Serious New Infections Continue With Biologics

LIVERPOOL, ENGLAND — Serious and even fatal infections continue to occur in patients being treated with tumor necrosis factor-blocking agents and other biologics, emphasizing the need for heightened vigilance.

This was demonstrated in a series of posters presented at the annual meeting of the British Society for Rheumatology. In one case report, a 49-year-old woman with rheumatoid arthritis (RA) who had been treated unsuccessfully with methotrexate, sulfasalazine, leflunomide, and high doses of prednisone was started on etanercept. She developed lesions on her palms and soles typical of pustular psoriasis, and was then switched to infliximab, prednisone, and methotrexate. Following the third infusion she was hospitalized with fever and a widespread vesicular rash, according to Dr. Elizabeth A. Justice of University Hospital Birmingham (England).

The patient's C-reactive protein level was 153 mg/L, but the results of a sepsis screen and chest x-ray were normal. Fluid from the skin vesicles was found to contain herpes simplex virus type 1 (HSV-1).

The TNF blocker was stopped and acyclovir was given in dosages of 800 mg five times daily. The rash began to resolve within 48 hours, and after 2 weeks the acyclovir dosage was reduced to 400 mg twice daily.

Two months later she commenced adalimumab, 40 mg every other week, continuing on acyclovir prophylaxis in dosages of 200 mg every other day, with no recurrence of the HSV lesions.

“This is the first reported case of disseminated cutaneous HSV-1 infection following treatment with infliximab, an unusual adverse reaction we believe to be a direct result of her immunosuppressive therapy,” Dr. Justice wrote.

A second case involved a 49-year-old man with a 14-year history of seropositive nonerosive eosinophilic RA. He presented with shortness of breath but no cough, fever, or chest pain, said Dr. Deepak R. Jadon. The patient had been treated previously with etanercept and adalimumab with limited benefit, and 2 months earlier he had begun treatment with rituximab. He also had previously been on sulfasalazine for 13 years, but 2 months earlier switched to leflunomide, 10 mg/day, plus methotrexate, 15 mg/wk. He developed low-grade fever, tachycardia, dyspnea, and orthopnea, with end-inspiratory crackles audible bilaterally in the mid-lower chest. Arterial blood gases showed saturation of 75% and partial pressure of oxygen of 5.63 mm Hg. He also had neutrophilia and eosinopenia, and his C-reactive protein level was 174 mg/L.

A chest film showed patchy shadowing, and a CT scan revealed extensive ground glass parenchymal abnormalities affecting both mid and lower zones, according to Dr. Jadon of the department of rheumatology, Royal Berkshire Hospital, Reading (England).

Methotrexate and leflunomide were stopped, and calcium folinate (leucovorin calcium), 15 mg four times a day, and cholestyramine, 8 g three times a day, were administered. Three 1-g doses of intravenous methylprednisolone were given, along with amoxicillin with clavulanic acid in doses of 1.2 g intravenously three times daily. (There is no parenteral preparation of amoxicillin with clavulanic acid available in the United States.)

“This is the first-ever reported case of leflunomide-associated pneumonitis in a patient concurrently on rituximab and methotrexate. The patient was diagnosed early, therapy initiated promptly, and he survived the ordeal,” Dr. Jadon wrote. Leflunomide should be used with caution in patients with preexisting lung disease or in combination with rituximab and methotrexate, he said.

A third case, presented by Dr. Ahmad A. Al-Shami, was a 51-year-old woman diagnosed with RA at age 37. She was treated initially with steroids and azathioprine, but developed neutropenia, which necessitated withdrawal of the azathioprine. She later was started on sulfasalazine and then methotrexate in dosages of 22.5 mg/wk.

Because the disease remained active she was started on infliximab, but after two doses she developed fever and headache. The results of blood cultures, chest x-ray, and cerebrospinal fluid were normal, so she was restarted on infliximab but 3 months later she was readmitted with dyspnea, erythema nodosum, and ocular pruritus. The TNF blocker was once again stopped.

A chest x-ray at this time showed bilateral hilar lymphadenopathy, pulmonary function testing found reduced gas transfer, and a CT scan of the chest confirmed the hilar lymphadenopathy as well as mediastinal lymphadenopathy. Test results for tuberculosis and fungi were negative.

