Discussion
Calcium channel blockers and statins have been rarely associated with
leukocytoclastic vasculitis, with only a few case reports in the
literature.2-6 Of calcium channel blockers, only
diltiazem,3 lercarnidipine,4 and
amlodipine5 have been implicated. We present a case of
leukocytoclastic vasculitis associated with atorvastatin and verapamil.
Using the Naranjo scale,7 this case scored five
points, making it a probable association. To the best of our knowledge,
this represents the first formal report of leukocytoclastic vasculitis
associated with verapamil, and only the second report associated with
atorvastatin.2
Given both medications were started and ceased simultaneously, it is
unclear whether the inciting agent was verapamil, atorvastatin, or the
combination. It is well recognised that verapamil and atorvastatin
interact via CYP3A4 enzyme and P-glycoprotein
inhibition.8 In this case, use of this combination may
have increased the concentration of either drug to supratherapeutic
levels and therefore increased the risk of inducing leukocytoclastic
vasculitis – assuming a dose-dependent mechanism.
We postulate that the leukocytoclastic vasculitis resulted from a type
III hypersensitivity reaction – where drug-induced aberrant antibody
production leads to immune complex formation and deposition in small
vessels causing vasculitis – thought to be the general mechanism in
drug-induced leukocytoclastic vasculitis.9 This is
supported by positive IgM and complement staining on immunofluorescence,
skin-limited disease, and rash onset within the typical window of seven
to ten days after commencing medications.1
However, the patient also had typical features of mixed
cryoglobulinaemic vasculitis – the purpuric rash with leukocytoclastic
vasculitis, C4 hypocomplementaemia, elevated RF and type II
cryoglobulinaemia with polyclonal and monoclonal IgM components – which
would also account for positive IgM and C3 staining on
immunofluorescence studies. Cryoglobulinaemia is most likely secondary
to Sjogren’s syndrome given the recognised
association.10 Given the temporal relationship between
initiation of the medications and development of leukocytoclastic
vasculitis, a second postulated mechanism is drug-induced augmentation
of cryoglobulinaemia – leading to an immune complex-mediated flare of
cryoglobulinaemic vasculitis.10 To the best of our
knowledge, this would be the first reported case of a cryoglobulinaemic
vasculitis flare associated with atorvastatin and verapamil.
It is possible that both mechanisms contributed in this case. Given the
vasculitis was skin-limited, we favour the former hypersensitivity
reaction as the predominant mechanism over a drug-induced flare of
cryoglobulinaemic vasculitis – as this typically exhibits joint, renal
and neurological manifestations,10 which were absent
in this patient.
Future research into molecular mechanisms would be beneficial to better
understand the properties of certain medications which mediate
autoimmunity and clarify genetic susceptibility to drug-induced
vasculitis.9
In summary, we present a case of biopsy-proven leukocytoclastic
vasculitis associated with verapamil and atorvastatin. We postulate the
mechanism to be a type III hypersensitivity reaction or a drug-induced
flare of cryoglobulinaemic vasculitis secondary to Sjogren’s syndrome.
This case report highlights the need to carefully consider drug
interactions and monitor for rare adverse effects after initiating the
relatively commonly prescribed medications of atorvastatin and verapamil
– particularly in patients with autoimmune disease.