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TABLE 1. HLA tissue typing
Patient
I/1
I/2
I/3
II/1
II/2
II/3
II/4
357
The authors have declared no conflicts of interest.
A
B
Cw
DRB1
1/11
1/2
2/11
2/30
2/30
2/30
26/30
51/57
14/57
18/51
8/62
8/41
8/62
8/38
2/6
6
07/11
07/11
11
04
04/13
04
04/13
3
3
I/1, father; I/2, daughter; I/3, healthy sister.
II/1, younger sister; II/2, her healthy daughter; II/3, older sister;
II/4, her healthy son.
she was treated with local CS for keratoconjunctivitis. Her father
died at the age of 59 yr of pulmonary cavitation. Admission
laboratory data showed creatinine 180 mol/l, perinuclear (p)ANCA antimyeloperoxidase (anti-MPO) positive (72.66 U/ml) and
erythrocyturia. A chest X-ray showed diffuse interstitial thickening. An RB showed a pauci-immune crescentic GN. The patient
was diagnosed with microscopic polyangiitis (MPA) with renal,
lung, eye, skin and musculoskeletal involvement. Treatment with
CS and CYC led to remission, creatinine decreased to 112 mol/L.
This patient’s sister (56 yr old) had suffered from polyarthralgia,
fever and anorexia for 2 months prior to admission in October
2004. Her erythrocyturia persisted after antibiotic treatment.
The initial work-up revealed creatinine 160 mol/l and p-ANCA
anti-MPO positive (41.72 U/ml). Chest X-ray was negative. An RB
confirmed the diagnosis of MPA. Induction therapy with CS and
CYC led to remission, creatinine dropped to 81 mol/l.
This observation illustrates the diversity of the AAV determined
by the sites and the activity/chronicity of organ involvement.
Generalized ‘flu-like’ manifestation, ENT or respiratory symptoms
lead mostly to antibiotic treatment. The detection of erythrocyturia often prompts another course of antibiotics and/or
urological work-up. A temporary spontaneous remission of the
symptoms further delays the diagnosis. As the disease persists, it
may start to resemble a malignancy. Nevertheless, an erroneous
diagnosis of carcinoma in the setting of a histological diagnosis of
cutaneous vasculitis is a grave mistake. However varied the AAV
may be, their clinical presentation in the two families described was
in some aspects very similar. Both the father and daughter had
WG, c-ANCA and a history of ENT involvement that preceded
dialysis-requiring renal failure with some corresponding features
in renal histology. The two sisters both had MPA, p-ANCA, nonspecific constitutional symptoms and histological and laboratory
evidence of a rather slower decline in the renal function. We were
unable to obtain objective data on their father. Nevertheless,
the daughters described a suggestive picture of a pulmonary
involvement in AAV. The difference in the presentation in the two
families shows that PR3-ANCA and MPO-ANCA are markers of
different diseases within the spectrum of AAV with a more acute
presentation of patients with PR3-ANCA [1–3]. Last, but not
least, the presented case reports raise the question of a familial
predisposition to AAV. A number of familial cases have been
described. A shared environment with exposure to silica has been
thought to explain the cluster occurrence in some [4], whereas
others have stressed the genetic predisposition [5, 6]. No consistent
HLA association has been identified. Our patients within the
two families shared a similar genetic background (Table 1). As
mutations in the gene encoding -1 antitrypsin (AAT) are more
frequent in patients with AAV [7], we tested all our patients and
found their AAT levels to be within the normal range. Our patients
did not share the same environment. The fact that two members of
the two families fell ill with the same disease and their similar HLA
typing seem to favour the role of a genetic predisposition to AAV.
Z. RIHOVA, E. HONSOVA1, J. ZAVADA, Z. VANKOVA, E. JANCOVA,
J. REITEROVA, V. TESAR
Nephrology Unit, 1st Medical Faculty, Charles University and
1
Pathology Department, Institute for Clinical and Experimental
Medicine, Prague, Czech Republic
Accepted 15 November 2005
Correspondence to: Z. Rihova, U Nemocnice 2, 128 08
Prague 2, Czech Republic. E-mail: [email protected]
1. Franssen CFM, Gans ROB, Arends B et al. Differences between antimyeloperoxidase and anti-proteinase 3 associated renal disease.
Kidney Int 1995;61:80–9.
2. Hauer HA, Bajema IM, Van Houwelingen HC et al. Renal histology
in ANCA-associated vasculitis: differences between diagnostic and
serologic subgroups. Kidney Int 2002;61:80–9.
3. Franssen CFM, Gans ROB, Kallenberg CGM et al. Disease spectrum
of patients with antineutrophil cytoplasmic antibodies of defined
specificity: distinct differences between patients with anti-proteinase 3
and anti-myeloperoxidase autoantibodies. J Intern Med 1998;
244:209–16.
