Rituximab ameliorated PR3-ANCA positive vasculitis with rheumatoid
arthritis simultaneously
Akihiro Yamada1 Ayuko Sogabe1Yasuaki Okuda1
1Dohgo Spa Hospital Center for rheumatic diseases
Ehime, Japan
Correspondence
Akihiro Yamada Center for rheumatic diseases Dogo Spa Hospital Matsuyama
dohgo-himezuka otsu 21-21 Japan
E mail:akyamada8@hotmail.com
Abstract
We treated PR3-ANCA positive vasculitis patient with bilateral ischemic
peroneal nerve paralysis accompanying rheumatoid arthritis. Pathology
showed rare to mild vasculitis. Along with PR3-ANCA amelioration, the
level of complement 3, anti-CCP and neurological disability normalized
simultaneously responding to rituximab (anti-CD20 monoclonal antibody
RTX) therapy. This could be clue to clarify the shared pathogenic
pathway of PR3-ANCA vasculitis and rheumatoid arthritis
Key Words
PR3-ANCA positive vasculitis, rheumatoid arthritis, Rituximab
Key clinical message
We treated PR3-ANCA positive vasculitis patient with rheumatoid
arthritis. By applying monoclonal antibody therapy patients suffering
more than one collagen disease are relieved at the same time from
collagen diseases. That is pathogenic pathways are shared among collagen
diseases.
Introduction
PR3-ANCA positive vasculitis is generally known as granulomatosis with
polyangiitis (GPA) with autoimmune small vessel necrotization. The
clinical manifestations of GPA usually include in paranasal sinuses,
lung and kidney. We treated a PR3-ANCA positive vasculitis presenting
rare manifestation of ischemic peroneal nerve paralysis complicated
with rheumatoid arthritis by monoclonal antibody (rituximab) therapy.
To our knowledge, successful RTX therapy against PR3-positive vasculitis
with rheumatoid arthritis at the same time has never been reported in
literature to date.
Case presentation
An eighty-year-old female admitted to our hospital on
25st Jul in 2014 with intermittent fever above 39.0
centigrade degree for the last a few months. In previous hospital, she
was diagnosed development of rheumatoid arthritis (Stage Ⅴ Class Ⅲ, four
swollen joints and seven tender joints) and intake of methotrexate was
up to 6mg from 4mg/week. Nevertheless, morning stiffness, joint pain of
bilateral shoulder, elbow, wrist and fever continued. On admission to
our hospital computed tomography showed infiltrative shadow in right
lower bronchi and bronchiectasia presenting the history of
paragonimiasis. First we suspected bronchilitis of bacterial infection
and administered antibiotics (Tazobactam/Piperacillin) for two weeks in
vain. Several days after admission to our hospital, she bled slightly
from right nasal cavity once. As the level of titer of antibody to
myeloperoxidase 3 showed so high soon, we suspected GPA secondly
(Table). On 1st Sep we biopsied right peroneal
paralytic vasculitic lesion with disability of dorsal flexion caused by
vasculitic ischemia. She presented slight nasal bleeding, intermittent
fever, body weight loss polyneuritis of lower extremities. Pathological
examination showed pauci-immune vasculitis and granuloma is formed outer
side of adventitia of vasculitis leading to the diagnosis of PR3-ANCA
positive vasculitis (Fig.4) clinically
(1).
On 17th Sep, 24th Sep and
1st Oct, this patient received 495mg of rituximab
standard loading therapy. Three days after third administration, she
experienced melena diagnosed as cytomegalovirus colitis. Valgancyclovir
was prescribed and recovered soon. On 19th Feb, for
maintenance therapy, 495mg of RTX was executed with valgancyclovir
(Fig1). With this loading therapy, she was afebrile caused by
ANCA-associate vasculitis and she got better from swollen and tender
joint of rheumatoid arthritis. Four months after admission her
rheumatoid arthritis flared, we add methotrexate. From admission to our
hospital she was taking physical therapy with ankle supportive devices.
Three years after RTX therapy her peroneal nerve paralysis steadily
recoverd to fair (3/5) from trace (1/5) of manual muscle test.
Discussion
The aetiological background HLA genes of GPA is reported HLADPB1
*04:01(2,
3). Of this patient, HLADPB1 is *04:02:01
and *05:01. It is unique to this patient.
