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Multicentric reticulohistiocytosisA systemic osteoclastic disease.

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Arthritis & Rheumatism (Arthritis Care & Research)
Vol. 59, No. 3, March 15, 2008, pp 444 – 448
DOI 10.1002/art.23320
© 2008, American College of Rheumatology
CASE REPORT
Multicentric Reticulohistiocytosis: A Systemic
Osteoclastic Disease?
KATERINE A. CODRIANSKY,1 THOMAS M. RÜNGER,1 JAG BHAWAN,1 ALPDOGAN KANTARCI,2
1
AND EUGENE Y. KISSIN
Introduction
Multicentric reticulohistiocytosis (MRH) is a rare systemic
disorder of unknown etiology, characterized by erosive
polyarthritis and papulonodular lesions on the skin, mucous membranes, and internal organs. MRH is the most
destructive chronic inflammatory arthritis, progressing to
arthritis mutilans in 45% of cases (1), compared with 5%
for rheumatoid arthritis and psoriatic arthritis (2,3). Cutaneous lesions are pink-brown, asymptomatic, firm papules
and nodules, most commonly located over the dorsal aspects of proximal and distal interphalangeal joints of the
hands, on elbows, and on the forehead. Such papules
located along the proximal nailfold have been described as
“coral beads” and are very characteristic of the disease (1).
Histologically, cutaneous nodules and synovium demonstrate infiltrates of multinucleated giant cells with eosinophilic, periodic acid–Schiff–positive granular material in
the cytoplasm, giving the appearance of “ground glass” (4).
MRH nodules are reported to stain with CD68 and CD45,
but not with S100 or CD1a (5), and are therefore thought to
be of monocyte/macrophage lineage. These cells also have
been shown to stain positively with the osteoclast marker
tartrate-resistant acid phosphatase (TRAP) (5). MRH is difficult to control with common immunosuppressive agents
(5–7). Recently, there have been several reports of intravenous bisphosphonates showing efficacy in MRH arthritis
Presented at the New England Dermatological Society
meeting, Boston, Massachusetts, November 2006.
1
Katerine A. Codriansky, MD, Thomas M. Rünger, MD,
PhD, Jag Bhawan, MD, Eugene Y. Kissin, MD: Boston University Medical Center, Boston, Massachusetts; 2Alpdogan
Kantarci, DDS, PhD: Boston University Goldman School of
Dental Medicine, Boston, Massachusetts.
Dr. Bhawan received consultant fees (more than $10,000)
from Galderma for contract work for a research project. Dr.
Kantarci holds a patent for “Delivery of H2 Antagonists”
(patent WO2006/071659A1).
Address correspondence to Eugene Y. Kissin, MD, Section
of Rheumatology, Boston University School of Medicine,
715 Albany Street E-503, Boston, MA 02118. E-mail:
Eugene.kissin@bmc.org.
Submitted for publication May 22, 2007; accepted in revised form September 6, 2007.
444
and nodulosis (5–7), further implicating osteoclasts in the
pathogenesis of MRH.
We present an additional case of MRH with novel histologic evidence of osteoclast-like cells in nodular skin
lesions, as well as response to treatment with zoledronic
acid, an intravenous bisphosphonate.
Case Report
A 40-year-old woman with an 8-year history of Sjögren’s
syndrome manifested by xerostomia and xerophthalmia
with positive anti-Ro, anti-La, and antinuclear (1:1,280;
speckled pattern) antibodies developed inflammatory
polyarthritis involving the proximal interphalangeal (PIP),
metacarpophalangeal (MCP), wrist, elbow, and knee joints.
Knee aspiration revealed 9,000 white blood cells/␮l, 54%
mononuclear cells, 36% polynuclear cells, and 10% lymphocytes with no crystals seen on polarized light microscopy. After serologic tests yielded positive rheumatoid
factor (75 IU/ml) and anti– cyclic citrullinated peptide antibody (29 units), the patient was initially diagnosed with
rheumatoid arthritis. Treatment with a combination of
prednisone, hydroxychloroquine, and methotrexate failed
to control the arthritis. Eight months after the start of joint
symptoms, the patient suddenly developed asymptomatic,
skin-colored to slightly erythematous, firm, nontender
papules and nodules over the proximal and distal interphalangeal joints, elbows, forehead, and ears (Figure 1A
and 1B). Characteristic “coral beads” (Figure 1B) were
noted over the proximal nailfolds. The distal interphalangeal joints (DIP), PIP joints, MCP joints, and knee joints
were effused with decreased range of motion, warmth, and
tenderness to palpation. The patient’s conjunctivae were
injected and her oral mucosa was dry with poor dentition.