Transbronchial biopsy showed nonnecrotizing granulomatous inflammation, and she was diagnosed with sarcoidosis and treated with prednisone. “Hitherto there have been two case reports of pulmonary and extrapulmonary sarcoidosis, both in patients on etanercept, and we believe this is the first report on infliximab as a possible cause for sarcoidosis. We should be vigilant for this new adverse event,” wrote Dr. Al-Shami of University Hospitals of Leicester (England).

Finally, a 33-year-old man with stage IVB non-Hodgkin's lymphoma presented following a third cycle of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. He had received a total of 2,190 mg of rituximab in three divided doses given at 21-day intervals, according to Dr. Charlotte M. Ford of the department of hematology, Newham University, London.

He had pyrexia, diarrhea, and a dry cough, along with clinical and radiologic evidence of left lower lobe pneumonia that persisted despite treatment with antibiotics and granulocyte colony-stimulating factor.

Adenovirus was isolated from bronchoalveolar lavage fluid, blood, and stool samples, and despite treatment with immunoglobulin and cidofovir plus intensive supportive care, he died on day 22.

Adenoviridae are lytic DNA viruses with varying degrees of pathogenicity, and infection is rarely fatal in otherwise healthy patients. “To our knowledge, this is the first case of fulminant adenovirus infection following rituximab therapy in doses similar to those used in the treatment of RA. Adenovirus infection should be considered in any patient presenting post rituximab with a febrile illness,” Dr. Ford wrote.

LIVERPOOL, ENGLAND — Serious and even fatal infections continue to occur in patients being treated with tumor necrosis factor-blocking agents and other biologics, emphasizing the need for heightened vigilance.

This was demonstrated in a series of posters presented at the annual meeting of the British Society for Rheumatology. In one case report, a 49-year-old woman with rheumatoid arthritis (RA) who had been treated unsuccessfully with methotrexate, sulfasalazine, leflunomide, and high doses of prednisone was started on etanercept. She developed lesions on her palms and soles typical of pustular psoriasis, and was then switched to infliximab, prednisone, and methotrexate. Following the third infusion she was hospitalized with fever and a widespread vesicular rash, according to Dr. Elizabeth A. Justice of University Hospital Birmingham (England).

The patient's C-reactive protein level was 153 mg/L, but the results of a sepsis screen and chest x-ray were normal. Fluid from the skin vesicles was found to contain herpes simplex virus type 1 (HSV-1).

The TNF blocker was stopped and acyclovir was given in dosages of 800 mg five times daily. The rash began to resolve within 48 hours, and after 2 weeks the acyclovir dosage was reduced to 400 mg twice daily.

Two months later she commenced adalimumab, 40 mg every other week, continuing on acyclovir prophylaxis in dosages of 200 mg every other day, with no recurrence of the HSV lesions.

“This is the first reported case of disseminated cutaneous HSV-1 infection following treatment with infliximab, an unusual adverse reaction we believe to be a direct result of her immunosuppressive therapy,” Dr. Justice wrote.

A second case involved a 49-year-old man with a 14-year history of seropositive nonerosive eosinophilic RA. He presented with shortness of breath but no cough, fever, or chest pain, said Dr. Deepak R. Jadon. The patient had been treated previously with etanercept and adalimumab with limited benefit, and 2 months earlier he had begun treatment with rituximab. He also had previously been on sulfasalazine for 13 years, but 2 months earlier switched to leflunomide, 10 mg/day, plus methotrexate, 15 mg/wk. He developed low-grade fever, tachycardia, dyspnea, and orthopnea, with end-inspiratory crackles audible bilaterally in the mid-lower chest. Arterial blood gases showed saturation of 75% and partial pressure of oxygen of 5.63 mm Hg. He also had neutrophilia and eosinopenia, and his C-reactive protein level was 174 mg/L.

A chest film showed patchy shadowing, and a CT scan revealed extensive ground glass parenchymal abnormalities affecting both mid and lower zones, according to Dr. Jadon of the department of rheumatology, Royal Berkshire Hospital, Reading (England).

Methotrexate and leflunomide were stopped, and calcium folinate (leucovorin calcium), 15 mg four times a day, and cholestyramine, 8 g three times a day, were administered. Three 1-g doses of intravenous methylprednisolone were given, along with amoxicillin with clavulanic acid in doses of 1.2 g intravenously three times daily. (There is no parenteral preparation of amoxicillin with clavulanic acid available in the United States.)