4. Brener Z, Cohen L, Goldberg SJ et al. ANCA-associated vasculitis
in Greek siblings with chronic exposure to silica. Am J Kidney Dis
2001;30:E28.
5. Hull CM, Couser WG, Knostman JD. A familial case of p-ANCA
glomerulonephritis presenting in a father and daughter. Am J Kidney
Dis 2000;35:E23.
6. Nowack R, Lehmann H, Flores-Suarez LF et al. Familial occurrence
of systemic vasculitis and rapidly progressive glomerulonephritis.
Am J Kidney Dis 1999;34:364–73.
7. Callea F, Gregorini G, Sinico A et al. Alpha 1-antitrypsine (AAT)
deficiency and ANCA-positive systemic vasculitis: genetic and clinical
implications. Eur J Clin Invest 1997;27:696–702.
Rheumatology 2006;45:357–359
doi:10.1093/rheumatology/kei264
Advance Access publication 20 December 2005
Infliximab treatment in a patient with rheumatoid
arthritis on haemodialysis
SIR, Anti-tumour necrosis factor (TNF) has been shown to be
very effective in rheumatoid arthritis (RA). Patients with RA with
renal failure are difficult to treat. Special attention is required to
the possible increase in toxicity and to dose adjustment of the drugs
used to treat this disease. We report our experience in treating such
a patient with infliximab, a monoclonal TNF antagonist.
A 45-yr-old female university professor presented in April 2002
with a 2-month history of painful and swollen joints of the small
joints of both hands, wrists, knees, elbows and shoulders
associated with morning stiffness of 2–3 h duration.
In 1984 she was diagnosed with chronic glomerulonephritis of
no obvious cause and in 1985 she had cadaveric renal transplant.
The transplanted kidney was removed in 1995 because of chronic
rejection and since then she has been on regular haemodialysis. In
1996 she was found to have hepatitis C, with a positive polymerase
chain reaction (PCR) test, and was treated with interferon for
6 months. The PCR test became negative at the end of 6 months of
therapy. One year later the liver enzymes increased again and the
hepatitis C PCR test became positive at a high titre. She was again
given interferon for 1 yr, which normalized the liver enzymes. Liver
biopsy done in 1999 showed changes of very early fibrosis only.
The patient has severe allergic reaction to sulpha drugs in
ß The Author 2005. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected]
Letters to the Editor
childhood and had had marked hypertrichosis during treatment
with cyclosporin associated with her kidney transplant.
Physical examination showed very tender and swollen MCPs,
PIPs, wrists, elbows, knees and shoulders. Laboratory investigations revealed positivity for rheumatoid factor of 320 IU, CRP
96 mg/dl, ANA 1:160, and negativity for anti-double-stranded
DNA antibodies. Her ESR was 105 mm/h and haemoglobin was
9.7 gm/dl.
She was treated with small doses of steroids and non-steroidal
anti-inflammatory drugs (NSAIDs) but the response was inadequate. She frequently required joint aspiration and local steroid
injection in different joints. She was tested for anti-cyclic
citrullinated peptides in April 2004 and was positive, at more
than 100 U. In May 2004 she presented with an acute flare, with
very painful, swollen joints of the hands, both wrists, shoulders and
the knees. Her ESR was 93 mm/h and CRP was 96 mg/l. The use of
infliximab was discussed with the patient and this drug was given
at 3 mg/kg at 0, 2 and 6 weeks, and then every 8 weeks. The arthritis
improved remarkably with dramatic reduction of pain, swelling
and improvement of the functional status. After the initial two
infusions she developed post-infusion transient itching that
responded to cetirizine 10 mg daily.
When she was seen in December 2004 she had no significant
stiffness but still had mild swelling of the both knees with little
pain. Her ESR was 34 mm/h and CRP was 28 mg/dl. She was
maintained on infliximab infusions every 8 weeks.
The literature contains little information on the treatment of RA
in patients with end-stage renal failure who are on haemodialysis.
The potential toxicity of the drugs used, such as NSAIDs and
disease-modifying drugs, deserves special attention.
NSAIDs expose dialysis patients to an increased risk of
gastroduodenal ulceration and bleeding, and it is advised that
their use should be limited to short courses [1].
Methotrexate, which is the most commonly used drug and one
of the most effective drugs in RA, is cleared primarily by the kidney
and has been associated with life-threatening complications in a
patient on haemodialysis who was on a small dose [2].
Azathioprine may be used but the dose should be reduced by
50% if the glomerular filtration rate is less than 10% [3]. In
haemodialysis the drug was found to be effectively eliminated,
suggesting that the dose of azathioprine can be maintained if the
patient is on haemodialysis [4].