Examination of her heart, lungs, and abdomen was unremarkable. The timeline of clinical progression is illustrated in Figure 1D.
Laboratory studies revealed a white blood cell count of
12,000/⬀l, normocytic anemia with a hematocrit of 34%,
and a platelet count of 820,000/␮l. Liver enzymes, electrolytes, creatinine, urinalysis, creatine phosphokinase, C3,
C4, and thyroid function tests were all within normal
limits. Radiologic examination of the hands revealed well-
Multicentric Reticulohistiocytosis
445
circumscribed marginal erosions at the DIP joints (Figure
1C).
Histologic and immunohistochemical methods and
findings. A skin biopsy sample of a cutaneous nodule
from a dorsal finger showed a dermal nodular infiltrate
composed predominantly of multinucleated histiocytes
with “glassy” cytoplasm. These cells stained faintly and
focally with CD68 (Figure 2A) (mouse monoclonal antibody, DakoCytomation, Carpinteria, CA) as a macrophage
marker, whereas S100 (rabbit polyclonal, Ventana Medical
Systems, Tucson, AZ) and CD1a (Leu-6; mouse monoclonal, Immunotech, Miami, FL), a calcium-binding protein
and neurotrophic factor and a surface antigen of Langerhans’ cells, respectively, were negative, confirming the
diagnosis of MRH. These cells also stained strongly with
the osteoclast markers TRAP (Sigma, St. Louis, MO) and
cathepsin K (mouse monoclonal, Vision Biosystems, Norwell, MA), a cysteine protease with high matrix-degrading
activity (Figures 2C and 2E). Comparative staining of a
rheumatoid nodule showed only trace cathepsin K staining in the region of fibroblasts surrounding the nodule, and
no significant TRAP staining (Figures 2D and 2F), while no
staining for cathepsin K or TRAP was detected in normal
control skin (data not shown).
Followup and treatment. Computed tomography scans
of the chest and abdomen, positron emission tomography
scan, transvaginal ultrasound, mammogram, and gynecologic examinations did not reveal an associated malignancy. Treatment with intravenous infusions of 4 mg
zoledronic acid resulted in improvement of arthritis and
concurrent reduction in the size and number of cutaneous
MRH nodules (Figure 3). However, this response was transient, with worsening of both arthritis and skin nodules 8
weeks after infusion. Repeat infusions resulted in less
dramatic, transient improvement of joint and skin symptoms. However, over a period of 8 months with zoledronic
acid infusions, hand radiographs did not show any progression of bony erosions.
Discussion
Figure 1. Asymptomatic, skin-colored to slightly erythematous, firm, nontender papules and nodules a, over
the ears and b, on the fingers, with characteristic “coral
beads” over the proximal nailfolds. c, A hand radiograph with early marginal erosions at the distal interphalangeal joints. d, A timeline of clinical disease progression.
MRH is a rare autoimmune disease most frequent in
women in their fourth decade of life (60 –75%) (4). It has
been associated with a wide variety of malignancies in
15–28% of cases (1), but does not run a course parallel to
the neoplasm (4). MRH is also associated with autoimmune diseases (15% of reported cases), including hypothyroidism, Sjögren’s syndrome, diabetes mellitus,
primary biliary cirrhosis, systemic sclerosis, idiopathic
inflammatory myopathy, and systemic lupus erythematosus (1,8). It is unclear whether MRH is also associated with
rheumatoid arthritis (8), as it is often misdiagnosed as such
due to similarities in arthritis presentation and association
with cutaneous nodules. In the present case, the presence
of both rheumatoid factor and the highly specific anti–
cyclic citrullinated peptide antibody makes a strong argument for co-occurrence of the 2 diseases.
Internal organ involvement has been described, with
20% of cases having pulmonary lesions. Other described
446
Codriansky et al
Figure 2. CD68 (a macrophage marker) stains a, faintly throughout the multicentric reticulohistiocytosis (MRH) nodule and b, brightly around an area of central necrosis in a rheumatoid nodule.
The osteoclast marker tartrate-resistant acid phosphatase (TRAP) c, stains brightly throughout the
MRH nodule d, but not the rheumatoid nodule, whereas cathepsin K (also an osteoclast marker
with high matrix-degrading activity) e, stains throughout the MRH nodule f, but only in the
surrounding fibroblasts of the rheumatoid nodule.
organ involvement includes thyroid, salivary glands,
heart, kidney, liver, and gastrointestinal tract (4). MRH can
present with arthritis only, skin nodules only, or both, and
commonly involves the hands, shoulder, knees, and
wrists, but can affect any joint (4). Similar to rheumatoid
arthritis, MRH is an erosive arthritis, with radiographs
commonly showing well-circumscribed periarticular
“punched out” erosions and resorption of the juxtaarticular zone but without periarticular osteopenia typical in
rheumatoid arthritis or heterotrophic new bone typical in
the spondylarthritides and gouty arthritis (1). MRH is a
highly destructive disease with up to 45% of cases progressing to arthritis mutilans before the disease remits,
usually after 5–10 years (1).