“This is the first-ever reported case of leflunomide-associated pneumonitis in a patient concurrently on rituximab and methotrexate. The patient was diagnosed early, therapy initiated promptly, and he survived the ordeal,” Dr. Jadon wrote. Leflunomide should be used with caution in patients with preexisting lung disease or in combination with rituximab and methotrexate, he said.

A third case, presented by Dr. Ahmad A. Al-Shami, was a 51-year-old woman diagnosed with RA at age 37. She was treated initially with steroids and azathioprine, but developed neutropenia, which necessitated withdrawal of the azathioprine. She later was started on sulfasalazine and then methotrexate in dosages of 22.5 mg/wk.

Because the disease remained active she was started on infliximab, but after two doses she developed fever and headache. The results of blood cultures, chest x-ray, and cerebrospinal fluid were normal, so she was restarted on infliximab but 3 months later she was readmitted with dyspnea, erythema nodosum, and ocular pruritus. The TNF blocker was once again stopped.

A chest x-ray at this time showed bilateral hilar lymphadenopathy, pulmonary function testing found reduced gas transfer, and a CT scan of the chest confirmed the hilar lymphadenopathy as well as mediastinal lymphadenopathy. Test results for tuberculosis and fungi were negative.

Transbronchial biopsy showed nonnecrotizing granulomatous inflammation, and she was diagnosed with sarcoidosis and treated with prednisone. “Hitherto there have been two case reports of pulmonary and extrapulmonary sarcoidosis, both in patients on etanercept, and we believe this is the first report on infliximab as a possible cause for sarcoidosis. We should be vigilant for this new adverse event,” wrote Dr. Al-Shami of University Hospitals of Leicester (England).

Finally, a 33-year-old man with stage IVB non-Hodgkin's lymphoma presented following a third cycle of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. He had received a total of 2,190 mg of rituximab in three divided doses given at 21-day intervals, according to Dr. Charlotte M. Ford of the department of hematology, Newham University, London.

He had pyrexia, diarrhea, and a dry cough, along with clinical and radiologic evidence of left lower lobe pneumonia that persisted despite treatment with antibiotics and granulocyte colony-stimulating factor.

Adenovirus was isolated from bronchoalveolar lavage fluid, blood, and stool samples, and despite treatment with immunoglobulin and cidofovir plus intensive supportive care, he died on day 22.

Adenoviridae are lytic DNA viruses with varying degrees of pathogenicity, and infection is rarely fatal in otherwise healthy patients. “To our knowledge, this is the first case of fulminant adenovirus infection following rituximab therapy in doses similar to those used in the treatment of RA. Adenovirus infection should be considered in any patient presenting post rituximab with a febrile illness,” Dr. Ford wrote.

LIVERPOOL, ENGLAND — Serious and even fatal infections continue to occur in patients being treated with tumor necrosis factor-blocking agents and other biologics, emphasizing the need for heightened vigilance.

This was demonstrated in a series of posters presented at the annual meeting of the British Society for Rheumatology. In one case report, a 49-year-old woman with rheumatoid arthritis (RA) who had been treated unsuccessfully with methotrexate, sulfasalazine, leflunomide, and high doses of prednisone was started on etanercept. She developed lesions on her palms and soles typical of pustular psoriasis, and was then switched to infliximab, prednisone, and methotrexate. Following the third infusion she was hospitalized with fever and a widespread vesicular rash, according to Dr. Elizabeth A. Justice of University Hospital Birmingham (England).

The patient's C-reactive protein level was 153 mg/L, but the results of a sepsis screen and chest x-ray were normal. Fluid from the skin vesicles was found to contain herpes simplex virus type 1 (HSV-1).

The TNF blocker was stopped and acyclovir was given in dosages of 800 mg five times daily. The rash began to resolve within 48 hours, and after 2 weeks the acyclovir dosage was reduced to 400 mg twice daily.

Two months later she commenced adalimumab, 40 mg every other week, continuing on acyclovir prophylaxis in dosages of 200 mg every other day, with no recurrence of the HSV lesions.

