methotrexate treatment in felty's syndrome - Semantic Scholar

British Journal of Rheumatology 1998;37:908–911

METHOTREXATE TREATMENT IN FELTY’S SYNDROME S. WASSENBERG, G. HERBORN and R. RAU Department of Rheumatology, Evangelisches Fachkrankenhaus, Ratingen, Germany SUMMARY Felty’s syndrome is a rare disorder characterized as a systemic manifestation of severe rheumatoid arthritis associated with granulocytopenia and splenomegaly. We report a retrospective analysis of a series of seven patients treated successfully with low-dose methotrexate, leading to sustained clinical improvement (number of swollen joints) and normalization of the granulocyte count for an observation period of 1 yr. Our cohort is the largest ever published with methotrexate treatment of this rare condition. Our results confirm earlier single case reports suggesting methotrexate to be the first-choice treatment nowadays in Felty’s syndrome. K : Felty’s syndrome, Methotrexate therapy, Granulocytopenia.

P with severe, long-lasting and seropositive rheumatoid arthritis (RA), leucopenia, especially granulocytopenia, and splenomegaly present the characteristic features of Felty’s syndrome, first described in 1924 by A. R. Felty [1]. Felty’s syndrome is now considered a very rare systemic complication of RA, occurring in 2.0 × 109 granulocytes at the time, when methotrexate therapy was started, but these patients had documented granulocytopenia earlier in the course of their disease, thus fulfilling the diagnostic criteria. Table I shows baseline demographic and clinical characteristics of the seven patients. All patients were female, their mean age was 60.6 yr (range 46–76). The mean disease duration of RA before entering the study was 10.3 yr (range 4–18). All but one patient had positive rheumatoid factor testing, the seronegative patient also showed erosive disease. Table II shows the clinical data of the patients at baseline (t0) and 4 weeks (t1) and 1 year (t2) after the

PATIENTS AND METHODS Patients labelled as having a diagnosis of Felty’s syndrome were identified using a computerized data bank containing the diagnoses of all patients who were admitted to our hospital between 1978 and 1991. Then we reviewed the records of these patients, and confirmed the diagnosis, if the patients fulfilled the following criteria: RA according to ACR criteria [4], splenomegaly confirmed by ultrasound and granulocytopenia of 2.0 × 109/l. These patients had documented granulocytopenia earlier in the course of their disease unrelated to any other condition, thus confirming the diagnosis of Felty’s syndrome. Spontaneous variations in the granulocyte count occurring in a considerable number of patients in long-term observation have been described before [35]. The indication for starting methotrexate in our patients did not depend primarily on the haematological findings, but was based on a still active rheumatic disease, as documented by the number of swollen joints before treatment. The effect of methotrexate treatment on the clinical status of RA in Felty’s syndrome in the published cases has only been described in general terms, with the exception of three cases. We therefore evaluated the count of swollen joints of all patients and found a significant decrease in the mean number of swollen joints from 19.0 to 7.4 after 1 yr of treatment. There was a complete remission according to the clinical status (no swollen joints and ESR within normal values) in three patients (patients 4, 5 and 6), a substantial improvement in two patients (patients 3 and 7) and an almost unchanged status in two patients (patients 1 and 2). Of the laboratory signs of inflammation, only the ESR was available for all patients at all time points; the CRP was not regularly recorded. There was a substantial decrease in ESR in four patients (patients 1, 2, 4 and 7), a small increase in two patients (patients 3 and 6) and almost no change in one patient (patient 5). The mean ESR decreased from 50.9 to 26.6, but

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BRITISH JOURNAL OF RHEUMATOLOGY VOL. 37 NO. 8 TABLE III Published cases of low-dose weekly methotrexate (MTX ) in Felty’s syndrome

Patient 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Author Allen and Groff [23] Fiechtner et al. [24] Fiechtner et al. [24] Fiechtner et al. [24] Fiechtner et al. [24] Tan et al. [31] Tan et al. [31] Hughes and Abdulla [28] Isasi et al. [25] Natmeßnig et al. [26 ] Wollenhaupt et al. [27] Guillemin and Pourel [29] Puechal et al. [30] Gerster [32]

SwJC t0

SwJC t1

ESR t0

ESR t1

? 37 14 36 ? ? ? ? ? ?

? 0 2 2 ? ? ? ? ? ?

