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Multicentric reticulohistiocytosis.

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Multicentric Reticulohistiocytosis
John W. Melton, Ill and Robert lrby
The thirty-fourth case of multicentric reticulohistiocytosis with skin
nodules and arthritis exhibiting typical histiocytic infiltrates in skin and
synovium in a 16-year-old white female high school school student is
presented. Unlike the usual reported course of this disease, the arthritis
is currently of moderate degree and has been only slowly progressive. A
brief review of the major manifestations of this disorder is given.
Multicentric reticulohistiocytosis is a rare
systemic disorder of unknown etiology manifested by the development of nodules containing infiltrates of characteristic histiocytic and
multinucleated giant cells in synovium, skin,
subcutaneous tissues and occasionally bone and
other tissues. T h e hallmarks of the disease are
arthritis which may be of a severe mutilating
type, associated with skin and mucosal lesions
which may become disfiguring, especially in the
face. Although over a dozen names have been
proposed, multicentric reticulohistiocytosis
(MR) and the term lipoid dermotoarthritis have
found the widest acceptance, the former becoming the more accepted of the two.
In a recent critical review of the world
literature, Barrow and Holubar (1) assembled a
total of 33 cases of this disorder which met the
criteria of both arthritis and skin lesions,
though they noted that there were probably
From the Division of Connective Tissue Diseases, Department of Medicine, Medical College of Virginia School
of Medicine, Virginia Commonwealth University, Richmond, Va 23219.
This is publication No. 45 from the Charles W. Thomas
Arthritis Fund.
JOHN w. MELTON, 111, MD: Fellow, Division of Connective
Tissue Diseases, Medical College of Virginia, Richmond,
Va 23219. ROBERT IRBY, MD: Professor of Medicine, Division of Connective Tissue Diseases, Medical College of
Virginia, Richmond, Va 23219.
Reprint requests should be addressed to Dr. Irby.
Submitted for publication June 3, 1971; accepted August
18, 1971.
other cases with possible incomplete expression
of the syndrome. M R is thus an unusual entity
seldom seen in rheumatologic practice.
T h e case presented here represents, we believe, the thirty-fourth case report of this entity.
P M is a 16-year-old white female high school student
admitted to the Clinical Center of the Medical College of
Virginia Hospitals on October 16, 1970. In February 1970,
she noted the gradual onset of arthritis which primarily involved all proximal interphalangeal joints and elbows, to- gether with marked arthralgia of the metacarpal
phalangeal joints, wrists, elbows, and shoulders, and to
some extent the knees and ankles. The distal interphalangeal joints were not involved. There was definite
morning stiffness in the affected joints with generalized
malaise and lack of energy. Her local physician made a
tentative diagnosis of rheumatoid arthritis. Three months
later the patient developed multiple 2-4 mm reddishbrown, initially tender papular hand lesions which were
predominantly periungual in distribution though lesions
were also elsewhere on the dorsa of the fingers. There were
no symptoms of weight loss, fever, xanthelasma, or lymphadenopathy. In September 1970, because of these lesions,
she was referred to a local dermatologist who performed a
biopsy which he reported as being consistent with multicentric reticulohistiocytosis (MR).
When the diagnosis of rheumatoid arthritis had been
suggested, the patient initially received salicylates with little
relief. A trial of indomethacin was given but had to be discontinued because of dizziness and a feeling of detachment.
Prednisone was begun after the diagnosis of M R was reported with an initial dose of 30 mg per day with intention
to taper the drug gradually to a maintenance dosage. However, over several weeks she failed to improve and discon-
Arthritis and Rheumatism, Vol. 15, No. 2 (March-April 1972)
tinued the drug on her own accord because of lack of benefit. A brief trial of phenylbutazone was associated with
depression of the polymorphonuclear portion of the white
blood cell count. The patient had been in good health all her
life with no previous musculoskeletal complaints or skin
lesions other than mild facial acne. Family history reveals
that her mother and maternal grandmother have been
affected with migratory arthralgias of unknown origin and
that a maternal uncle had died with crippling arthritis.
However, none had skin lesions or a course such as the pat ient 's.
