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Multicentric reticulohistiocytosis associated with primary biliary cirrhosissuccessful treatment with cytotoxic agents.

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BRIEF REPORT
MULTICENTRIC RETICULOHISTIOCYTOSIS ASSOCIATED WITH
PRIMARY BILIARY CIRRHOSIS: SUCCESSFUL TREATMENT WITH
CYTOTOXIC AGENTS
M. DOHERTY, M. F. R. MARTIN, and P. A. DIEPPE
Multicentric reticulohistiocytosis (MRH) is a
rare systemic disease of unknown etiology characterized histologically by widespread infiltrations of multinucleate giant cells and lipid-laden histiocytes. Rapidly destructive polyarthritis and nodular skin lesions
are the most significant manifestations that may result
in mutilating deformity, particularly of the hands and
face (1-3). Involvement of other tissues including
muscle, bone, pleura, pericardium, and endocardium
has also been reported (2,4). The rarity of the disease,
with fewer than 50 cases reported in the literature, has
resulted in uncertainty over the clinical course of the
condition (2,5) and precluded any possibility of controlled treatment trials.
A case of MRH, presenting with polyarthritis
and skin lesions, is reported in an HLA-A1,B8 positive woman, who in addition had vitiligo, primary
biliary cirrhosis (PBC), and autoimmune thyroid disease. Marked improvement in her arthritis and skin
lesions was observed during two 3-month periods
while she received oral cyclophosphamide. Relapse
followed treatment cessation on both occasions. Sub-
~~
From the University Department of Medicine, Bristol Royal Infirmary, Bristol, England and the Department of Rheumatology, University of Leeds, Leeds, England.
Supported by the Arthritis and Rheumatism Council.
M. Doherty, MRCP: Senior Registrar, University Department of Medicine, Bristol Royal Infirmary; M. F. R. Martin, MRCP:
Senior Registrar, University of Leeds, Department of Rheumatology; P. A. Dieppe, FRCP: Consultant Senior Lecturer, University
Department of Medicine, Bristol Royal Infirmary.
Address reprint requests to M. Doherty, MRCP, Senior
Registrar, University Department of Medicine, Bristol Royal Infirmary, Bristol, BS2 8HW, England.
Submitted for publication July 18, 1983, accepted in revised
form September 30, 1983.
Arthritis and Rheumatism, Vol. 27, No. 3 (March 1984)
sequent long-term remission appears to have followed
6 months’ treatment with chlorambucil.
Case report. A 56-year-old woman first presented with a 4-year history of pain and stiffness affecting
the knees, wrists, metacarpophalangeal, and finger
interphalangeal joints. Apart from developing vitiligo
at age 13, she gave no medical or family history of
note.
Examination revealed inflammatory synovitis
with mild functional impairment of her symptomatic
joints. Apart from non-tender, “warty” nailfold swellings on several fingers and widespread vitiligo, no
other abnormalities were noted. Test values showed:
plasma viscosity was 1.86 centipoise (cp), (normal
1.5-1.72 cp), a normal full blood count, and negative
findings on serum rheumatoid and antinuclear factor
tests. Small erosions of the carpus, metacarpophalangeal, and interphalangeal joints were seen on radiographic examination of the hand, and a diagnosis of
probable seronegative rheumatoid arthritis was made.
Her symptoms responded to nonsteroidal antiinflammatory drugs and she was discharged from followup.
Over the next 6 years, increasing pain and
stiffness in her hands and knees and progressive hand
deformity resulted in inability to continue her work.
Incidental hospitalization for colonic diverticular
bleeding at age 62 permitted a reassessment of her
joint disease 10 years after onset of symptoms. Examination at this time revealed boggy synovitis of the
wrists with “sausage” fingers and lateral subluxation
of several proximal and distal interphalangeal joints
(Figure 1). Synovial thickening and joint line tenderness were detected in both knees, but other joints
appeared normal. Numerous yellow-brown, tender
nodules 0.2-1 .O cm in diameter with surrounding ery-
BRIEF REPORTS
345
Figure 1. Hands of patient at time of diagnosis, showing wrist
synovitis, “sausage” fingers, lateral subluxation of interphalangeal
joints, finger nodules, and vitiligo.
thema were present in finger nailfolds (Figure I),
finger pulps, alae nasi, and lower nasal septum (Figure
2). She had extensive vitiligo, coarse dry skin, slowrelaxing reflexes, and a goiter. Bilateral xanthelasmata
and jaundice were also noted. There was no hepatosplenomegaly and the remainder of the examination
results were normal.
