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The Cutting Edge |

Treatment of Multicentric Reticulohistiocytosis With Etanercept FREE

Bradley T. Kovach, MD; Kenneth T. Calamia, MD; John S. Walsh, MD; William W. Ginsburg, MD
[+] Author Affiliations

From the Mayo Clinic, Jacksonville, Fla.


Section Editor: George J. Hruza, MD
Assistant Section Editor: Michael P. Heffernan, MD
Assistant Section Editor: Elaine Siegfried, MD

More Author Information
Arch Dermatol. 2004;140(8):919-921. doi:10.1001/archderm.140.8.919.
Text Size: A A A
Published online

An otherwise healthy 46-year-old man presented with a 1-year history of an ill-defined acral eruption that had evolved over several weeks into reddish-brown papules and nodules, together with a progressive inflammatory polyarthritis. Skin lesions ranging from several millimeters to several centimeters in diameter were present on the dorsal and palmar aspects of the hands (Figure 1) and on the forearms, extensor elbows, chest, paranasal face, neck, pinnae, and scalp. A skin biopsy revealed an intradermal infiltrate composed predominantly of histiocytes and multinucleated giant cells. Many of the cells had abundant "ground glass" cytoplasm with fine periodic acid-Schiff–positive granules (Figure 2). There was severe stiffness, pain, and swelling associated with bilateral synovitis of the metacarpophalangeal joints, distal and proximal interphalangeal joints, wrists, elbows, shoulders, knees, ankles, and forefeet.

Place holder to copy figure label and caption
Figure 1.

Hands before treatment with etanercept.

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Figure 2.

A skin biopsy specimen revealed dermal infiltrate of histiocytes and multinucleated giant cells with abundant "ground glass" cytoplasm.

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Laboratory values, including complete blood cell count, general chemistry panel, erythrocyte sedimentation rate, rheumatoid factor, and antinuclear antibodies were within normal limits except for an elevated total cholesterol level of 262 mg/dL (6.80 mmol/L). The test result for perinuclear antineutrophil cytoplasmic antibodies was positive but no titer was reported and antibodies to myeloperoxidase were not obtained. A chest radiograph was unremarkable.

The patient was diagnosed with multicentric reticulohistiocytosis (MRH) and initially managed with 20 mg of methotrexate weekly and 20 to 40 mg of prednisone daily for 2 months. Hydroxychloroquine was added to this regimen for 7 months with little benefit. Subsequent treatment with chlorambucil and prednisone for 3 months was accompanied by a worsening of the skin and joint disease. Radiographs taken 2 years after disease onset revealed erosive articular damage in the hands (Figure 3) and right hip. Combination therapy with cyclophosphamide (up to 200 mg daily), methotrexate (up to 25 mg weekly), and prednisone (20 mg daily) resulted in gradual improvement of only the skin eruption over 8 months, but cyclophosphamide was discontinued after the onset of gross hematuria.

Place holder to copy figure label and caption
Figure 3.

Radiograph of the left hand. Marginal erosions are present at multiple joints in the hand and wrist (most pronounced at the distal interphalangeal joint of the index finger), with relatively mild osteopenia. Similar changes were found in a radiograph of the right hand.

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Multicentric reticulohistiocytosis is a potentially disfiguring and crippling disease for which no consensus has been reached regarding treatment. Therapies with corticosteroids, hydroxychloroquine, methotrexate, alkylating agents such as chlorambucil and cyclophosphamide, and azathioprine have been used with mixed success.14 The challenge in this case was to determine a safe and effective treatment for both the skin and joint manifestations of the disease.

Immunohistochemical staining of the inflammatory infiltrate in MRH has demonstrated the presence of histiocytes of a monocyte-macrophage origin and an abundance of cytokines, including tumor necrosis factor α (TNF-α).57 The production of TNF-α and other cytokines by monocytes and macrophages plays a central role in many inflammatory conditions: TNF-α has been found in synovium and synovial fluid from joints of patients with several forms of inflammatory arthritis810 that may be successfully treated with anti-TNF agents. The predominance of histiocytes in the infiltrate of MRH and the detection of TNF-α inspired a trial of an anti-TNF agent, etanercept, as treatment for our patient.

Biweekly treatment with etanercept, 25 mg by subcutaneous injection, was started in addition to continuing treatment with prednisone, 20 mg daily, and methotrexate, 15 mg weekly. With this regimen there was improvement in skin and joint symptoms within 1 month, and prednisone was tapered over 7 months. The patient experienced a flare of skin lesions and arthritis as the dose of prednisone was reduced to 10 mg daily. At that time, treatment with etanercept, 25 mg biweekly, and prednisone, 10 mg daily, was continued, and methotrexate was replaced with leflunamide, 20 mg daily. Skin lesions and synovitis completely resolved with this regimen, which permitted a decrease of the prednisone dosage to 5 mg daily without a flare of symptoms for 10 months (Figure 4). There was some progression of articular deformities despite the control of synovitis. We believe that this resulted from articular damage that had previously occurred. The dosages of leflunamide and prednisone were recently decreased to 20 mg every other day and 4 mg daily, respectively, and treatment with etanercept was continued. The patient has remained symptom free for 2 months. We plan to continue tapering prednisone and leflunamide dosages if symptoms remain controlled.