The hydroxychloroquine dose should be reduced by 50% in
renal impairment [3]. Renal failure predisposes to a higher
incidence of myopathy, neuropathy and cardiac myotoxicity in
patients on hydroxychloroquine [5].
Cyclosporin may be given to patients with renal impairment on
haemodialysis, at the same dose for patients with normal renal
function [3]. A patient with bone marrow aplasia during haemodialysis was reported to improve after treatment with cyclosporin
while he was on dialysis [6].
Leflunomide may be used in patients on haemodialysis and
reduction of the dose does not appear to be required [7].
There are no reports or standards for the use of sulphasalazine
in haemodialysis patients. However, Akiyama et al. reported the
pharmacokinetics of this drug in a gastrectomized patient on
haemodialysis who also had amyloidosis, and found that the drug
metabolites did not differ from those in healthy controls during the
5 days after drug administration [8].
Anti TNF- is a new category of drug used in the treatment of
RA, but very little is known about its use in renal impairment or in
haemodialysis. The three available TNF antagonist are etanercept,
infliximab and adalimumab. Infliximab is a chimeric monoclonal
antibody composed of the human constant region and murine
variable region.
Singh et al. reported a patient with RA who failed to respond to
treatment with several DMARDs and responded well to infliximab
[9]. Yee et al. reported the use of infliximab in complicated
sarcoidosis in a patient who required haemodialysis during the
course of the disease [10]. Although the patient’s symptoms
improved, the clinical course was complicated by the development
of a hypercoagulable state, which improved after discontinuation
of infliximab therapy. Ortiz-Santamaria et al. [11] reported the
use of infliximab in six patients with amyloidosis (related to RA in
five cases and to ankylosing spondylitis in one). Two of the six
patients were on haemodialysis; one developed transient pancytopenia concurrently with renal function impairment and the
infliximab was withdrawn. The other patient did not have any
adverse event but the infliximab therapy was interrupted because
at that time it was not known whether infliximab therapy could
be administered to end-stage renal failure patients requiring
haemodialysis.
Searching the literature, we could not find any other reported
cases of the use of other antagonists in rheumatoid patients with
renal failure on haemodialysis.
Our patient, like the patient of Singh et al., responded very well
to treatment with infliximab and was able to return to her
activities. She tolerated the drug well and did not show any
unusual side-effects, which suggests that patients on haemodialysis
can tolerate this drug and that the drug maintains its efficacy.
The exact pharmacokinetics of infliximab in patients on dialysis
are not known. However, in patients with normal renal function,
infliximab has the lowest volume of distribution among the
available TNF antagonists, which indicates that the distribution
of infliximab outside the blood circulation and the inflamed tissue
is limited [12].
Our case and the case of Singh et al. demonstrate the potential
use of infliximab and possibly other anti-TNF biologicals in the
treatment of rheumatoid patients with end-stage renal failure on
haemodialysis.
Key messages
Rheumatology
358
Infliximab was effective and safe as
monotherapy in a patient with RA on
haemodialysis.
The author has declared no conflicts of interest.
M. HAMMOUDEH
Rheumatology, Hamad Medical Corporation, P.O. Box 3050,
Doha, Qatar
Accepted 18 November 2005
Correspondence to: [email protected]
1. Bardin T, Kuntz D. Dialysis arthropathy. In: Hochberg MC,
Silman AJ, Smolen JS, Weinblatt ME, Weisman MH, eds.
Rheumatology, Vol. 2, 3rd edn. Pittsburgh: Mosby, 2003:1983–6.
2. Boulanger H, Launay-Vacher V, Hierniaux P, Fau JB, Deray G.
Severe methotrexate intoxication in a hemodialysis patient treated for
rheumatoid arthritis. Nephrol Dial Transplant 2001;16:1087.
3. Aronoff GR, Brier M. Prescribing drugs in renal disease. In:
Brenner BM, ed. Brenner and Rector’s The Kidney, Vol. 2. 7th edn.
Philadelphia: Saunders, 2004:2850–70.
4. Schusziarra V, Ziekursch V, Schlamp R, Siemensen HC.
Pharmacokinetics of azathioprine under hemodialysis. Int J Clin
Pharmacol Biopharm 1976;14:298–302.
5. Stein M, Bell MJ, Ang LC. Hydroxychloroquine neuromyotoxicity.
J Rheumatol 2000;27:2927–31.
Letters to the Editor
6. Vega J, Rodriguez M de L, Vasquez A, Torres C. Bone marrow
aplasia during hemodialysis successfully treated with cyclosporin.
Report of one case. Rev Med Chil 2004;132:989–94.