Laboratory test results included the following
values: hematocrit 32% with normal indices, leukocyte
count 4,800/mm3, plasma viscosity 2.2 cp, negative
rheumatoid factor, negative antinuclear antibody, positive thyroid microsomal and thyroglobulin antibodies
(titers > 1:80,000), positive antimitochondrial antibody
test (titer 1:640), serum IgM 12 gm/liter (normal 0.52.0), other immunoglobulins normal. Serum-free thy-
Figure 2. Nodular deformity of lower nasal septum and alae nasi
(xanthelasmata and intercurrent left subconjunctival hemorrhage
also visible).
Figure 3. Radiographic appearance of finger interphalangcal joints
showing articular erosions, expansion of joint space, and wellpreserved bone density.
roxine index was 50 units (normal 70-180), serum
thyroxine 52 nmole/liter (normal 70-160), serum thyroid-stimulating hormone 69pU/ml (normal 0-2). Liver
function test findings included: bilirubin 36 pmole/
liter (normal 0-17), alkaline phosphatase 110 King
Armstrong units/dl (normal 3-1 3), D-glutamyltransferase 114 units/liter (normal 4-20), serum glutamic oxaloacetic transaminase (SGOT) 36 unitdliter (normal 317), albumin 39 gm/liter (normal 35-55). Fasting serum
cholesterol was 9.50 mmole/liter (normal 3.10-7.301,
serum triglycerides were normal.
Histologic examination of liver tissue obtained
by needle biopsy revealed portal tract infiltration with
granuloma formation, bile duct disruption, periportal
pigmentation, and several foci of “piecemeal” necrosis, consistent with PBC. Histology of nodules taken
from the nose and one finger showed changes characteristic of MRH with focal dermal collections of histiocytes exhibiting “ground glass” cytoplasm, many being multinucleate and containing lipid globules.
Radiographs of the hand revealed gross soft tissue
swelling of fingers and well-defined articular erosions
with apparent expansion of joint space, particularly
involving proximal and distal interphalangeal joints
(Figure 3) and carpus. Mild juxtaarticular osteopenia
was present. Her HLA phenotype was A1,2;B8,Bw35.
Rose bengal staining confirmed asymptomatic keratoconjunctivitis sicca.
A diagnosis of MRH with PBC, vitiligo, and
autoimmune hypothyroidism was made. She recov-
346
BRIEF REPORTS
Figure 4. Appearance of hands after 3 months’ treatment with
cyclophosphamide, showing marked reduction in nodule size and
improvement in soft tissue swelling as compared with Figure 1 .
ered rapidly from her diverticular bleeding and jaundice was gone in 2 weeks (bilirubin levels fell to 23
pmolefliter, SGOT to 24 units/liter). Thyroxine replacement rendered her euthyroid and she was given
artificial tears. Lack of symptomatic control of her
arthritis by nonsteroidal antiinflammatory agents, together with progressive hand and nasal deformity led
to consideration of other therapies which might suppress the disease process.
D-penicillamine was tried initially, starting with
250 mg daily and increasing the dose to 500 mg at 6
weeks. It was stopped, however, after 5 months
because of the development of a widespread rash.
During this period there had been no amelioration of
the patient’s symptoms and fresh nodules had appeared on her face and hands. Oral cyclophosphamide
2 mg/kg/day was then given and resulted in dramatic
symptomatic improvement within 3 weeks. Hemorrhagic cystitis, however, necessitated cessation of
treatment after 3 months, by which time all nodules on
her face and hands had receded (Figure 4).
Within 4 months of stopping cyclophosphamide, her nodules had returned to their original size
and she was again experiencing severe symptoms.