Place holder to copy figure label and caption
Figure 4.

Hands after 7 months of treatment with etanercept.

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A rare multisystem disease of unknown etiology characterized by a histiocytic infiltrate in the dermis and synovium, MRH manifests as a papulonodular eruption and symmetric inflammatory polyarthritis. It tends to have an insidious onset, most commonly in the fourth decade of life, and is slightly predominant in women. At presentation, about 40% of patients have only joint symptoms, 30% only skin symptoms, and 30% both skin and joint symptoms.11 Active disease often remits after approximately 8 years12 and, although it is not considered a paraneoplastic syndrome, it occurs with an associated malignancy in about 20% of cases.11 Other sites of involvement can include the heart, lungs, thyroid, and bone marrow.11,13 Constitutional symptoms such as fever, malaise, and weight loss have been described, as have an elevated erythrocyte sedimentation rate, anemia, and hypercholesterolemia.11 Antibodies to neutrophil cytoplasmic antigens have not been reported in MRH. Antibody specificity was not determined in our patient.

Cutaneous manifestations include pink, red, or brown papules and nodules ranging from 1 millimeter to several centimeters in diameter and occurring most frequently on the dorsal aspect of the hands and on the face. Other sites of involvement include the arms, scalp, pinnae, and neck. Papules often occur in a periungual distribution, producing a characteristic "coral beads" appearance. Mucosal involvement, which includes the tongue and buccal or nasal mucosa, occurs in roughly one third of cases.11

A symmetric inflammatory polyarthritis can affect any synovial joint, including the hands, knees, wrists, shoulders, elbows, ankles, hips, feet, and spine.11 The arthritis can be rapidly progressive and destructive. Well-circumscribed marginal erosions and juxtarticular reabsorption are typical, often creating the appearance of a widening of the joint space.11,12 Severe involvement of the interphalangeal joints may cause shortening and telescoping of the involved fingers, forming characteristic "opera glass hands." It has been proposed that this joint destruction is mediated by urokinase released by activated histiocytes.14

Histologically, MRH can be recognized by a dermal or synovial infiltrate containing histiocytes and multinucleated giant cells with abundant eosinophilic, finely granular, ground-glasslike cytoplasm. The cytoplasm is periodic acid–Schiff positive and diastase resistant.13 These giant cells may be few in early lesions. In addition to histiocytes, small numbers of lymphocytes may be found in the infiltrate. As mentioned, immunohistochemical staining has revealed the presence of inflammatory cytokines, including TNF-α, interleukin 1 β, and interleukin 12.57

As in MRH, high levels of TNF-α have been found in the synovium and synovial fluid of joints affected by other inflammatory arthritides such as rheumatoid arthritis, juvenile rheumatoid arthritis, and psoriatic arthritis,810,15 all of which have been successfully treated with anti-TNF agents.1618 Mice overexpressing TNF-α also develop joint inflammation.19 Etanercept is a genetically engineered fusion protein made up of soluble TNF-α receptor fused to the Fc portion of IgG1 that binds circulating TNF-α. The predominance of histiocytes and presence of TNF-α in the inflammatory infiltrate of affected skin and joints make anti–TNF-α agents a logical therapeutic option in MRH. Matejicka et al20 recently reported a case of MRH in a 22-year-old woman resistant to treatment with prednisone, methotrexate, nonsteroidal anti-inflammatory drugs, hydroxychloroquine, cyclophosphamide, and cyclosporine who responded well to a combination of etanercept, methotrexate, and prednisone. This patient remained symptom free with a regimen of etanercept and hydroxychloroquine. Our experience with etanercept also suggests that anti-TNF agents may have an important role in the treatment of MRH.

Correspondence: Kenneth T. Calamia, MD, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224 (calamia@mayo.edu).

Accepted for publication October 10, 2003.

The authors have no relevant financial interest in this article.

Submissions

Clinicians, local and regional societies, residents, and fellows are invited to submit cases of challenges in management and therapeutics to this section. Cases should follow the established pattern. Submit 4 double-spaced copies of the manuscript with right margins nonjustified and 4 sets of the illustrations. Photomicrographs and illustrations must be clear and submitted as positive color transparencies (35-mm slides) or black-and-white prints. Do not submit color prints unless accompanied by original transparencies. Material should be accompanied by the required copyright transfer statement, as noted in "Instructions for Authors." Material for this section should be submitted to George J. Hruza, MD, Laser and Dermatologic Surgery Center Inc, 14377 Woodlake Dr, Suite 111, St Louis, MO 63017.