On physical examination the patient was found to be an
alert adolescent white female appearing her stated age. Vital signs were temperature 98.6, pulse 97, blood pressure
120/66mmHg and weight 105 pounds. Positive physical
findings included mild facial acne, the liver palpable just
below the right costal margin, smooth and not tender,
without splenomegaly. Numerous 2-4 mm salmon-colored
papular lesions in a periungual distribution were present on
both hands (Fig l), and a single papule was noted on the
donum of the right third finger. There was moderate
proximal interphalangeal swelling and tenderness and
metacarpophalangeal tenderness with reduced grip strength
in both hands. The wrists demonstrated decreased range of
motion and synovial thickening. Bilateral flexion contrac-
tures of the elbows were present with limitation of extension
to approximately 165 degrees as well as synovial thickening. Full range of motion of the shoulders was present
though with some pain at the full limit. The spine, hips and
lower extremities appeared clinically uninvolved.
Laboratory studies revealed hemoglobin of 13.5 g% with
WBC 7,00O/cu mm and a normal differential. Platelet
count was 200,000 reticulocyte count 2.2% and sed rate
22mm/hr (Wintrobe). Urinalysis revealed specific gravity
1.015, trace protein, numerous white blood cells, and
myriad squamous epithelial cells, but urine has been normal on repeat testing. Fasting cholesterol was within normal limits as were blood sugar, BUN, total bilirubin,
alkaline phosphatase, SCOT, LDH, total protein and albumin. X-rays of the hands, elbows and chest were normal
except for soft tissue swelling over the proximal interphalangeal joints bilaterally.
A biopsy was obtained of a papule on the dorsum of her
left third finger (Fig 2A and B) and an open biopsy was
taken of the synovium of her left elbow (Fig 3). Both specimens revealed infiltration of tissue with large, occasionally
multinucleated, histiocytic cells. With hematoxylin and
eosin stain the cellular cytoplasm frequently took a ground
glass appearance. The cells contained a PAS-positive material which was stippled in areas of cytoplasm and was
Fig 1. Photograph of left
hand revealing red-brown
periungual nodules.
Arthritis and Rheumatism, Vol. 15, No. 2 (March-April 1972)
resistant to diastase digestion. These findings were compatible with a diagnosis of multicentric reticulohistiocytosis.
Because of uncertainty as to the best mode of treatment
and to allow the patient the benefit of investigation and
consultation by yet another group of physicians, she was
referred to the National Institute of Arthritis and Metabolic
Diseases, National Institutes of Health, Bethesda, Maryland, where she was admitted on January 11, 1971. There
the findings obtained at the Medical College of Virginia
Hospital were reviewed and confirmed, and additional
studies were carried out. These included fasting
triglycerides, lipase, amylase, CPK, total thyroxine, LE
preps, bentonite flocculation, protein electrophoresis,
Coombs test, serum complement and anti-DNA antibodies,
all of which were within normal limits. Cold agglutinins
were positive at a titer of 1:20 and cryoglobulins were noted
in her serum. An extensive radiologic evaluation including
chest, pelvis, lumbosacral and cervical spine, upper and
lower extremities, skull and sinuses were all normal except
for a spina bifida at L 3-4. Review of biopsy material
confirmed the earlier conclusions. Additional biopsies of
skin and bone marrow were obtained and studied including
fibroblast culture, glycolipid and lipoprotein analysis,
screening for mycoplasma, parasites, and viruses were begun. The results of these studies are not yet complete. So far
the fibroblasts appear normal.
Although M R is well known to cause a mutilating type
of arthritis, clinical and radiologic examinations do not bear
out such a course in our patient at the present time. Because
of the low grade activity she has manifested to date, it was
the consensus of the physicians who saw her that only expectant treatment with salicylates was indicated at the present time. Accordingly she has received buffered aspirin 1.2
g 4 times a day. Her arthritis remains stable at present and
the only objective evidence of activity of her disease has been
the appearance of several new nodules on her fingers. She is
currently attending high school and engages in the full activities of a normal 16-year-old girl.
T h e first description of MR (albeit by
another name) incorporating both arthritis and
skin lesions as part of a systemic, occasionally
fatal disorder, was in 1937 by Weber and
Freudenthal (2). It was not until 1954 that
Fig 2A. Section from biopsy of nodule from dorsum of finger revealing several macrophages containing ground glass cytoplasm and variable numbers of nuclei (low power,
H & E).