7. Beaman JM, Hackett LP, Luxton G, Illett KF. Effect of hemodialysis on leflunomide plasma concentrations. Ann Pharmacother
2002;36:75–7.
8. Akiyama Y, Fujimaki T, Sakurai Y. Pharmacokinetics of
salazosulfapyridine in a hemodialysis patient. Ryumachi 2003;43:
569–76.
9. Singh R, Cuchacovich R, Huang W, Espinoza L. Infliximab treatment
in a patient with rheumatoid arthritis on hemodialysis. J Rheumatol
2002;29:636–7.
10. Yee AM, Pochapin MB. Treatment of sarcoidosis with infliximab
anti-tumor necrosis factor-alpha therapy. Ann Intern Med
2001;135:27–31.
11. Ortiz-Santamaria V, Valls-Roc M, Sanmari M, Olive A. Anti-TNF
treatment in secondary amyloidosis. Rheumatology 2003;42:1425–6.
12. Nestrov I. Clinical pharmacokinetics of tumor necrosis factor
antagonists. J Rheumatol 2005;74:13–8.
Rheumatology 2006;45:359–360
doi:10.1093/rheumatology/kel006
Advance Access publication 25 January 2006
Bronchogenic carcinoma associated with rheumatoid
arthritis: role of FDG-PET scans
SIR, Lung involvement occurs in 50% of patients with rheumatoid
arthritis (RA). Its forms are variable, pulmonary nodules being
the least frequent [1]. It is occasionally necessary to establish
a differential diagnosis between rheumatoid nodules (RN) and
bronchogenic carcinoma (BC), especially in smokers or immunocompromised patients [1]. There are no clinical or laboratory
data to help with this differentiation and imaging techniques are
not specific enough, which is why histological confirmation is
recommended, either by bronchoscopy, transthoracic fine-needle
aspiration (TFNA) or even surgical biopsy [2]. Positron emission
tomography using 18-fluorodeoxyglucose (FDG-PET) is a noninvasive technique permitting the qualitative and semiquantitative
analysis of tissue metabolic activity, which is increased in BC, and
359
which can guide the diagnosis of a suspected malignant pulmonary
nodule in a patient with RA [3, 4]. We describe two RA patients
with pulmonary nodules in which FDG-PET allowed the diagnosis
and staging of BC, avoiding diagnostic surgical lung biopsy.
The first case was a 64-yr-old woman, a non-smoker, diagnosed
with seropositive RA in functional class I, undergoing treatment
with methotrexate (7.5 mg/week). The physical examination
showed mechanical pain and articulate tumefaction in the wrists
and metacarpal phalanges. Chest X-ray and computed tomography (CT) revealed a nodule measuring 2.1 cm located in the
upper right lobe. Bronchoscopy and TFNA were not conclusive.
FDG-PET discovered abnormal increased activity corresponding
to the location of the pulmonary nodule and hilar region, so
BC was suspected (Fig. 1). Video-assisted thoracoscopy (VAT)
biopsy of the nodule confirmed BC, so a right upper lobectomy and
lymphadenectomy was performed. The definitive histology was
infiltrant adenocarcinoma over an RN with mediastinal nodule
involvement (T2N2M0). The postoperative course was satisfactory
and the patient received adjuvant chemo-radiotherapy.
The second case was a 40-yr-old male, a smoker (30 cigarettes/
day) diagnosed with seropositive RA in functional class II.
Treatment was carried out combining methotrexate (7.5 mg/week)
with leflunomide (20 mg/day). A chest X-ray and CT confirmed
bilateral pulmonary nodules, one of them measuring 1.9 cm, in the
left upper lobe, which bronchoscopy showed was positive for BC.
FDG-PET was done to discard metastases in the rest of the
nodules, and showed abnormal increased FDG activity corresponding only to BC. An upper left lobectomy and biopsies of
the left lower lobe nodules were done. The definitive histology
was infiltrant adenocarcinoma (T2N1M0) and the biopsies of the
lower pulmonary nodules confirmed RN.
The appearance of a pulmonary nodule in a patient with
RA creates a diagnostic dilemma between RN and BC [1, 5].
Pulmonary RN are found in 1% of chest X-rays and up to 20%
in high-resolution CTs [2]. It is frequent in males and smokers
with subcutaneous RN and positivity for rheumatoid factor [1, 2].
Its radiological characteristics are not very specific, with central
cavitation in 50% of cases [2]. They are usually asymptomatic
and do not require treatment, except when there are complications
such as bronchopleural fistula or infection, which are present in up
to 50% of cases [2]. The possibility of developing BC in patients
with RA is higher than in the general population, and the most
FIG. 1. FDG-PET image showing abnormally increased FDG activity corresponding to the right upper pulmonary nodule visualized
on the chest CT scan.
ß The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected]