Remission of psoriasis and psoriatic arthritis during bevacizumab therapy for renal cell cancer.

Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), is employed for treatment of several cancers and retinopathies. Although previous reports of remission of psoriasis with bevacizumab do exist, but its current experience for psoriatic arthritis (PsA) is still limited. In this report, we describe a patient with metastatic renal cell cancer, psoriasis and PsA, who experienced a complete remission of psoriasis and PsA during bevacizumab therapy without any other management for psoriasis and PsA. We also found a flare up of his psoriatic disease after switching to other kinase inhibitors like sorafenib or sunitinib. This suggests that bevacizumab might have a promising future in the treatment of psoriasis and PsA.

What was known?

Bevacizumab is used to treat several cancers. There is only one published report that describe a patient with metastatic colon cancer and psoriasis who experienced complete remission of psoriasis during treatment with bevacizumab and combination chemotherapy without any other treatment for psoriasis.

Introduction

Apart from cancer growth and metastasis, neovascularization or angiogenesis is implicated in a variety of pathological conditions like retinopathies, psoriasis and inflammatory arthritis. Vascular endothelial growth factor (VEGF) is the best characterized angiogenic peptide and its selective inhibition by bevacizumab (Avastin™), a monoclonal antibody against VEGF, has been shown to be effective in different cancers, diabetic retinopathy and retinal macular degeneration.[1] VEGF is also overexpressed in psoriatic lesions,[2] plasma[3] and synovium of inflammatory arthritis[4] and correlates with disease activity.[5] Bevacizumab therapy for colon cancer have been found to be effective in complete resolution of psoriatic skin lesions,[6] however there are no such case reports on the effectiveness of bevacizumab in psoriatic arthritis (PsA). Herein, for the first time, we describe the case of a patient with psoriasis and PsA who had improvement of his skin lesions and arthritis during bevacizumab therapy for metastatic renal cancer.

Case Report

A 65-year-old male with a 40-year history of psoriasis and 30-year history of PsA presented with recurrence of metastatic renal cell carcinoma involving left adrenal gland, lung and bone in August 2004, 7 years following a left radical nephrectomy for a Fuhrman grade-3 renal cell carcinoma involving left kidney, renal vein, renal hilum and lymph nodes. During this presentation, the patient had active synovitis of wrists, metacarpo-phalangeal (MCP), proximal inter-phalangeal (PIP), distal inter-phalangeal (DIP) joints with disease activity score (DAS) 28 of 6.98 denoting high disease activity and extensive psoriatic lesions on face, scalp, trunk and extremities covering more than 50% of body surface area (BSA). The patient received 7.5 mg/day methotrexate for his psoriasis and arthritis without remission for about 20 years. After diagnostic workup, he was started on a combination of systemic bevacizumab (10 mg/kg body weight every 2 weeks) and subcutaneous Interferon-alpha (IFN-α) (9 million units three times weekly) on November 2004. A remarkable improvement in the patient's skin lesions (<1% BSA) occurred 3 months after the first infusion. After 24 months of this combination chemotherapy, the patient followed up with complete clearance of skin lesions and DAS28 of 2.8, denoting low disease activity. On February 2007, in spite of stabilization of his metastatic disease and clinical remission of psoriasis and PsA, due to asymptomatic but profound proteinuria (7 g/24 hr) with the combination therapy, the patient was switched to sorafenib (400 mg twice a day) and then to sunitinib (50 mg/day). However, on August 2007, the patient presented with metastatic renal cancer involving the right kidney and a relapse of psoriasis (>50% BSA) and PsA with DAS28 of 7.15. Sunitinib and methotrexate were stopped due to rising serum creatinine levels and he was restarted on bevacizumab monotherapy at a lower dose (10 mg/kg body weight every 4 weeks) due to his rising serum creatinine levels. On follow-up after 3 months of bevacizumab re-initiation, there was remission of his psoriatic skin lesions and synovitis and his serum creatinine leveled off. This treatment had continued since then owing to tumor stabilization and remission of psoriasis and PsA without any serious side effects. This remission can be attributed to the effect of bevacizumab only, as the patient went into remission then relapse and again into remission after bevacizumab initiation, stoppage and re-initiation respectively, more so in the absence of IFN-α and methotrexate during re-initiation therapy.

Discussion

The transformation of synovial tissue to fibrovascular pannus and its tumor-like expansion is related to neovascularization or angiogenesis. Increase in capillary density also induces lymphocytes homing perpetuates inflammation. Studies have shown that VEGF levels are increased in serum and synovium of rheumatoid arthritis (RA) as compared to osteoarthritis patients and the levels correlate with disease severity.[7] Moreover, there is no significant difference between the levels of VEGF in between RA and PsA, two forms of inflammatory arthritis, thus establishing a contributory role of angiogenesis in inflammation and joint destruction.[4]

Inhibition of VEGF is an area of dynamic research and effectiveness of anti-VEGF therapy in different in vivo models of arthritis is quite appealing.[8] Bevacizumab binds to VEGF-A and its isoforms, inhibits interaction of VEGF with its receptors (VEGFR), thereby causing inhibition of new vessel formation and regression of existing vasculature. In a review by Khong et al.[9] it was suggested that inhibition of angiogenesis by bevacizumab might be a potential therapeutic option for rheumatoid synovium, as the pathological hallmark of pannus is angiogenesis. Quite in accordance with previous studies, we report a case which showed incredible improvement in psoriatic skin disease[6] and arthritis after initiation and re-initiation of bevacizumab therapy for renal cancer. However, one distinct case study was reported where a patient of chronic psoriasis developed PsA after initiation of bevacizumab therapy for brain tumor.[10] Although bevacizumab is generally well tolerated, several common adverse effects, including hypertension, proteinuria, impaired wound healing, thrombosis, perforation of nasal septum, leukoencephalopathy, rash, infusion-related hypersensitivity reactions and some fatal adverse events (hemorrhage, pulmonary embolism, neutropenia, gastrointestinal tract perforation, and cerebrovascular accident) raise concerns.[11] However, the risk of adverse events with bevacizumab increases significantly when combined with other chemotherapeutic agents like platinum and taxanes. It also depends on the tumour types where bevacizumab has been used and not on its dose.[12] Moreover, most of the impending serious complications of bevacizumab can be averted by close monitoring of patient-specific variables, which should be measured at baseline and then at predetermined intervals throughout the course of therapy to maximize patient safety.

Thus, before arriving at a definite conclusion regarding the efficacy of bevacizumab therapy in psoriasis and PsA, further pre-clinical and clinical studies are required to determine its safety and efficacy in these patient populations.

What is new?

Although, previous reports of remission of psoriasis with Bevacizumab and other combination chemotherapy do exist, but its current experience for psoriatic arthritis (PsA) is still limited. In this report we have shown that there is complete remission of both Psoriasis and PsA after initiation of Bevacizumab therapy. Moreover, stoppage of Bevacizumab led to relapse and its re-initiation as a monotherapy resulted in remission of the psoriatic disease, which redefines its antipsoriatic role.