ArthrAls and Rheumatism, Vol. 15, No. 2 (March-April 1972)
Fig26. High power view of nodule from dorsurn of finger. Note typical large macrophage with ground glass cytoplasm and 4 nuclei (H & E).
Goetz and Layman (3) introduced the term ally been seen in patients of Negro, Japanese
“multicentric reticulohistiocytosis” to empha- (American), and American Indian extraction.
size that lesions may arise in multiple sites The most common age of onset is in the fifth
simultaneously and to point out that the disease decade, though reports of onset from age 11 to
process is granulomatous and not neoplastic in 70 have appeared. T h e arthritis is generally
nature. Earlier names such as “reticulohistio- gradual in onset and may easily be mistaken for
cytoma” or “giant cell histiocytoma” suggested rheumatoid arthritis in its early stages. Involved
a tumor as the basis of the disease which is in- joints include the interphalangeal (including
correct. The name lipoid dermatoarthritis, the distal interphalangeal joints, unlike rheuwhich is the other most accepted designation for matoid arthritis), knees, shoulders, wrists, hips,
this disorder, was proposed in 1957 by Warin ankles, feet, elbows, spine and temporomandiet a1 (4). This term describes not only the clini- bular joints. Although there is variability in the
cal features of the syndrome, but it also hints at activity of the disease, the arthritis generally
the nature of the underlying pathology. With progresses rather rapidly and in nearly half of
skin lesions forming a prominent and distinctive the cases evolves into arthritis mutilans before
portion of MR, well over half of all references becoming “burned out.” The active involved
to the disorder and most new case reports have joints may be tender, hot, red and contain synappeared in the dermatologic literature.
ovial fluid. The skin lesions are yellow to red
MR is seen predominantly in females, with a papules which are found on the hands frefemale: male ratio of 3:l. Though most com- quently in a periungual distribution, ears,
monly reported in Caucasians, it has occasion- bridge of the nose, and scalp, Though the
Arthritis and Rheumatism,Vol. 15, No. 2 (March-April 1972)
Fig 3. Section from open synovial biopsy of left elbow demonstrating proliferating
synovial villae containing large numbers of typical giant cells of MR identical to those
seen in the skin (medium power, H & E).
lesions normally begin months to years after
the arthritis, they may precede or begin simultaneously with it and in some cases may be
pruritic. Also, mucosal nodules may appear on
the lips, nasal septum, tongue, gingivae and
buccal mucosa (1).
Nodules are seen frequently in subchondral
bone, and in one autopsied case were also identified in laryngeal mucosa, bronchial lymph
nodes and endocardium (4). Systemic symptoms
such as weight loss, fever, weakness, and
malaise are not uncommon and may be severe
but occur in less than half of all patients. Xanthelasma are commonly seen but bear no known
relation to MR. Laboratory findings such as
anemia, elevated sedimentation rate, hypercholesterolemia, and a positive TBC skin test are
nonspecific. X-rays taken early in the course of
the disease may reveal early widening of joints
due to subarticular resorption of bone, but later
there is narrowing and destruction of the articular surface (1).
T h e diagnosis is made by pathologically
demonstrating, in the skin nodules and synovium, histiocytes and histocytic multinucleated
giant cells of varying size and shape containing
up to 20 nuclei and cytoplasm which may be
foamy or of a ground glass type. These cells
contain PAS-positive material resistant to
diastase and a variety of other enzymes but
which may be removed by pepsin digestion, indicating the presence of a glycolipid or lipoid
polypeptide (5, 6). On histochemical analysis
for lipids, the cells have been shown to contain
triglycerides, both free and esterified cholesterol
and phospholipids (7).