Computed tomography didn’t show vasculitic lesions in nasal and
maxillary sinuses in spite of nasal bleeding nor lung field. This didn’t
show respiratory involvements. Urinalysis showed no proteinuria nor
hematuria (Table). She was suffering intermittent fever for at least a
few months and lost bodyweight from about 50kg to 40kg for the six
months before hospitalization. She was aware of paralytic disability of
dorsal flexion of both ankles. Pathological examination from suffered
peroneal artery revealed thrombotic or apparent granulomatous tissue in
adventitia suggesting umbiguous GPA. In case of GPA, granulomatous
tissue is in the elastic lamina media. The titer of PR-3 ANCA is high
(170 U/ml). We conclude that she is suffering PR3-ANCA positive
vasculitis associated with rheumatoid arthritis on both lower legs.
Immune histopathological examination showed pauci-immune vasculitis.
That is, CD3 positive T cells and CD68 positive or CD163 positive
macrophages apparently invade. CD138 positive plasma cells existed outer
area of adventitia. C3 staining was slightly positive.
It is difficult to differentiate histology between GPA and rheumatoid
vasculitis. Rheumatoid vasculitis has serological feature of lower level
of circulating immune complex, von Willebrand factor antigen, ICAM-1,
VCAM, E-selectin c fibronectin, IgM RF, IgG RF and IgA RF compared with
rheumatoid arthritis(4). In this case we
couldn’t detect immune complexes, IgG RF on admission (Table).
Rheumatoid vasculitis is important different diagnosis of
ANCA-associated vasculitis. Hypocomplementemia is shared among GPA,
rheumatoid vasculitis and systemic lupus erythematosus. But the titer of
anti-PR3 ANCA is high, pauci-immune vasculitis is eminent and no
circulating immune complex, no symptom suggesting SLE. From these
results, we diagnosed granulomatosis with polyangiitis complicated with
rheumatoid arthritis.
She was afebrile just after taking first RTX infusion on
17th September. The titer of anti-PR3-ANCA decreased
from 142U/ml to 78.4U/ml in four months. We were to add administering
standard dose of RTX every 6 months as maintenance therapy
(5). The level of titer of anti-PR3-ANCA
gradually went down again with maintenance RTX therapy to 85U/ml
(1st Apr). Hypocomplementemia was gradually
ameliorating. Among complements, C3 went up to normal range on
18th Nov. C4 was recovering slowly
(2nd Feb) (Fig2). GPA activates alternative pathway of
complement(6). ANCA associated renal
lesion also related to complement
pathway(7). GPA could be reflecting the
level of C3.
Clinical symptom of rheumatoid arthritis was getting better with loading
RTX(Fig 3). The neurological recovery of standard maintenance therapy of
RTX against GPA is not well known. Neurological deficit of
polymononeuritis seems to following amelioration of vasculitis. AAV
often occurs with significant delay from the first rheumatological
manifestations(8). Preceding mechanism of
complication of AAV with RA is genetic disposition. The points are HLA
region, PTPN22
((9) (10) (11) (12)),
polymorphism of uteroglobin (13) and of
NF-κB2.
The risk of lymphoproliferative disorder is higher than general
population with or without reactivation of EB virus with methotrexate
(14). We couldn’t detect EB virus
activation nor abnormal accumulation of radioisotope from PET CT on
admission.
For the six months of RTX therapy, granulomatosis of polyangiitis was
improving slowly. The level of complement is normalizing monthly. In
patients with MPO-ANCA related nephropathy low level of C3 means poor
prognosis (15) . This case vasculitis is
mild and localized lower legs atypically. If we could follow the natural
course of this patient, symptoms of nose, lung, kidney lesions could
occur afterward. Federico reported the BVAS is an excellent tool for
assessing the in-ICU mortality risk of patients with systemic vasculitis
(16). In case of senile patient adverse
event of RTX is more important to mortality than BVAS assessment. We
need more sensitive marker of granulomatosis of polyangiitis than
MPO-ANCA. With the improvement of PR3-ANCA positive vasculitis with RTX
therapy, serological data reflecting RA activity were getting better
especially in loading phase (17).
Conclusion
We treated PR3-ANCA positive vasculitis patient with rheumatoid
arthritis. This patient got better from both collagen diseases
simultaneously. This could be clue to clarify the shared pathogenic
pathway of PR3-ANCA vasculitis and rheumatoid arthritis.
Acknowledgments
Thanks to Eijiro Adachi for biopsying vasculitic lesion of peritoneal
neuritis in left lower limb.
Thanks to Tatsuhiko Miyazaki for immunostaininig of biopsied specimens.
Published with written consent of the patient.
Conflict of interest
None.
Author Contributions
YA, SA and OY performed the patient care and collected clinical
information and blood samples. YA and OY coordinated this study and
wrote the paper.
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