Background/Purpose: Rituximab is a monoclonal chimeric antibody targeting the CD20 on the surface of normal and abnormal maturing B cells. Late onset neutropenia (LON) is defined as an unexplained absolute neutrophil count of <1.5X10­­­­_­­⁹/liter occurring at a time point at least 4 weeks after therapy. LON following rituximab treatment has been described extensively in hematological malignancies. However it has been reported infrequently in association with rheumatological diseases. To the best of our knowledge only 29 such cases have been published so far in the English literature. The aim of this work is to review cases in Israel and to compare them to published cases in the literature thus adding to the body of knowledge regarding this unusual phenomenon.

Methods:  Members of the Israeli Rheumatology Association were encountered by e-mail, requesting reports of cases of LON after therapy with rituximab. Submitted cases were reviewed, with demographics and clinical data collated and tabled. Current cases were compared to previously published rheumatology cases.

 Results: Eight episodes in seven patients were reported throughout the country after encounting 150 Israeli rheumatologists. Five of the patients had RA, one SLE and one MCTD. The average neutrophil count was o.275/cubic mm in compare to 0.380/cubic mm in previously published cases. One patient had cellulitis of the forearm and all other patients did not have any infection. Five patients were treated with G- CSF. All patients had complete recovery. In comparison to published cases, a larger percentage were RA patients reflecting current usage of the medication in Israel. The average time to LON diagnosis was 177 days as compared to 148 days in published cases.

Table 1: LON: current series compared to previous published cases

 

Age/Gender	Dg	No of tx	Additional tx	Days since tx	WBC (% neu)	Repeat tx	Infection	Action taken
32/F	RA	4	MTX PRED	151	1100(10)	Yes	No	G-CSF
34/F	MCTD	1	CYC AZA PRED	105	1000(42)	Yes	No	G-CSF
22/F	SLE	1	CYC	240	0	No	Cellulitis	G-CSF
38/F	RA	1	MTX PRED	120	0	No	No	G-CSF
68/F	RA	1	PRED ABITREN	330	1270 (50)	No	No	G-CSF
50/F	RA	1	MTX HCQ	138	2300 (47)	Yes	No	MTX D/C
51/F (same patient on following year)	RA	2	HCQ	180	2600 (45)	No	No
78/F	RA	1	MTX PRED	150	1800 (39)	No	No	MTX D/C Increase PRED
Published cases average age: 52             17(60%)Females8 (40%)Males	RA -12 GPA =12 SLE =3 VASCULITIS=1 JRA=1	n/a	MTX -8 MMF -4	148	380 neutrophiles	n/a	Sepsis- 5 Fever – 3	G-CSF – 11

TX= treatment  Dg = Diagnosis  RA = rheumatoid arthritis  MCTD = mixed connective tissue disease     SLE = systemic lupus erythematosus MTX = Methotrexate Pred = prednisone   CYC =  cyclophosphamide                    AZA = azathyoprine HCQ = hydroxychloroquine D/C = discontinued MMF = micophenolate mofetyl

Conclusion: LON is a well described finding and should be taken into consideration when following rheumatological patients treated with rituximab. In most cases it can be managed with a single dose of G-CSF and does not put the patient in an additional risk. Periodic complete blood count monitoring is recommended.

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