The patient presented is among the younger
patients with documented MR. She has not as
yet exhibited mucosal nodules, and skin nodules, though numerous, are confined to her
Arthritis and Rheumatism,Vol. IS,No. 2 (March-April 1972)
hands. Her arthritis, though definite and persistent, has progressed slowly over the past 14
months and has caused flexion contracture in
only two joints. There has been no distal interphalangeal joint involvement. She has suffered
no systemic symptoms such as weight loss or
fever, and of her extensive laboratory examinations, the only positive finding has been histiologic. There has been no anemia or hypercholesterolemia associated with this disorder to
date, and all X-ray examinations have been
normal. In view of this patient’s clinical course,
it would seem that not all cases of MR exhibit a
rapidly progressive and incapacitating arthritis
as has been the usual course to date. Since there
is no known effective treatment for MR (l),it is
well to recognize that not all victims may have
to bear the ravages of an active destructive arthritis.
The authors wish to thank Dr. Daniel Anderson who
referred the patient to us and Dr. Harry Pariser who first
made the diagnosis of M R in this patient from the initial
biopsy of a skin nodule.
1. Barrow MV, Holubar K: Multicentric reticulohistiocytosis: A review of 33 patients. Medicine
(Baltimore) 48:287-305, 1969
2. Weber FP, Freudenthal W: Nodular, nondiabetic
cutaneous xanthomatosis with hypercholesterolemia and atypical histological features. Proc
R SOCMed 30522-526, 1937
3. Goltz RW, Layman CW: Multicentric reticulohistiocytosis of the skin, Arch Dermatol Syphol
4. Warin RP, Evans CD, Hewitt M , Taylor AL,
Price CHG, Middlemiss JH: Reticulohistiocytosis (lipoid dermatoarthritis). Br Med J 1:13871391,1957
5. Orkin M , Goltz RW, Good RA, Michael A,
Fisher I: A study of multicentric reticulohistiocytosis. Arch Dermatol89:640-654, 1964
6. Davies NEJ, Roenigh HH, Hawk WA, O’Duffy
JD: Multicentric reticulohistiocytosis. Arch
Dermatol97543-547, 1968
7. Barrow MV, Sunderman FW Jr, Hachett RL,
Colvin WS: Identification of tissue lipids in lipoid
dermatoarthritis (multicentric reticulohistiocytosis). Am J Clin Pathol47:312-325,1967
Nortin M . Hadler, MD, Bethesda, Md: As mentioned in
the text of this report, the subject was recently hospitalized in the Clinical Center of the National Institutes of
Health. At that time several studies were undertaken in an
attempt to gain some insight intothe etiology of MR. Fibroblast culture lines were readily established by Dr. E. F.
Neufeld, and no abnormal sulfated mucopolysaccharide
could be detected. Complement fixing antibody titers
against mycoplasma antigens were determined by Dr. R. H.
Purcell. Titers against M. orale (I, 11, 111), M saliuarium,
M fernentans and M horninis were all less than 1 :2, and
against M. pneumoniae 1:16. The lipid content of biopsy
specimens of skin nodules was analyzed in the laboratories
of Drs. R. 0. Brady and H. R. Sloan. No significant abnormalities of the glycerophospholipids, neutral glycerides, or sphingolipids were noted.
This case report serves well to remind rheumatologists
not only of the existence of this entity, but also that it may
be a disease of considerable low grade chronicity. The hallmarks of this entity are the coincidence of destructive
arthritis and cutaneous infiltration by lipid-laden multinucleate giant cells. However, similarities with several
other cutaneous and systemic lipidoses have been emphasized previously (1). Furthermore, as in our studies, attempts to implicate a specific enzyme defect either biochemically (2) or histochemically (3) have been unrewarding. It is likely that the pathophysiology of M R involves
either aberrance of histiocyte function, or the presence of
an unusual extrinsic insult. Investigation along these lines
may prove more fruitful.
1. Barrow MV, Holubar K: Multicentric reticulohistiocytosis: a review of 33 patients. Medicine
(Baltimore) 48:287-305, 1969
2. Barrow MV, Sunderman FW, Hackett RL,
Colvin WS: Identification of tissue lipids in lipoid
dermatoarthritis (multicentric reticulohistiocytosis). Am J Clin Path 47:312-325, 1967
3. Orkin M , Goltz RW, Good RA, Michael A: A
study of multicentric reticulohistiocytosis. Arch
Dermatol89:640-654, 1964
Arthrltls and Rheumatism,Vol. 15, No. 2 (March-April1972)
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