The cause of the severe, erosive nature of MRH has not
been well established. Prior reports indicate that cells of a
monocyte/macrophage lineage infiltrate both skin lesions
and synovium (1).
Similarly, in rheumatoid arthritis, mononuclear cells
are found in areas of pannus erosion into bone marrow.
In MRH, these cells exhibit properties of osteoclasts such
as expression of TRAP and cathepsin K (9). Our case
provides evidence of the osteoclastic nature of multinucleated cells infiltrating the skin nodules in MRH, as
they strongly express the osteoclast, tissue lytic markers
TRAP and cathepsin K.
Speculation that decreasing osteoclast formation and
activity by blocking stimulatory signals, such as RANKL,
Multicentric Reticulohistiocytosis
Figure 3. Multicentric reticulohistiocytosis nodules
over the elbows shrunk after an infusion of zoledronic
acid (photograph taken 43 days after infusion).
might attenuate the progression of destructive arthritis (9),
and findings that RANKL levels can be reduced by
bisphosphonate therapy (10) have led to trials of bisphosphonates to prevent focal bone resorption in inflammatory
arthritis. These studies demonstrated that bisphosphonates can decrease bone erosion in both animal models of
inflammatory arthritis (11) and in humans with rheumatoid arthritis (12). In MRH, synovial fluid macrophages
have been shown to differentiate into osteoclasts after
stimulation with a combination of macrophage colonystimulating factor (M-CSF) and RANKL (5), whereas such
macrophages obtained after treatment with pamidronate
were less likely to be induced to differentiate into osteoclasts by M-CSF/RANKL treatment and had lower boneeroding activity after stimulation (5). We also confirmed
reports of skin and joint disease improvement after treatment with an intravenous bisphosphonate (5–7). Although
the palliation of disease observed in our patient is modest,
we are encouraged by the lack of progressive joint erosion
on hand radiographs. We speculate that the efficacy of
zoledronic acid is mediated through its effect on osteoclast-like cells in the skin and synovium. In addition to
effects on RANKL, an aminobisphosphonate may promote
osteoclast apoptosis directly by inhibiting farnesyl pyrophosphate synthase in the mevalonate pathway and impairing isoprenylation of proteins (13).
Our observations are consistent with the report by Goto
et al (6), who also demonstrated the TRAP osteoclast
marker in skin and synovial tissue from a patient with
MRH. Our article is the first to report that the skin-infiltrating cells also highly express cathepsin K, a strong cysteine proteinase that mediates bone resorption. The ca-
447
thepsin K staining of the cutaneous MRH nodule was very
different from the staining seen in a rheumatoid nodule
(Figure 3), where palisading histiocytic cells surrounding
the fibrinoid necrosis were cathepsin K and TRAP negative. Only surrounding fibroblasts, similar to those seen in
cutaneous scars (14), were cathepsin K positive (but TRAP
negative).
Cathepsin K has been shown to be present in low concentrations in normal synovium, but up-regulated in synovial fibroblasts of patients with rheumatoid arthritis, at
sites of bone invasion and destruction (15). Furthermore, a
transgenic mouse model has demonstrated that overexpression of the cathepsin K gene increases susceptibility to
both synovitis and destruction of articular cartilage (16).
While TRAP and cathepsin K expression is highly suggestive of osteoclast differentiation, it is not completely
specific (9). TRAP is also detected in macrophages that
lack bone resorptive properties (9). While cathepsin K has
long been considered to be expressed only in osteoclasts, it
has more recently also been shown to be expressed in lung
fibroblasts, synovial fibroblasts, and skin fibroblasts during
wound healing, presumably to counteract the profibrotic
processes through degradation of the extracellular matrix
(14,15).
However, the combined expression of both tissue lytic
markers by the multinucleated cells found in the highly
erosive MRH strongly suggests osteoclastic activity. Cathepsin K inhibition is currently under investigation for
the treatment of osteoporosis and might be an alternative
treatment approach for MRH.
AUTHOR CONTRIBUTIONS
Dr. Kissin had full access to all of the data in the study and
takes responsibility for the integrity of the data.
Study design. Codriansky, Rünger, Kissin.
Acquisition of data. Codriansky, Rünger, Bhawan, Kantarci, Kissin.
Analysis and interpretation of data. Codriansky, Rünger, Bhawan, Kantarci, Kissin.
Manuscript preparation. Codriansky, Rünger, Bhawan, Kissin.
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