophosphamide but was referred to Dr. Roccatello's center because of persistent fever, elevated cytoplasmic ANCA (c-ANCA) levels, weight loss, dyspnea, chest pain, and sinusitis characterized by complete blockage of the maxillary sinuses.

She also had multiple nodular lesions in the superior lobes of the lungs. Treatment with rituximab resulted in a 30% decrease in the number of pulmonary lesions by week 7, and in complete clearance by 9 months. Following treatment, this patient's urinary and inflammation markers and c-ANCA levels all normalized, he said.

Dr. Roccatello also has used rituximab in severe cryoglobulinemia, which is a systemic vasculitis usually associated with hepatitis C infection and sustained by the proliferation of oligoclonal B cells. A total of 12 patients with symptomatic type II mixed cryoglobulinemia were treated with six courses of rituximab in the same dose and schedule as the eight patients with ANCA-associated vasculitides, he said.

All 12 patients had polyneuropathy and renal involvement, with 6 having biopsy-proven diffuse membranoproliferative glomerulonephritis. Five patients had bone marrow clonal restriction, and three had large necrotizing skin ulcers.

Significant decreases were seen in levels of proteinuria, ESR, and RF during 18 months of follow-up, and bone marrow abnormalities were shown to have normalized in the three patients who underwent repeat biopsy. Skin ulcers and purpura, arthralgias, weakness, paresthesias, and fever improved or resolved in all patients, Dr. Roccatello reported.

Rituximab has been used in combination regimens, such as with corticosteroids and immunosuppressants for relapsing Wegener's granulomatosis. In another series presented at the congress, Dr. Achille Aouba reported on eight patients with Wegener's granulomatosis who experienced flares or failed to respond to multiple other immunomodulatory therapies, including anti-tumor necrosis factor-α blockers.

Disease manifestations included lung nodules in four patients, orbital pseudotumor in two, and gingival hyperplasia, mononeuritis multiplex, glomerulonephritis, rectal perforation, pyoderma gangrenosum, and myocardial involvement in one each.

While continuing on corticosteroids and immunosuppressants, seven of the patients received four weekly infusions of rituximab in doses of 375 mg/m

The median Birmingham vasculitis activity score (BVAS) before rituximab treatment was 14.3, with a range of 0–30.

At 4 months, five patients had BVAS scores of zero and three were in complete remission, said Dr. Aouba of the National Reference Center for Vasculitides, Hospital Cochin, Paris, and of the French Vasculitis Study Group.

An additional three were in partial remission, with BVAS scores of zero but persistent lung nodules, and two failed to respond.

Constitutional and vasculitis-related symptoms resolved more quickly than granulomatous manifestations, which regressed slowly over several months, Dr. Aouba said.

Rituximab was well tolerated, with the only adverse event being an urticarial rash in one patient, which developed after the third infusion.

In conclusion, the addition of rituximab to conventional treatment for relapsing Wegener's granulomatosis improved clinical outcome, Dr. Aouba said.

Necrotizing skin ulcers (above) developed in association with severe mixed cryoglobulinemia. Photos courtesy Dr. Dario Roccatello

SORRENTO, ITALY — Rituximab may provide a therapeutic option for patients with refractory, potentially life-threatening autoimmune vasculitic conditions that do not respond to conventional therapies or when dose-limiting toxicity occurs, Dr. Dario Roccatello said at the Fifth International Congress on Autoimmunity.

Although prognosis in the once rapidly fatal systemic vasculitides improved following the introduction of treatment with corticosteroids and cyclophosphamide, approximately one-fourth of patients cannot tolerate the associated side effects, and many relapse. Recent interest in the long-term management of these disorders therefore has centered on cyclophosphamide-sparing approaches, Dr. Roccatello said.

He reported on eight patients with systemic vasculitis who have been treated with this B cell-depleting agent. Their diagnoses included systemic micropolyangiitis, Wegener's granulomatosis, and Churg-Strauss syndrome. Six had kidney involvement, and necrotizing glomerulonephritis was present in four who underwent renal biopsy.

Intravenous rituximab was given in doses of 375 mg/m

Levels of the antineutrophil cytoplasmic antibodies (ANCA) that characterize these vasculitides decreased by fivefold following rituximab treatment, and one patient became ANCA-negative by week 4, said Dr. Roccatello of the University of Turin (Italy).

Treatment also resulted in significant decreases in pain and disease activity scores as measured on visual analog scales, with statistically significant decreases seen in levels of erythrocyte sedimentation rate (ESR), serum creatinine levels, proteinuria, and hematuria.

Weakness, paresthesias, arthralgias, and fever also resolved in the majority of patients.

One of the patients was a 38-year-old man who had involvement of the left carotid artery and elevations of ESR, C-reactive protein, and rheumatoid factor (RF). He was antibody positive for phospholipids and perinuclear ANCA (p-ANCA), and had symptoms including hematuria, fever, severe weakness, and paresthesia.

