434

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[6] Belimumab Ding C. an anti-BLyS human monoclonal antibody for potential treatment of inammatory autoimmune diseases. Expert Opin Biol Ther
2008;8:180514.
[7] Bracewell C, Isaacs JD, Emery P, et al. Atacicept, a novel B cell-targeting biological therapy for the treatment of rheumatoid arthritis. Expert Opin Biol Ther
2009;9:90919.
[8] La DT, Collins CE, Yang HT, et al. B lymphocyte stimulator expression in patients
with rheumatoid arthritis treated with tumour necrosis factor antagonists: differential effects between good and poor clinical responders. Ann Rheum Dis
2008;67:11328.

Fabienne Niederer a
Almut Scherer b
Diego Kyburz c
Renate E. Gay a
Steffen Gay a
Beat A. Michel c
Adrian Ciurea c,
a Center of Experimental Rheumatology, University
Hospital, Zurich, Switzerland
b University of Zurich, Zurich, Switzerland
c Department of Rheumatology, University Hospital,
Gloriastrasse 25, 8091 Zurich, Switzerland
Corresponding

author. Tel.: +41 44 255 29 58;

fax: +41 44 255 44 15.
E-mail address: adrian.ciurea@usz.ch (A. Ciurea)

Table 1
Comparison between ovarian failure group and menstruating group.

Age (years)
Age at onset of SLE (years)
Disease duration (years)
Disease activity (SLEDAI)
Age at initiation of CYC
Total cumulative CYC dose,
gm
AFC
AMH levels (ng/ml)

5.6
4.6
2.7
5.9
4.7
2.5

2.4
2.1
2.0
2.4
2.8
3.8

0.01*
0.04*
0.05
0.02
0.01*
0.001**

7.2 1.1
1.8 0.3

8.2
14.8

0.001**
0.001**

28.3
23.5
4.8
10.4
25.7
9.5

4.2 1.1
0.6 0.2

Model

Independent

POF

R2 = 0.74
F = 56.82

Included
Cumlative
dose of CYC
Age

(P < 0.001)

Excluded
Age at
initiation of
CYC
SLEDAI
Anticardiolipin
antibodies

Anti-Mllerian hormone: A marker for ovarian function in

systemic lupus erythematosus patients treated with cyclophosphamide

The occurrence of premature ovarian failure (POF) in systemic

lupus erythematosus (SLE) patients treated with cyclophosphamide (CYC) has been reported variably [1,2]. Plasma levels of
FSH, estradiol or inhibin B are of limited value in predicting the
presence of an ovarian reserve in such patients [3]. Anti-Mllerian
hormone (AMH) has been suggested as good indicator of ovarian
reserve [4] and is considered a more accurate indicator of the presence of ovarian follicles [5]. This study aimed at evaluating the
prevalence of ovarian failure in SLE patients treated with CYC and to
identify the most predictive factors for this treatment complication.
Of the 96 female SLE patients studied from January 2010 through
October 2011; 52 patients had received intravenous CYC therapy
whereas 44 had not. We compared the occurrence of POF in both
CYC treated and non-CYC treated groups of female SLE patients. We
found that SLE patients who were on CYC treatment were signicantly younger, had an earlier disease onset, a lower disease activity
index than SLE patients who never treated with CYC (Table 1).
Within SLE patients treated with CYC therapy, twelve patients
(23.1%) had documented ovarian failure, while none of the patients
who did not receive CYC therapy had developed this complication.
POF was dened as secondary amenorrhea for more than
3 months duration documented with serum level AMH less than
1.26 ng/ml [6]. and Low AFC cut off was set at less than ve follicles
as assessed by transvaginal ultrasound [7].

3.9
3.6
2.0
8.6
3.6
1.4

Dependent

doi:10.1016/j.jbspin.2012.10.004

Keywords:
Systemic lupus erythematosus
Cyclophosphamide
Premature ovarian failure
Anti-Mllerian hormone

Table 2
Determinants of premature ovarian failure by stepwise regression.

