AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

In 1954, Goltz and Laymon coined the term multicentric reticulohistiocytosis (MRH) to describe patients with destructive arthritis and multiple cutaneous nodules that histologically manifest as an infiltrate of histiocytic multinucleated giant cells with eosinophilic ground-glass cytoplasm.¹ This is a rare condition; fewer than 200 cases have been reported in the world literature. Various diseases have been associated with MRH, including malignancy.²

Pathophysiology

The pathogenesis of this condition is unknown but probably has an immunologic basis. Some studies have demonstrated increased levels of tumor necrosis factor (TNF)–alpha in the blood and in the tissue.^{3, 4}

Frequency

United States

This is a rare condition.

International

This is a rare condition.

Mortality/Morbidity

The disease is a debilitating process but rarely causes death unless the patient has an associated malignancy.

Race

This disease has been reported primarily in whites.

Sex

Women are affected more commonly than men, with a female-to-male ratio of 2:1.

Age

The disease may occur at any age, but it has been reported primarily in middle-aged adults, with a mean age of 43 years.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

• The primary manifestations of multicentric reticulohistiocytosis (MRH) are joint and skin diseases.
• • Inflammatory joint disease is a frequent presenting symptom, and it is the sole symptom in 45% of patients.
  • Skin disease is common, and it is the presenting manifestation in 30% of patients.

Physical

• The joint disease usually manifests as destructive and deforming symmetrical polyarthritis with a predilection for the distal interphalangeal joints.
• The classic skin lesions are multiple nodules that have a predilection for the hands, particularly the base of the nails, but they may occur on any body surface.
• • The lesions are usually nontender.
  • The nodules may be skin colored, red, or yellowish.
  • They vary in size from 1-10 mm and can coalesce to form plaques with a cobblestone surface.
  • One third of patients also have a xanthelasma.
  • The nodules grow slowly, and they rarely ulcerate.
  • Infiltrated plaques may resemble mucinosis.

Causes

The cause of MRH is unknown, but various associated diseases have been reported in patients with MRH.

• Malignancy has been reported in multiple patients (as many as 25%).
• • No specific site or type of malignancy has been reported.
  • Those reported include melanoma, sarcoma, leukemia, lymphoma, and carcinomas (usually adenocarcinoma) of the breast,⁵ colon, bronchus, cervix, stomach, and ovaries.
• Various endocrinopathies have been reported, including diabetes mellitus and hypothyroidism.
• Other associated conditions include rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, primary biliary cirrhosis, and pregnancy.

DIFFERENTIALS

Section 4 of 11  

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• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Generalized eruptive histiocytosis
Juvenile rheumatoid arthritis
Juvenile xanthogranuloma
Langerhans cell histiocytosis
Non–X histiocytosis
Xanthomas
Psoriatic arthritis
Fibroblastic rheumatism

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• No specific laboratory studies are specific for multicentric reticulohistiocytosis (MRH). Rheumatoid factor findings are usually negative.

Imaging Studies

• Radiography of the affected joints reveals destruction of bone disproportionate to loss of cartilage. Lesions may resemble gouty erosions.
• • Mild osteopenia is noted.
  • Marked resorption of subchondral bone is common.
  • The findings may develop rapidly and can resemble arthritis mutilans.
• The cutaneous nodules may be seen as soft tissue swellings.

Other Tests

• Findings on joint fluid analysis vary. The effusions may demonstrate polymorphonuclear leukocytes or mononuclear cells.

Histologic Findings

Early skin lesions demonstrate a lymphohistiocytic infiltrate. Mature lesions demonstrate a dermis filled by giant multinucleated cells with a pale, fine, granular (ie, ground glass) eosinophilic cytoplasm. Periodic acid-Schiff stain results are positive and are diastase-resistant. Lipid stain results may be positive. Results of acid phosphatase, nonspecific esterase, and lysozyme stains are usually positive. Results of S100 protein and alpha-1-antitrypsin are negative. Langerhans granules are absent on electron microscopy. In synovial biopsy, lipid-laden giant cells and histiocytes are similar to those seen on skin biopsy.