Initially he was treated with anticoagulants, gabapentin, and high-dose immunoglobulins, but after 2 months he had further elevations of p-ANCA and RF, as well as worsening neuropathy, and was treated with three steroid pulses and mycophenolate mofetil. One month later, he developed a leukocytic vasculitis with motor disability and underwent plasma exchange. Methotrexate was substituted for the mycophenolate mofetil, which he was not tolerating.

The patient continued to experience severe neuropathy until given rituximab. Subsequent nerve conduction studies showed resolution of the neuropathic symptoms, with amelioration in velocity, amplitude, and latency, Dr. Roccatello said.

A second patient was a 61-year-old woman who had been treated for necrotizing glomerulonephritis with corticosteroids and cylophosphamide but was referred to Dr. Roccatello's center because of persistent fever, elevated cytoplasmic ANCA (c-ANCA) levels, weight loss, dyspnea, chest pain, and sinusitis characterized by complete blockage of the maxillary sinuses.

She also had multiple nodular lesions in the superior lobes of the lungs. Treatment with rituximab resulted in a 30% decrease in the number of pulmonary lesions by week 7, and in complete clearance by 9 months. Following treatment, this patient's urinary and inflammation markers and c-ANCA levels all normalized, he said.

Dr. Roccatello also has used rituximab in severe cryoglobulinemia, which is a systemic vasculitis usually associated with hepatitis C infection and sustained by the proliferation of oligoclonal B cells. A total of 12 patients with symptomatic type II mixed cryoglobulinemia were treated with six courses of rituximab in the same dose and schedule as the eight patients with ANCA-associated vasculitides, he said.

All 12 patients had polyneuropathy and renal involvement, with 6 having biopsy-proven diffuse membranoproliferative glomerulonephritis. Five patients had bone marrow clonal restriction, and three had large necrotizing skin ulcers.

Significant decreases were seen in levels of proteinuria, ESR, and RF during 18 months of follow-up, and bone marrow abnormalities were shown to have normalized in the three patients who underwent repeat biopsy. Skin ulcers and purpura, arthralgias, weakness, paresthesias, and fever improved or resolved in all patients, Dr. Roccatello reported.

Rituximab has been used in combination regimens, such as with corticosteroids and immunosuppressants for relapsing Wegener's granulomatosis. In another series presented at the congress, Dr. Achille Aouba reported on eight patients with Wegener's granulomatosis who experienced flares or failed to respond to multiple other immunomodulatory therapies, including anti-tumor necrosis factor-α blockers.

Disease manifestations included lung nodules in four patients, orbital pseudotumor in two, and gingival hyperplasia, mononeuritis multiplex, glomerulonephritis, rectal perforation, pyoderma gangrenosum, and myocardial involvement in one each.

While continuing on corticosteroids and immunosuppressants, seven of the patients received four weekly infusions of rituximab in doses of 375 mg/m

The median Birmingham vasculitis activity score (BVAS) before rituximab treatment was 14.3, with a range of 0–30.

At 4 months, five patients had BVAS scores of zero and three were in complete remission, said Dr. Aouba of the National Reference Center for Vasculitides, Hospital Cochin, Paris, and of the French Vasculitis Study Group.

An additional three were in partial remission, with BVAS scores of zero but persistent lung nodules, and two failed to respond.

Constitutional and vasculitis-related symptoms resolved more quickly than granulomatous manifestations, which regressed slowly over several months, Dr. Aouba said.

Rituximab was well tolerated, with the only adverse event being an urticarial rash in one patient, which developed after the third infusion.

In conclusion, the addition of rituximab to conventional treatment for relapsing Wegener's granulomatosis improved clinical outcome, Dr. Aouba said.

Necrotizing skin ulcers (above) developed in association with severe mixed cryoglobulinemia. Photos courtesy Dr. Dario Roccatello

SORRENTO, ITALY — Rituximab may provide a therapeutic option for patients with refractory, potentially life-threatening autoimmune vasculitic conditions that do not respond to conventional therapies or when dose-limiting toxicity occurs, Dr. Dario Roccatello said at the Fifth International Congress on Autoimmunity.

Although prognosis in the once rapidly fatal systemic vasculitides improved following the introduction of treatment with corticosteroids and cyclophosphamide, approximately one-fourth of patients cannot tolerate the associated side effects, and many relapse. Recent interest in the long-term management of these disorders therefore has centered on cyclophosphamide-sparing approaches, Dr. Roccatello said.

He reported on eight patients with systemic vasculitis who have been treated with this B cell-depleting agent. Their diagnoses included systemic micropolyangiitis, Wegener's granulomatosis, and Churg-Strauss syndrome. Six had kidney involvement, and necrotizing glomerulonephritis was present in four who underwent renal biopsy.