Available online 16 November 2012

i n f o

32.5
26.2
6.2
15.6
29.3
11.7

Difference

SLEDAI: systemic lupus eryhtematosus disease activity index; CYC: cyclophosphamide; AFC: antral follicular count; AMH: anti-mllerian hormone.
*
Signicant difference P < 0.05.
**
Signicant difference P < 0.01.

Accepted 4 October 2012

a r t i c l e

Menstruating
patients
(n = 40)
Mean SD

Ovarian failure
patients
(n = 12)
Mean SD

% of
variance

0.520

6.782

0.001

49

0.373

4.812

0.001

21

0.031

0.370

0.710

0.125
0.127

1.828
1.463

0.072
0.149

POF: premature ovarian failure; CYC: cyclophosphamide; SLEDAI: systemic lupus

erythematosus disease activity index.

The presence of POF was signicantly correlated with age of SLE

patients, activity of SLE, age at initiation of CYC treatment, anticardiolipin antibodies and was highly correlated with the cumulative
dose of CYC (r = 0.37, P < 0.005). On the other hand, neither using
of corticosteroids or azathioprine, nor increasing the weight of the
patients was associated with occurrence of POF.
Stepwise regression analysis showed that cumulative CYC dose
and age of SLE patients were the only signicant predictors of POF
among the variables tested (Table 2).
In the literature, there are a few reports commented on the use
of AMH assay in SLE patients [8]. To our knowledge, this is the rst
study to examine AMH levels in Egyptian women with SLE receiving
CYC compared with those who did not receive it.
In conclusion, CYC treated SLE patients having a frequency of
POF of 23.1%. So, for older SLE patients in whom the use of CYC is
warranted, a shorter course and lower dosage could be considered.
Assessment for AMH assay and AFC can be done before initiating
CYC therapy as a better step towards counseling women at risk for
ovarian failure.
Disclosure of interest
The authors declare that they have no conicts of interest concerning this article.
References
[1] Blumenfeld Z, Mischari O, Schultz N, et al. Gonadotropin releasing hormone agonists may minimize cyclophosphamide associated gonadotoxic-

Letters to the editor / Joint Bone Spine 80 (2013) 432440

[2]

[3]

[4]

[5]
[6]
[7]

[8]

ity in SLE and autoimmune diseases. Semin Arthritis Rheum 2011;41:

34652.
Mok CC, Lau CS, Wong RW. Risk factors for ovarian failure in patients with
systemic lupus erythematosus receiving cyclophosphamide therapy. Arthritis
Rheum 1998;41:8317.
Massin N, Gougeon A, Meduri G, et al. Signicance of ovarian histology in the
management of patients presenting a premature ovarian failure. Hum Reprod
2004;19:255560.
Fridn B, Sjblom P, Menezes J. Using anti-Mllerian hormone to identify a good
prognosis group in women of advanced reproductive age. Aust N Z J Obstet
Gynaecol 2011;51:4115.
Durlinger AL, Visser JA, Themmen AP. Regulation of ovarian function: the role of
anti-Mllerian hormone. Reproduction 2002;124:6019.
Gnoth C, Schuring AN, Friol K, et al. Relevance of anti-Mullerian hormone measurement in a routine IVF program. Hum Reprod 2008;23:135965.
Knauff EA, Eijkemans MJ, Lambalk CB, et al. Anti-Mllerian hormone, inhibin B,
and antral follicle count in young women with ovarian failure. J Clin Endocrinol
Metab 2009;94:78692.
Browne H, Armstrong A, Decherney A, et al. Assessment of ovarian function with
anti-Mllerian hormone in systemic lupus erythematosus patients undergoing
hematopoietic stem cell transplant. Fertil Steril 2009;91:152932.

