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Treating vasculitis with conventional immunosuppressive agents

November 1, 2012|Cleveland Clinic Journal of Medicine
David Jayne, MD, FRCP
Author and Disclosure Information

David Jayne, MD, FRCP
Director, Vasculitis and Lupus Clinic, Addenbrooke’s Hospital, Cambridge, UK

Correspondence: David Jayne, MD, FRCP, Vasculitis and Lupus Clinic, Box 57, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ; dj106@cam.ac.uk

Dr. Jayne reported that he has received research grant support from Roche/Genentech and Vifor Pharma.

This article was developed from an audio transcript of Dr. Jayne’s presentation at the “New Directions in Small-Vessel Vasculitis: ANCA, Target Organs, Treatment, and Beyond” symposium held at Cleveland Clinic on May 4, 2011. The transcript was formatted and edited by Cleveland Clinic Journal of Medicine staff for clarity and conciseness, and was then reviewed, revised, and approved by Dr. Jayne.

ABSTRACTStandard therapy for granulomatosis with polyangiitis and other vasculitides is a combination of cyclophosphamide and glucocorticoids. Although most patients achieve remission, relapses and treatment-related morbidities are common. Clinical trials have yielded a wealth of data about less toxic alternatives to standard therapy, including new agents and methods of delivery. All aim to reduce long-term exposure to cyclophosphamide and glucocorticoids and so maintain safety while effectively preventing relapse. Individualized evaluation of risk and treatment selection will help maximize effectiveness and minimize toxicity.

EVALUATING RISK AND CHOOSING THERAPIES

Figure. Azathioprine and methotrexate have comparable efficacy in maintaining remission (A).15 The relapse rate with mycophenolate mofetil, on the other hand, is nearly double that observed with azathioprine (B).16
Considering all of the available data, the question arises regarding what to prescribe for patients who present in a variety of contexts. On the basis of evidence and consensus, the European League Against Rheumatism (EULAR) has published recommendations for the evaluation, investigation, treatment, and monitoring of patients with primary, small-vessel,12 large-vessel,13 and ANCA-associated14 vasculitides (see “Summary of treatment recommendations”).15–20

CONSIDERATIONS IN CHOOSING REMISSION THERAPY

Overall, when planning remission therapy and its duration, clinicians must balance the efficacy of CYC and glucocorticoids against their toxicity. Close monitoring and the patient’s capacity to adhere to instructions are two critical issues. Other important considerations include the risk and consequences of relapse, which vary in different circumstances, and the association of cancer with CYC therapy.

Relapse risk is variable

Certain patients are at higher risk of relapse than others. Patients with GPA or proteinase-3-ANCA–positive disease are at higher relapse risk than those who have MPA. ANCA-positive disease in remission or rising ANCA markers both increase the risk of relapse. Ear, nose, throat, and lung diseases increase the likelihood of relapse. Patients with GPA who are Staphylococcus aureus carriers have increased risk. Serum creatinine levels of 2.0 to 3.0 mg/dL at the end of induction therapy should arouse concern about renal relapse.

Most relapses affect the ear, nose, and throat system and do not threaten vital organs. Relapse does not increase the risk of end-stage renal disease or death.

Consider mortality and cancer data

Although the strongest predictor of early death is infection, advanced age and renal impairment also predict death. Chronic kidney disease stage at entry and glomerular filtration rate significantly predict mortality.21 More than 36 g CYC (equivalent to 9 to 12 months of standard oral therapy) increases the risk of bladder cancer 10-fold and myeloid leukemia 60-fold, but the cancer risk is time-dependent; malignancy requires 12 years on average to emerge.22

CONCLUSION

Cyclophosphamide in combination with glucocorticoids remains the standard therapy for GPA and related vasculitides, despite the risk of significant treatment-related comorbidities. Several strategies can be employed to reduce exposure, such as sequential withdrawal of CYC and IV administration. The optimization of glucocorticoid dosing will be a major research focus in the next decade. Newer agents may improve the maintenance of remission; for example, azathioprine and methotrexate show equal efficacy and safety, while MMF is less effective. When planning remission maintenance therapy, the relapse risk should be considered carefully because it varies among clinical scenarios. Other factors in the decision include the consequences for the patient, monitoring requirements, and the patient’s ability to understand and adhere to instructions.

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