Reinstitution of cyclophosphamide, 2 mg/kg/day, together with oral 2-mercaptoethane sulfonate sodium
(mesnum, used to reduce the risk of urothelial toxicity)
again resulted in rapid symptomatic improvement and
slower reduction in nodule size. Recurrence of the
hemorrhagic cystitis after 3 months necessitated permanent withdrawal of cyclophosphamide.
Three months later, new nodules were appearing and her symptoms were again severe. She was next
treated with oral chlorambucil 0.1 mg/kg/day which led
to marked symptomatic improvement and reduction in
nodule size by 10 weeks. After 6 months’ treatment
with chlorambucil, uncomplicated hematuria was detected. Although hematuria is not a recognized complication of chlorambucil, the drug was stopped: cystoscopy, intravenous urogram, and repeat urine cultures
revealed no abnormality and the hematuria resolved
after 2 weeks. While she was receiving chlorambucil,
the finger nodules diminished markedly in size (comparable with those in Figure 4), the nodules around her
nose became impalpable, and no fresh lesions appeared. The patient remains well with no clinical
evidence of disease progression 12 months after stopping chlorambucil.
During treatment with penicillamine and cytotoxic agents, there was no alteration in results of
biochemical tests of liver function; repeat liver biopsy
was not performed. Apart from diminution in soft
tissue swelling, no appreciable difference was perceived on the hand radiographs taken during the
treatment period. A summary of drug treatments and
response is shown in Table 1.
Discussion. Several of this patient’s features are
typical of those described for MRH, including: insidious onset of joint and skin disease (1-3), initial
misdiagnosis as rheumatoid arthritis ( I ) , major in-
Table 1. Summarv of drug treatments and resuonse
Drug
Daily dose
Duration
(months)
D-penicillamine
Cyclophosphamide
250-500 mg
5
2 mg/kg
3
Cyclophosphamide
+ mesnum
Chlorambucil
2 mg/kg
3
0.1 mg/kg
6
Symptomatic
improvement
Decrease in
nodule size
Appearance of
new nodules
None
Marked, within
3 weeks
Marked, within
3 weeks
Marked, within
10 weeks
No
Yes
Yes
Yes
NO
Yes
N0
NO
Complications
during
treatment
Rash
Hemorrhagic
cystitis
Hemorrhagic
cystitis
Hcmaturia
Recurrence of
disease after
stopping drug
NO
Yes
Yes
N O
BRIEF REPORTS
volvement of finger interphalangeal joints (1-5), and
progression over 7-8 years to mutilating arthritis with
nodular facial deformity (1-3). Radiographic findings
of well-circumscribed articular erosions with widened
joint spaces are also characteristic (1-3). The diagnosis
was confirmed by histologic examination of skin nodules showing typical lipid-laden histiocytes and multinucleate giant cells of foreign body type (2,4,6). In
addition to MRH, this patient demonstrated biochemical, serologic, and histologic evidence of PBC.
Concomitance of MRH and PBC has not previously been reported. The association is of interest,
however, in that both disorders show lipid accumulation and a tendency to granuloma formation. In MRH,
an abnormality of lipid handling is suggested by a 30%
incidence of hypercholesterolemia and xanthelasmata
(1,2) and by the histiocytic accumulation of phospholipid, neutral fats, and lipoid-polypeptide complexes
(4,6): the varied and inconsistent nature of the intracellular lipid suggests secondary, nonspecific accumulation rather than a primary lipid disorder. In PBC, a
disease with similarities to chronic graft-versus-host
disease (7), intrahepatic cholestasis with resultant hypercholesterolemia and xanthelasmata is a cardinal
feature. Keratoconjunctivitis sicca occurs in 70-100%
of patients (8), but the only rheumatic disease reported
to occur with increased frequency is scleroderma (9).
Although concurrence of MRH and PBC could
have arisen by chance, the rarity of these conditions
suggests more than coincidental association. It is
tempting to speculate that an “autoimmune diathesis,” reflected in this patient by an HLA-A1,B8
phenotype and by development of PBC, thyroid disease, and vitiligo, may play a part in the pathogenesis
of MRH, perhaps by influencing the function of the
mononuclear phagocyte system. To our knowledge,
however, there are no data on the incidence of HLA
haplotypes or of autoantibodies, other than rheumatoid and antinuclear factors (1-6), in patients with
MRH.