Rasha M. Ghaleb a,
Khaled A. Fahmy b
a Rheumatology and Rehabilitation Department,
El-Minia University, El-Minia, Egypt
b Obstetrics and Gynecology Department, El-Minia
University, El-Minia, Egypt
Corresponding

author. Tel.: +20 01 00 37 79 545;

fax: +20 02/08 62 34 25 03.
E-mail address: Rashaghaleb2000@yahoo.com
(R.M. Ghaleb)

435

2. Observation
A 42 year-old Cambodian woman was followed for an active,
erosive and ACPA positive RA. She was treated with methotrexate
(15 mg/week) and corticosteroids (10 mg/day). Despite this treatment, DAS28 score was 5.2. She had a thyroid carcinoma
contraindicating TNF blockers. Appropriate screening for hepatitis, VIH status, immunoglobulin levels and infection risk
was performed. Chest radiography was normal. No systematic
screening of latent tuberculosis was performed [4,5]. Three months
after the fourth course of rituximab, she reported a left knee
swelling. Synovial uid analysis revealed high blood cell count
(22.000/mm3 , > 80% neutrophils) without bacterial agent. After
two relapses of swelling of her knee, the fourth synovial uid
analysis showed high blood cell count with a majority of lymphocytes and presence of acid-fast bacilli. Synovial biopsy revealed
gigantocellular epithelioid granuloma (Fig. 1) and presence of
Mycobacterium tuberculosis. Rituximab was withdrawn and treatment anti-TB was started (ethambutol, rifampicin, pyrazinamid
and isoniazid). After 3 months of anti-TB treatment, fever and
painful posterior swelling of her knee occurred with cutaneous stulization of a popliteal cyst. MRI showed a major synovial effusion
with capsular rupture and skin stulization (Fig. 1). Joint uid analysis found acid-fast bacilli. The diagnosis of Immune Reconstitution
Inammatory Syndrome was done. Surgical lavage and increasing
of corticosteroids (30 mg/day) were performed with improvement
of symptoms and blood tests.
3. Discussion

Accepted 17 October 2012

Available online 21 December 2012
doi:10.1016/j.jbspin.2012.10.016

Knee tuberculosis under rituximab therapy for rheumatoid

arthritis

a r t i c l e

i n f o

Keywords:
Tuberculosis
Rituximab
Rheumatoid arthritis

1. Introduction
Anti-TNF immunotherapy has revolutionized the treatment of
rheumatoid arthritis (RA). However, patients receiving this therapy
have an increased risk of reactivating latent tuberculosis (TB) [1].
International guidelines recommend screening of latent TB before
introducing TNF blockers [2,3], but not before rituximab therapy
[4].
We herein report a RA patient, who developed knee tuberculous
arthritis during rituximab therapy.

TB is a complication of TNF blockers therapy [6]. TNF

plays a central role in the maintenance of granuloma and cellular immune response to TB [1]. To our knowledge, this is the
rst case of TB under rituximab therapy. The fact that rituximab is administered in RA with two pulses of glucocorticoid
may by itself contribute to the risk of reactivation of tuberculosis [7]. However, there is no evidence of an increased frequency
of tuberculosis in patients with lymphoma treated with rituximab
[8] and there is no evidence indicating the necessity to screen
patients systematically for tuberculosis before using rituximab in
RA [4].
It should be noted that rituximab has been approved for the
treatment of RA in patients with inadequate response to TNF
inhibitors; therefore, patients were pre-screened for latent TB.
Our patient having a contra-indication to TNF blockers (thyroid
carcinoma) was not screened for latent TB. No signicant risk of
tuberculosis under MTX therapy has been reported [9]. If the role of
glucocorticosteroids could not be denitely excluded, the involvement of rituximab should be considered. Finally, regarding our
patient a novo TB cannot be excluded.
In summary, we report here the rst case of TB arthritis following rituximab therapy in a RA patient. Therefore we suggest
the need for routine tuberculosis screening in RA patients before
initiating rituximab.