55 48 26 62 ? 64 49 109 109 80

20 24 9 23 ? 30 20 8 ? 28

? ? 6

? ? 2†

45 ? ?

? ? ?

Granulocytes ×109/l t0

Granulocytes ×109/l t1

0 2.500 792 2.500 300 6.000 2.700 6.000 300 3.700 160 2.500 1281 3.266 302 2.495 80 > 2.500 132 2.700 No detailed information 1.760 1.036 500 3.700* 2.400 ~ 2.400†

MTX dose ~6.25 mg 7.5 mg 7.5 mg 7.5 mg 7.5 mg 7.5 mg 7.5 mg 7.5 mg 7.5 mg 7.5 mg 7.5 mg 25 mg 7.5 mg

Observation period 30 15 9 14 12 24 24 9 16 1.5

months months months months months months months months months months

1 month 3 weeks 12 years

t0, data reported immediately before the beginning of methotrexate therapy; t1, data reported at the end of the observation period. *Data reported after 4 days of therapy. †Data reported after 6 months of therapy.

this did not reach statistical significance due to the small numbers and the not normal distribution of the data. The improvement of clinical and laboratory signs of Felty’s syndrome in our patients was not due to the concomitant therapy, especially not to corticosteroids. Before treatment, only two patients were on low-dose corticosteroids of no more than 5 mg prednisone/day. During the 1 yr of observation, one patient could stop taking corticosteroids and in one patient prednisone was introduced at a dosage of 5 mg/day. The daily dose of prednisone could be reduced from a mean of 1.75 to 0.96 mg after 1 yr of treatment. Compared with the other published cases, the methotrexate dose in our patients was higher (mean dose 12.86 mg). This may also explain the good response of our patients. Besides this, the therapy was very well tolerated and no major side-effects leading to discontinuation of the therapy occurred. The time of onset of the effect of methotrexate is usually expected at 4–6 weeks after initiation of therapy [33]. Consistent with these expectations, an increase in the granulocyte count and a decrease in the ESR were already observed after 4 weeks of treatment in our patients, even if this did not reach statistical significance. Allen and Groff [23] observed a response to methotrexate in their patient after several months, Puechal et al. [30] found a dramatic increase in neutrophils within 4 days after i.v. infusion of 25 mg methotrexate. All the other published cases on weekly oral low doses showed a similar onset of improvement after a few weeks, which is concordant with our findings. This effect was sustained in our patients for a period of at least 1 yr. Most of the other published cases (see Table III ) reported a comparable or even longer duration of effective treatment. Gerster [32] reported a sustained efficacy on the clinical signs of the disease up to 12 yr despite a decrease in granulocytes after 4 yr of treatment. This might have been avoided by

using higher doses of methotrexate in the long-term treatment. The cause of the neutropenia in Felty’s syndrome is still not sufficiently explained. Several hypotheses have been proposed and numerous factors influencing granulocyte production or survival in peripheral blood have been identified in patients with Felty’s syndrome [24, 36, 37]. Which of these factors plays the most important role is still unclear. Our data cannot contribute to a further clarification of this problem, but as methotrexate is capable of various immunosuppressive actions [38] our findings again stress the important role of immunological factors in the development of neutropenia in Felty’s syndrome. In conclusion, our data confirm earlier reports that low-dose methotrexate therapy is a safe and effective treatment of Felty’s syndrome and that patients with unexplained neutropenia in RA should not be excluded from methotrexate treatment. R 1. Felty AR. Chronic arthritis in the adult, associated with splenomegaly and leukopenia: A report of five cases of an unusual clinical syndrome. Johns Hopkins Hosp Bull 1924;35:16–20. 2. Pinals RS. Felty’s syndrome. In Kelley WN, Harris ED Jr, Ruddy S, Sledge CB, eds. Textbook of rheumatology, 3rd edn. WB Saunders, 1989:993–8. 3. Rau R, Schleusser B, Herborn G, Karger T. Longterm treatment of destructive rheumatoid arthritis with methotrexate. J Rheumatol 1997;24:1881–9. 4. Arnett FC, Edworthy SM, Bloch DA et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315–24. 5. Nakamura H, Ohishi A, Asano K et al. Partial splenic embolization for Felty’s syndrome: a 10 year follow up. J Rheumatol 1994;21:1964–6. 6. Lakhanpal S, Luthra HS. D-penicillamine in Felty’s syndrome. J Rheumatol 1985;12:703–6.

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