Cash  JMTyree  JRecht  M Severe multicentric reticulohistiocytosis: disease stabilization with methotrexate and hydroxychloroquine J Rheumatol. 1997;242250- 2253
PubMed
Gourmelen  OLe Loet  XFortier-Beaulieu  M  et al.  Methotrexate treatment of multicentric reticulohistiocytosis J Rheumatol. 1991;18627- 628
PubMed
Ginsburg  WWO'Duffy  DMorris  JLHuston  KA Multicentric reticulohistiocytosis: response to alkylating agents in 6 patients Ann Intern Med. 1989;111384- 388
PubMed Link to Article
Guillen  CFortea  JMSerrano  G  et al.  Multicentric reticulohistiocytosis Dermatologica. 1984;169311- 317
PubMed Link to Article
Gorman  JDDanning  CSchumacher  HRKlippel  JHDavic Jr  JC Multicentric reticulohistiocytosis: a case report with immunohistochemical analysis and literature review Arthritis Rheum. 2000;43930- 938
PubMed Link to Article
Nakamura  HYoshino  SShiga  HTanaka  HKatsumata  S A case of spontaneous femoral neck fracture associated with multicentric reticulohistiocytosis: oversecretion of interleukin-1 beta, interleukin-6, and tumor necrosis factor alpha by affected synovial cells Arthritis Rheum. 1997;402266- 2270
PubMed Link to Article
Salisbury  JRHall  PAWilliams  HCMangi  MHMufti  GJ Multicentric reticulohistiocytosis: detailed immunophenotyping confirms macrophage origin Am J Surg Pathol. 1990;14687- 693
PubMed Link to Article
Partsch  GSteiner  GLeeb  BFDunky  ABroll  HSmolen  JS Highly increased levels of tumor necrosis factor-alpha and other proinflammatory cytokines in psoriatic arthritis synovial fluid J Rheumatol. 1997;24518- 523
PubMed
Mangge  HKenzian  HGallistl  S  et al.  Serum cytokines in juvenile rheumatoid arthritis: correlation with conventional inflammation parameters and clinical subtypes Arthritis Rheum. 1995;38211- 220
PubMed Link to Article
Chu  CQField  MFeldman  MMaini  RN Localization of tumor necrosis factor alpha in synovial tissues and at the cartilage-pannus junction in patients with rheumatoid arthritis Arthritis Rheum. 1991;341125- 1132
PubMed Link to Article
Luz  FBGaspar  APKalil-Gaspar  NRamos-e-Silva  M Multicentric reticulohistiocytosis J Eur Acad Dermatol Venereol. 2001;15524- 531
PubMed Link to Article
Barow  MVHolubar  K Multicentric reticulohistiocytosis: a review of 33 patients Medicine (Baltimore). 1969;48287- 305
PubMed Link to Article
Rapini  RP Multicentric reticulohistiocytosis Clin Dermatol. 1993;11107- 111
PubMed Link to Article
Lotti  TSantucci  MCasigliani  RFabbri  PBondi  RPanconesi  E Multicentric reticulohistiocytosis: report of three cases with the evaluation of tissue proteinase activity Am J Dermatopathol. 1988;10497- 504
PubMed Link to Article
Ritchlin  CHaas-Smith  SAHicks  DCappuccio  JOsterland  CKLooney  JR Patterns of cytokine production in psoriatic synovium J Rheumatol. 1998;251544- 1552
PubMed
Bathon  JMMartin  RWFleischmann  RM  et al.  A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis N Engl J Med. 2000;3431586- 1593
PubMed Link to Article
Lovell  DJGiannini  EHReiff  A  et al. Pediatric Rheumatology Collaborative Study Group, Etanercept in children with polyarticular juvenile rheumatoid arthritis N Engl J Med. 2000;342763- 769
PubMed Link to Article
Mease  PJGoffe  BSMetz  JVanderStoep  AFinck  BBurge  DJ Etanercept in the treatment of psoriatic arthritis and psoriases: a randomised trial Lancet. 2000;356385- 390
PubMed Link to Article
Keffer  JProbert  LCazlaris  H  et al.  Transgenic mice expressing human tumor necrosis factor: a predictive genetic model of arthritis EMBO J. 1991;104025- 4031
PubMed
Matejicka  CMorgan  GJSchlegelmilch  JG Multicentric reticulohistiocytosis treated with an anti-tumor necrosis factor agent: comment on the article by Gorman et al Arthritis Rheum. 2003;48864- 866
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Hands before treatment with etanercept.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

A skin biopsy specimen revealed dermal infiltrate of histiocytes and multinucleated giant cells with abundant "ground glass" cytoplasm.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Radiograph of the left hand. Marginal erosions are present at multiple joints in the hand and wrist (most pronounced at the distal interphalangeal joint of the index finger), with relatively mild osteopenia. Similar changes were found in a radiograph of the right hand.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Hands after 7 months of treatment with etanercept.