Intravenous rituximab was given in doses of 375 mg/m

Levels of the antineutrophil cytoplasmic antibodies (ANCA) that characterize these vasculitides decreased by fivefold following rituximab treatment, and one patient became ANCA-negative by week 4, said Dr. Roccatello of the University of Turin (Italy).

Treatment also resulted in significant decreases in pain and disease activity scores as measured on visual analog scales, with statistically significant decreases seen in levels of erythrocyte sedimentation rate (ESR), serum creatinine levels, proteinuria, and hematuria.

Weakness, paresthesias, arthralgias, and fever also resolved in the majority of patients.

One of the patients was a 38-year-old man who had involvement of the left carotid artery and elevations of ESR, C-reactive protein, and rheumatoid factor (RF). He was antibody positive for phospholipids and perinuclear ANCA (p-ANCA), and had symptoms including hematuria, fever, severe weakness, and paresthesia.

Initially he was treated with anticoagulants, gabapentin, and high-dose immunoglobulins, but after 2 months he had further elevations of p-ANCA and RF, as well as worsening neuropathy, and was treated with three steroid pulses and mycophenolate mofetil. One month later, he developed a leukocytic vasculitis with motor disability and underwent plasma exchange. Methotrexate was substituted for the mycophenolate mofetil, which he was not tolerating.

The patient continued to experience severe neuropathy until given rituximab. Subsequent nerve conduction studies showed resolution of the neuropathic symptoms, with amelioration in velocity, amplitude, and latency, Dr. Roccatello said.

A second patient was a 61-year-old woman who had been treated for necrotizing glomerulonephritis with corticosteroids and cylophosphamide but was referred to Dr. Roccatello's center because of persistent fever, elevated cytoplasmic ANCA (c-ANCA) levels, weight loss, dyspnea, chest pain, and sinusitis characterized by complete blockage of the maxillary sinuses.

She also had multiple nodular lesions in the superior lobes of the lungs. Treatment with rituximab resulted in a 30% decrease in the number of pulmonary lesions by week 7, and in complete clearance by 9 months. Following treatment, this patient's urinary and inflammation markers and c-ANCA levels all normalized, he said.

Dr. Roccatello also has used rituximab in severe cryoglobulinemia, which is a systemic vasculitis usually associated with hepatitis C infection and sustained by the proliferation of oligoclonal B cells. A total of 12 patients with symptomatic type II mixed cryoglobulinemia were treated with six courses of rituximab in the same dose and schedule as the eight patients with ANCA-associated vasculitides, he said.

All 12 patients had polyneuropathy and renal involvement, with 6 having biopsy-proven diffuse membranoproliferative glomerulonephritis. Five patients had bone marrow clonal restriction, and three had large necrotizing skin ulcers.

Significant decreases were seen in levels of proteinuria, ESR, and RF during 18 months of follow-up, and bone marrow abnormalities were shown to have normalized in the three patients who underwent repeat biopsy. Skin ulcers and purpura, arthralgias, weakness, paresthesias, and fever improved or resolved in all patients, Dr. Roccatello reported.

Rituximab has been used in combination regimens, such as with corticosteroids and immunosuppressants for relapsing Wegener's granulomatosis. In another series presented at the congress, Dr. Achille Aouba reported on eight patients with Wegener's granulomatosis who experienced flares or failed to respond to multiple other immunomodulatory therapies, including anti-tumor necrosis factor-α blockers.

Disease manifestations included lung nodules in four patients, orbital pseudotumor in two, and gingival hyperplasia, mononeuritis multiplex, glomerulonephritis, rectal perforation, pyoderma gangrenosum, and myocardial involvement in one each.

While continuing on corticosteroids and immunosuppressants, seven of the patients received four weekly infusions of rituximab in doses of 375 mg/m

The median Birmingham vasculitis activity score (BVAS) before rituximab treatment was 14.3, with a range of 0–30.

At 4 months, five patients had BVAS scores of zero and three were in complete remission, said Dr. Aouba of the National Reference Center for Vasculitides, Hospital Cochin, Paris, and of the French Vasculitis Study Group.

An additional three were in partial remission, with BVAS scores of zero but persistent lung nodules, and two failed to respond.

Constitutional and vasculitis-related symptoms resolved more quickly than granulomatous manifestations, which regressed slowly over several months, Dr. Aouba said.

Rituximab was well tolerated, with the only adverse event being an urticarial rash in one patient, which developed after the third infusion.

In conclusion, the addition of rituximab to conventional treatment for relapsing Wegener's granulomatosis improved clinical outcome, Dr. Aouba said.

Necrotizing skin ulcers (above) developed in association with severe mixed cryoglobulinemia. Photos courtesy Dr. Dario Roccatello