TREATMENT

Section 6 of 11  

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• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

• No effective treatment is known for multicentric reticulohistiocytosis (MRH).
• Therapy with nonsteroidal anti-inflammatory agents may help the arthritis.
• Systemic corticosteroids and/or cytotoxic agents, particularly cyclophosphamide,^{6, 7} chlorambucil,⁶ or methotrexate,^{8, 9, 7, 10} may affect the inflammatory response, prevent further joint destruction, and cause skin lesions to regress.
• Antimalarials have also been used.
• Alendronate and other bisphosphonates have been reported to be effective in an individual patient.¹¹
• TNF-alpha antagonists have been reported to be effective in many, but not all, patients. Reports of both etanercept^{3, 4} and infliximab¹² have been reported as effective in recent literature, and one would expect that adalimumab might also be effective in an individual patient.

Surgical Care

Joint replacement may improve function in patients with burned-out disease that has resulted in deformity.

Consultations

A rheumatologist and a dermatologist may be consulted.

Activity

Activity may be limited by the severity of the disease. Physical therapy may prevent deformities and relieve symptoms.

MEDICATION

Section 7 of 11  

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• Follow-up
• Miscellaneous
• Multimedia
• References

No drug of choice is known. Most patients with multicentric reticulohistiocytosis (MRH) are treated with oral prednisone, with or without a cytotoxic/immunosuppressive agent such as methotrexate, cyclophosphamide, or chlorambucil.

Drug Category: Corticosteroids

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.

Drug Category: Cytotoxic/immunosuppressive agents

These are steroid sparing. None have been documented to be effective, except in anecdotal reports.

Drug Category: Antimalarial

Derivatives of 4-aminoquinoline are active against various autoimmune disorders.

Drug Category: TNF antagonists

Individual case reports suggest a benefit.

Drug Category: Bisphosphonates

These agents are analogs of pyrophosphate and act by binding to hydroxyapatite in bone matrix, thereby inhibiting the dissolution of crystals. These drugs prevent osteoclast attachment to the bone matrix and osteoclast recruitment and viability.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Inpatient care is often unnecessary.

Further Outpatient Care

• Patients with multicentric reticulohistiocytosis (MRH) should be monitored at regular intervals to track the activity of the disease and its therapy.

Transfer

• MRH is a rare condition. The patient should be referred to a medical center at least once following diagnosis.

Complications

• This disease can cause deformities of the joints and disfigurement due to the skin lesions.
• If cytotoxic agents are used, the patient should be monitored for development of a malignancy in the future.

Prognosis

• The disease is debilitating but is not life threatening.
• If the patient has an associated malignancy, the prognosis relates to that of the malignancy.

MISCELLANEOUS

Section 9 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Misdiagnosis
• Toxicity of therapy in patients who may not have been informed of the risks

MULTIMEDIA

Section 10 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Multiple erythematous nodules are present on the dorsal hands of this adolescent with an inflammatory arthropathy.
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Media file 2:  Multiple erythematous to brown nodules on the fingers.
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Media type:  CT