“This is the first reported case of disseminated cutaneous HSV-1 infection following treatment with infliximab, an unusual adverse reaction we believe to be a direct result of her immunosuppressive therapy,” Dr. Justice wrote.

A second case involved a 49-year-old man with a 14-year history of seropositive nonerosive eosinophilic RA. He presented with shortness of breath but no cough, fever, or chest pain, said Dr. Deepak R. Jadon. The patient had been treated previously with etanercept and adalimumab with limited benefit, and 2 months earlier he had begun treatment with rituximab. He also had previously been on sulfasalazine for 13 years, but 2 months earlier switched to leflunomide, 10 mg/day, plus methotrexate, 15 mg/wk. He developed low-grade fever, tachycardia, dyspnea, and orthopnea, with end-inspiratory crackles audible bilaterally in the mid-lower chest. Arterial blood gases showed saturation of 75% and partial pressure of oxygen of 5.63 mm Hg. He also had neutrophilia and eosinopenia, and his C-reactive protein level was 174 mg/L.

A chest film showed patchy shadowing, and a CT scan revealed extensive ground glass parenchymal abnormalities affecting both mid and lower zones, according to Dr. Jadon of the department of rheumatology, Royal Berkshire Hospital, Reading (England).

Methotrexate and leflunomide were stopped, and calcium folinate (leucovorin calcium), 15 mg four times a day, and cholestyramine, 8 g three times a day, were administered. Three 1-g doses of intravenous methylprednisolone were given, along with amoxicillin with clavulanic acid in doses of 1.2 g intravenously three times daily. (There is no parenteral preparation of amoxicillin with clavulanic acid available in the United States.)

“This is the first-ever reported case of leflunomide-associated pneumonitis in a patient concurrently on rituximab and methotrexate. The patient was diagnosed early, therapy initiated promptly, and he survived the ordeal,” Dr. Jadon wrote. Leflunomide should be used with caution in patients with preexisting lung disease or in combination with rituximab and methotrexate, he said.

A third case, presented by Dr. Ahmad A. Al-Shami, was a 51-year-old woman diagnosed with RA at age 37. She was treated initially with steroids and azathioprine, but developed neutropenia, which necessitated withdrawal of the azathioprine. She later was started on sulfasalazine and then methotrexate in dosages of 22.5 mg/wk.

Because the disease remained active she was started on infliximab, but after two doses she developed fever and headache. The results of blood cultures, chest x-ray, and cerebrospinal fluid were normal, so she was restarted on infliximab but 3 months later she was readmitted with dyspnea, erythema nodosum, and ocular pruritus. The TNF blocker was once again stopped.

A chest x-ray at this time showed bilateral hilar lymphadenopathy, pulmonary function testing found reduced gas transfer, and a CT scan of the chest confirmed the hilar lymphadenopathy as well as mediastinal lymphadenopathy. Test results for tuberculosis and fungi were negative.

Transbronchial biopsy showed nonnecrotizing granulomatous inflammation, and she was diagnosed with sarcoidosis and treated with prednisone. “Hitherto there have been two case reports of pulmonary and extrapulmonary sarcoidosis, both in patients on etanercept, and we believe this is the first report on infliximab as a possible cause for sarcoidosis. We should be vigilant for this new adverse event,” wrote Dr. Al-Shami of University Hospitals of Leicester (England).

Finally, a 33-year-old man with stage IVB non-Hodgkin's lymphoma presented following a third cycle of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy. He had received a total of 2,190 mg of rituximab in three divided doses given at 21-day intervals, according to Dr. Charlotte M. Ford of the department of hematology, Newham University, London.

He had pyrexia, diarrhea, and a dry cough, along with clinical and radiologic evidence of left lower lobe pneumonia that persisted despite treatment with antibiotics and granulocyte colony-stimulating factor.

Adenovirus was isolated from bronchoalveolar lavage fluid, blood, and stool samples, and despite treatment with immunoglobulin and cidofovir plus intensive supportive care, he died on day 22.

Adenoviridae are lytic DNA viruses with varying degrees of pathogenicity, and infection is rarely fatal in otherwise healthy patients. “To our knowledge, this is the first case of fulminant adenovirus infection following rituximab therapy in doses similar to those used in the treatment of RA. Adenovirus infection should be considered in any patient presenting post rituximab with a febrile illness,” Dr. Ford wrote.