February 2008
Fig.4
Fig.5
Fig.6
DIAGNOSIS: Wegener's Granulomatosis
Histology: Leukocytoclastic vasculitis with fibrinoid
necrosis (Figures 4-6)
Clinical course: After his admission to the hospital,
the patient developed respiratory distress and was intubated.
Bedside bronchoscopy showed evidence of Wegener's granulomatosis,
further supporting the preceding skin biopsy and lab findings.
The patient was started on Cytoxan and Solumedrol, and subsequently
developed pancytopenia that was attributed to his Cytoxan. He
eventually became bactermic and passed away from overwhelming
sepsis.
Discussion: Wegener's granulomatosis is classically
described by necrotizing granulomas of the upper and lower respiratory
tract, necrotizing angiitis of small and medium sized blood vessels,
and necrotizing glomerulonephritis. Prevalence rates are estimated
at 3 per 100,000, without any gender based predilection (1).
Despite the classic triad mentioned above, Wegener's granulomatosis
can affect many different organs. Manifestations of respiratory
involvement include sinusitis, nasal septal perforations, rhinorrhea,
hemoptysis, and dyspnea. The glomerulonephritis seen in Wegener's
granulomatosis is highly variable. The disease can be indolent,
or very aggressive leading to end stage renal disease. Progression
to end stage disease can be very rapid and occur in just a few
weeks. Cutaneous findings affect 45-50% of patients with WG,
and include palpable purpura, hemorrhagic pustules, pydoderma
gangrenosum-like lesions, subcutaneous nodules that may or may
not ulcerate, and petechiae. Mucous membranes may also be involved,
typically in the form of oral and nasal ulcerations, epistaxis,
and hypertrophic gingivitis ("strawberry gums") (2).
Musculoskeletal involvement is indicated by myalgias, arthralgias,
and even a fixed or migratory mono or polyarthritis.
The diagnosis of Wegener's granulomatosis is based on clinical,
laboratory, and histological findings. The presence of c-ANCA
along with the above clinical findings helps to solidify a diagnosis.
Approximately 75-80% of WG patients are c-ANCA positive. Histopathology
is generally nonspecific and usually shows evidence of a leukocytoclastic
vasculitis.
As represented in this case, the standard treatment regimen for
severe, active Wegener's granulomatosis consists of cyclophosphamide
and a corticosteroid. Oral cyclophosphamide has been used in
the past, but given the side effect profile, namely an increased
risk of bladder cancer and pancytopenia, recent studies have examined
the efficacy of pulse dosed therapy. Preliminary data from a recent
randomized control trial (CYCLOPS) showed that disease free periods
did not differ between the oral cyclophosphamide group and the
intravenous cyclophosphamide group (3). For less severe disease,
Methotrexate combined with corticosteroids is an alternative option.
In order to reduce relapse rates, prolonged immunosuppressive
thereapy is recommended. Again, the focus is to reduce the duration
of cyclophosphamide therapy, by switching to an alternative agent
once remission is achieved. Aziathioprine, Methotrexate, Leflunomide,
and Trimethoprim/Sulfamethoxazole, combined with a tapered dose
of oral corticosteroid have all been found as effective options
for maintenance therapy (4,5).
References:
1. Fitzpatrick's Dermatology in General Medicine, 5th ed.
(Freedberg IM, Eisen AZ, Wolff K, Austen KF, Goldsmith LA, Katz
SI eds.). New York: McGraw-Hill, 1999.
2. Andrews' Diseases of the Skin: Clincal Dermatology, 10th ed.
(James WD, Berger TG, Elston DM). Elsevier Inc, 2006.
3. de Groot K, Jayne D, Tesar V, SavageC.Randomised controlled
trial of daily oral versus pulse cyclophosphamide for induction
of remission in ANCA-associated systemic vasculitis. Kidney Blood
Press Res 2005; 28:195.
4. Jayne D, Rasmussen N, Andrassy K, et al. A randomized trial
of maintenance
therapy for vasculitis associated with antineutrophil cytoplasmic
autoantibodies.
N Engl J Med 2003; 349:3644.
5. Hellmich B, Lamprecht P, Gross WL. Advances in the therapy
of Wegener's granulomatosis. Curr Opin Rheumatol.2006 Jan;18(1):25-32.
Case presented by Drs. Jarod Conley & Liana Abramova
Special thanks to Dr. Nathan Walk for the histopathology pictures.