Graphic Jump Location

Tables

References

Cash  JMTyree  JRecht  M Severe multicentric reticulohistiocytosis: disease stabilization with methotrexate and hydroxychloroquine J Rheumatol. 1997;242250- 2253
PubMed
Gourmelen  OLe Loet  XFortier-Beaulieu  M  et al.  Methotrexate treatment of multicentric reticulohistiocytosis J Rheumatol. 1991;18627- 628
PubMed
Ginsburg  WWO'Duffy  DMorris  JLHuston  KA Multicentric reticulohistiocytosis: response to alkylating agents in 6 patients Ann Intern Med. 1989;111384- 388
PubMed Link to Article
Guillen  CFortea  JMSerrano  G  et al.  Multicentric reticulohistiocytosis Dermatologica. 1984;169311- 317
PubMed Link to Article
Gorman  JDDanning  CSchumacher  HRKlippel  JHDavic Jr  JC Multicentric reticulohistiocytosis: a case report with immunohistochemical analysis and literature review Arthritis Rheum. 2000;43930- 938
PubMed Link to Article
Nakamura  HYoshino  SShiga  HTanaka  HKatsumata  S A case of spontaneous femoral neck fracture associated with multicentric reticulohistiocytosis: oversecretion of interleukin-1 beta, interleukin-6, and tumor necrosis factor alpha by affected synovial cells Arthritis Rheum. 1997;402266- 2270
PubMed Link to Article
Salisbury  JRHall  PAWilliams  HCMangi  MHMufti  GJ Multicentric reticulohistiocytosis: detailed immunophenotyping confirms macrophage origin Am J Surg Pathol. 1990;14687- 693
PubMed Link to Article
Partsch  GSteiner  GLeeb  BFDunky  ABroll  HSmolen  JS Highly increased levels of tumor necrosis factor-alpha and other proinflammatory cytokines in psoriatic arthritis synovial fluid J Rheumatol. 1997;24518- 523
PubMed
Mangge  HKenzian  HGallistl  S  et al.  Serum cytokines in juvenile rheumatoid arthritis: correlation with conventional inflammation parameters and clinical subtypes Arthritis Rheum. 1995;38211- 220
PubMed Link to Article
Chu  CQField  MFeldman  MMaini  RN Localization of tumor necrosis factor alpha in synovial tissues and at the cartilage-pannus junction in patients with rheumatoid arthritis Arthritis Rheum. 1991;341125- 1132
PubMed Link to Article
Luz  FBGaspar  APKalil-Gaspar  NRamos-e-Silva  M Multicentric reticulohistiocytosis J Eur Acad Dermatol Venereol. 2001;15524- 531
PubMed Link to Article
Barow  MVHolubar  K Multicentric reticulohistiocytosis: a review of 33 patients Medicine (Baltimore). 1969;48287- 305
PubMed Link to Article
Rapini  RP Multicentric reticulohistiocytosis Clin Dermatol. 1993;11107- 111
PubMed Link to Article
Lotti  TSantucci  MCasigliani  RFabbri  PBondi  RPanconesi  E Multicentric reticulohistiocytosis: report of three cases with the evaluation of tissue proteinase activity Am J Dermatopathol. 1988;10497- 504
PubMed Link to Article
Ritchlin  CHaas-Smith  SAHicks  DCappuccio  JOsterland  CKLooney  JR Patterns of cytokine production in psoriatic synovium J Rheumatol. 1998;251544- 1552
PubMed
Bathon  JMMartin  RWFleischmann  RM  et al.  A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis N Engl J Med. 2000;3431586- 1593
PubMed Link to Article
Lovell  DJGiannini  EHReiff  A  et al. Pediatric Rheumatology Collaborative Study Group, Etanercept in children with polyarticular juvenile rheumatoid arthritis N Engl J Med. 2000;342763- 769
PubMed Link to Article
Mease  PJGoffe  BSMetz  JVanderStoep  AFinck  BBurge  DJ Etanercept in the treatment of psoriatic arthritis and psoriases: a randomised trial Lancet. 2000;356385- 390
PubMed Link to Article
Keffer  JProbert  LCazlaris  H  et al.  Transgenic mice expressing human tumor necrosis factor: a predictive genetic model of arthritis EMBO J. 1991;104025- 4031
PubMed
Matejicka  CMorgan  GJSchlegelmilch  JG Multicentric reticulohistiocytosis treated with an anti-tumor necrosis factor agent: comment on the article by Gorman et al Arthritis Rheum. 2003;48864- 866
PubMed Link to Article

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