There is no established treatment for the mutilating arthritis and nodular lesions of MRH. The rarity
of the condition and its tendency to eventual spontaneous remission (1-3) make treatment assessment difficult, and at present, there are no authoritative guidelines on patient management. Trials of low-fat diets,
clofibrate, prednisone, azathioprine, and isoniazid
(1,6,10-12) have not produced consistent improvement in skin or joint lesions, but in 2 case reports
remission appears to have coincided with use of cyclophosphamide (13) and sequential use of a number of
347
drugs including chlorambucil and nitrogen mustard
(14).
In our patient, uncontrolled severe symptoms
and progressive deformity appeared to warrant a policy of empirical drug treatment. Penicillamine has been
reported to be of benefit in PBC (15) and was, thercfore, tried first for both conditions; no influence on
disease course, however, was observed during the 5
months of treatment. The report by Hanauer (13)
prompted us to use cyclophosphamide which was
given in two 3-month courses, each terminated by
development of hemorrhagic cystitis. Attempts to prevent urothelial toxicity by concurrent use of mesnum
(16) were unsuccessful.
During both treatments with cyclophosphamide
there was marked symptomatic improvement, no new
nodules appeared, existing nodules regressed, and soft
tissue swelling was reduced. Recurrence of symptoms
and nodules following cessation of each treatment
strongly suggests that cyclophosphamide, rather than
disease fluctuation, was responsible for the improvement observed. Treatment with chlorambucil was associated with similar but slower regression of the
disease. Remission, however, has persisted since stopping the drug and the effect of chlorambucil is, therefore, less certain.
Not all patients with MRH progress to severe,
destructive arthritis (1-3,5). In those with mild disease, symptomatic treatment with analgesic antiinflammatory agents may well suffice. However, when a
patient presents with unrelenting symptoms and progressive joint and skin deformity, the outcome of the
present case and that reported by Hanauer (13) would
suggest that a trial of cyclophosphamide is warranted.
REFERENCES
1. Barrow MV, Holubar K: Multicentric reticulohistiocy-
tosis: a review of 33 patients. Medicine 48:287-305, 1969
2. Orkin M, Goltz RW, Good K, Michael A. Fisher I: A
study of multicentric reticulohistiocytosis. Arch Dermato1 89:640-654, 1964
3. Albert J , Bruce W-.Allen AC. Black H: Lipoid derrnatoarthritis: reticulohistiocytoma of the skin and joints. Am
J Med 28:661-667, 1960
4.. Warin RP, Evans CD, Hewitt M, Taylor AL, Price
CHG. Middlemiss JH: Reticulohistiocytosis (lipoid dermatoarthritis). Br Med J 2: 1387-1391, 1957
5 . Melton JW 111, Irby K: Multicentric reticulohistiocytosis. Arthritis Rheum 15:221-226, 1972
6. Krey PR, Comerford FR, Cohen AS: Multicentric reticulohistiocytosis: fine structural analysis of the syno-
348
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vium and synovial fluid cells. Arthritis Rheum 17:615633, 1974
Epstein 0, Thomas HC, Sherlock S: Primary biliary
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BRIEF REPORTS
12. Taylor DR: Multicentric reticulohistiocytosis. Arch Dermatol 113:330-332, 1977
13. Hanauer LB: Reticulohistiocytosis: remission after cyclophosphamide therapy. Arthritis Rheum 15:636-640,
1972
14. Davies NEJ, Roenigk HH, Hawk WA, O’Duffy JD:
Multicentric reticulohistiocytosis. Arch Dermatol
97:543-547, 1968
IS. Epstein 0, Jain S , Lee RG, Cook DG, Boss AM,
Scheuer PJ, Sherlock S: D-penicillaminc treatment irnproves survival in primary biliary cirrhosis. Lancet
1:1275-1277, 1981
16. Bryant BM, Jarman M, Ford HT, Smith IE: Prevention
of isophosphamide-induced urothelial toxicity with 2mercaptoethane sulphonate sodium (mesnum) in patients with advanced carcinoma. Lancet 2:657-659, 1980
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treatment, associates, cirrhosissuccessful, multicentric, agenti, biliary, primary, reticulohistiocytosis, cytotoxic
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