Media file 3:  Erythematous, poikilodermatous mamillated plaque on the anterior chest.
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Media file 4:  Histopathology of multicentric reticulohistiocytosis (MRH) skin lesions.
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Media file 5:  Histopathology of multicentric reticulohistiocytosis (MRH) skin lesions. Higher power demonstrating the ground glass cytoplasm and multinucleated giant cells.
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Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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2. Nunnink JC, Krusinski PA, Yates JW. Multicentric reticulohistiocytosis and cancer: a case report and review of the literature. Med Pediatr Oncol. 1985;13(5):273-9. [Medline].
3. Kovach BT, Calamia KT, Walsh JS, Ginsburg WW. Treatment of multicentric reticulohistiocytosis with etanercept. Arch Dermatol. Aug 2004;140(8):919-21. [Medline].
4. Lovelace K, Loyd A, Adelson D, Crowson N, Taylor JR, Cornelison R. Etanercept and the treatment of multicentric reticulohistiocytosis. Arch Dermatol. Sep 2005;141(9):1167-8. [Medline].
5. Valencia IC, Colsky A, Berman B. Multicentric reticulohistiocytosis associated with recurrent breast carcinoma. J Am Acad Dermatol. Nov 1998;39(5 Pt 2):864-6. [Medline].
6. Ginsburg WW, O'Duffy JD, Morris JL, Huston KA. Multicentric reticulohistiocytosis: response to alkylating agents in six patients. Ann Intern Med. Sep 1 1989;111(5):384-8. [Medline].
7. Liang GC, Granston AS. Complete remission of multicentric reticulohistiocytosis with combination therapy of steroid, cyclophosphamide, and low-dose pulse methotrexate. Case report, review of the literature, and proposal for treatment. Arthritis Rheum. Jan 1996;39(1):171-4. [Medline].
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10. Rentsch JL, Martin EM, Harrison LC, Wicks IP. Prolonged response of multicentric reticulohistiocytosis to low dose methotrexate. J Rheumatol. May 1998;25(5):1012-5. [Medline].
11. Goto H, Inaba M, Kobayashi K, et al. Successful treatment of multicentric reticulohistiocytosis with alendronate: evidence for a direct effect of bisphosphonate on histiocytes. Arthritis Rheum. Dec 2003;48(12):3538-41. [Medline].
12. Sellam J, Deslandre CJ, Dubreuil F, et al. Refractory multicentric reticulohistiocytosis treated by infliximab: two cases. Clin Exp Rheumatol. Jan-Feb 2005;23(1):97-9. [Medline].
13. Barrow MV, Holubar K. Multicentric reticulohistiocytosis. A review of 33 patients. Medicine (Baltimore). Jul 1969;DA - 19690930(4):287-305. [Medline].
14. Blanco JJ, Hernandez FJ, Cerezo JG, et al. Multicentric reticulohistiocytosis. The long course of a rare disease. Scand J Rheumatol. 2002;31(2):107-9. [Medline].
15. Callen JP. Miscellaneous disorders that commonly affect both skin and joints. In: Provost TT, ed. Cutaneous Manifestations of Rheumatic Diseases. Lippincott Williams & Wilkins; 1996:278-9.
16. Candell Chalom E, Elenitsas R, Rosenstein ED, Kramer N. A case of multicentric reticulohistiocytosis in a 6-year-old child. J Rheumatol. Apr 1998;25(4):794-7. [Medline].
17. Cox NH, West NC, Popple AW. Multicentric reticulohistiocytosis associated with idiopathic myelofibrosis. Br J Dermatol. Dec 2001;145(6):1033-4. [Medline].
18. Hiramanek N, Kossard S, Barnetson RS. Multicentric reticulohistiocytosis presenting with a rash and arthralgia. Australas J Dermatol. May 2002;43(2):136-9. [Medline].
19. Hsiung SH, Chan EF, Elenitsas R, et al. Multicentric reticulohistiocytosis presenting with clinical features of dermatomyositis. J Am Acad Dermatol. Feb 2003;48(2 Suppl):S11-4. [Medline].
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21. Orkin M, Goltz RW, Good RA, et al. A study of multicentric reticulohistiocytosis. Arch Dermatol. May 1964;89:640-54. [Medline].
22. Outland JD, Keiran SJ, Schikler KN, Callen JP. Multicentric reticulohistiocytosis in a 14-year-old girl. Pediatr Dermatol. Nov-Dec 2002;19(6):527-31. [Medline].
23. Peters MS. Histiocytic and Langerhans cell reactions. In: Farmer ER, Hood AF, eds. Pathology of the Skin. 1990:263-5.
24. Raphael SA, Cowdery SL, Faerber EN, et al. Multicentric reticulohistiocytosis in a child. J Pediatr. Feb 1989;114(2):266-9. [Medline].
25. Santilli D, Lo Monaco A, Cavazzini PL, Trotta F. Multicentric reticulohistiocytosis: a rare cause of erosive arthropathy of the distal interphalangeal finger joints. Ann Rheum Dis. Jun 2002;61(6):485-7. [Medline].
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27. Weber FP, Freudenthal W. Nodular non-diabetic cutaneous xanthomatosis with hypercholesterolemia and atypical histologic features. Proc R Soc Med. 1937;30:522-6.
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Article Last Updated: Oct 31, 2007