Multicentric Reticulohistiocytosis

Multicentric Reticulohistiocytosis

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Multicentric reticulohistiocytosis (MRH) is a rare disease in which papulonodular skin lesions containing a proliferation of true histiocytes (macrophages) are associated with arthritis that primarily affects the interphalangeal joints [1] (see the image below). MRH is not life threatening and, after an average course of 7-8 years, the disease often goes into remission. However, in 45% of cases, the associated arthritis may cause severe joint destruction known as arthritis mutilans.

In addition to the joints, MRH can involve the bones, tendons, and muscles, as well as almost any organ (eg, the eyes, larynx, thyroid, salivary glands, bone marrow, heart, lungs, kidneys, liver, gastrointestinal tract).

MRH is a rare, systemic histiocytic disease that mainly affects the skin and joints. Joint involvement primarily manifests with symmetric polyarthritis with a predilection for the distal interphalangeal joints. However, several other joints may be affected. The rates of distribution of joint disease are as follows:

Hands (76%)

Knees (73%)

Shoulders (64%)

Wrists (64%)

Hips (61%)

Ankles (58%)

Elbows (58%)

Feet (58%)

Spine (52%)

Skin involvement generally manifests with translucent reddish-brown to flesh-colored papulonodules varying from 1-2 mm to 1 cm in diameter or larger. Lesions may be isolated from one another, or they may be clustered, sometimes giving them a cobblestone appearance.

The lesions are usually nontender, although some patients may complain of pruritus, which can be diffuse. The nodules grow slowly and rarely ulcerate. Infiltrated plaques may resemble mucinosis. Although MRH lesions have a predilection for the hands and face, they may occur on any surface of the body.

See Clinical Presentation for more detail.

No laboratory studies are specific for MRH. Findings, however, are as follows:

Elevated erythrocyte sedimentation rate (ESR) or anemia: In about one half of patients

Thyroid function abnormalities: In some, but not all, patients

Diabetes: In about 6% of patients

Hypercholesterolemia: Found in one third of patients; often associated with xanthelasma, but this seems to be unrelated to MRH

Rheumatoid factor: Characteristically negative, but it has reportedly been positive in at least 4 cases

Paraproteinemia, cold agglutinins, cryoglobulinemia, antinuclear antibody, or hypergammaglobulinemia: Occasionally found

Synovial fluid abnormalities: Variable; reports exist of elevated counts of neutrophils or mononuclear cells.

Histiologic studies in MRH reveal the following:

Early skin lesions demonstrate a dermal lymphohistiocytic infiltrate

Histiocytes may be oncocytic, small, or multinucleated

Histiocytes may occasionally be lipid-laden, but are not usually foamy to the degree found in other histiocytic disorders

Mature lesions demonstrate multinucleated giant cells, with a pale, fine, granular (ie, ground-glass) eosinophilic cytoplasm filling the dermis

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

S100 protein, CD34, factor XIIIa, and alpha-1-antitrypsin results are typically negative

Histiocytes stain positive for vimentin, CD68, and CD45, and small activated histiocytes stain positive for MAC387 [2]

One study demonstrated aberrant expression of CD10 (a 90- to 110-kd cell surface zinc-dependent metalloprotease) in skin and synovial multinucleated giant cells in patients with MRH, whereas expression of CD10 was not detected in other histiocytic lesions, including skin samples of granuloma annulare, giant-cell tendon sheath tumor, ruptured epidermoid cyst, sarcoidosis, xanthogranuloma, and synovial samples of rheumatoid arthritis and pigmented villonodular synovitis [3]

Langerhans granules are absent on electron microscopy

In a synovial biopsy, lipid-laden giant cells and histiocytes are similar to those seen on skin biopsy; histiocytes are sometimes found after blind synovial biopsies in patients who have unclassified arthritis but no skin lesions [4]

Routine radiographs of joints may be helpful in the diagnosis of MRH. Changes, which may develop rapidly, are most commonly seen in the proximal or distal interphalangeal joints.

See Workup for more detail.

Although no consistently effective treatment is known for MRH, the associated arthritis may respond to therapy with nonsteroidal anti-inflammatory drugs (NSAIDs).

Systemic corticosteroids, such as prednisone, and/or cytotoxic agents, particularly cyclophosphamide, [5, 6] chlorambucil, [5] and methotrexate, [7, 8, 6, 9] may also affect the inflammatory response, as well as prevent further joint destruction and cause skin lesions to regress. Azathioprine, cyclosporine, antimalarials, bisphosphonates, leflunomide, and tumor necrosis factor-alpha (TNF-alpha) antagonists have also been used effectively. [10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25] More recently, a case of MRH responsive to tocilizumab has been reported, [26] and carbon dioxide laser has been reported to improve cosmetically disfiguring facial lesions of MRH. [27]

See Treatment and Medication for more detail.

Multicentric reticulohistiocytosis (MRH) is a rare disease in which papulonodular skin lesions containing a proliferation of true histiocytes (macrophages) are associated with arthritis. [1, 28] The arthritis involves the interphalangeal joints and in 45% of cases causes severe joint destruction known as arthritis mutilans. (See Pathophysiology, Clinical Presentation, and Workup.)

In addition to the skin and joints, MRH can involve the bones, tendons, and muscles, as well as almost any organ (eg, the eyes, larynx, thyroid, salivary glands, bone marrow, heart, lungs, kidneys, liver, gastrointestinal tract). (See the images below.)

MRH has been associated with an underlying internal malignancy in about one fourth of cases, suggesting that it may be a paraneoplastic condition. The proliferating histiocytes in this disease are thought to be reactive and are not themselves malignant. (See Etiology, Prognosis, and Workup.)

For patient education resources, see the Arthritis Center.

The pathogenesis of MRH is unknown but probably has an immunologic basis. The pathogenesis of MRH is unknown but probably has an immunologic basis. Increased interleukin-12, interleukin-1b, interleukin-6, and urokinase have been described and are thought to play a role in bone destruction. [29, 30, 31] Some studies have demonstrated increased levels of tumor necrosis factor (TNF)–alpha in the blood and in the tissue. [10, 11] A report on one patient with MRH described overexpression of monocyte chemoattractant protein–1 (MCP-1), which is stimulated by TNF-alpha, in the serum and lesional epidermis. In this patient, serum levels of MCP-1 decreased with treatment. The authors hypothesized that MCP-1 may play a role in attracting histiocytes and giant cells in patients with MRH. [32]

In addition, increased osteoclastic activity has been implicated in the pathogenesis of MRH, and synovial macrophages in patients with MRH may possess the ability to differentiate into osteoclasts. [33] These findings may help explain the success of bisphosphonate treatment in some cases. [33, 34]

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

Malignancy is the most commonly recognized association with the disorder, having been reported in multiple patients with MRH (perhaps as many as 25-33%); MRH precedes the development of cancer in 73% of these cases. No specific site or type of malignancy has been identified as most commonly found with MRH, and most of the reported specific cancer types have been reported less than 5 times each in the literature.

Reported malignancies include the following:

Breast cancer (scirrhous, intraductal, unspecified types) [35]

Cervical cancer

Colon cancer (adenocarcinoma)

Stomach cancer (adenocarcinoma)

Bladder cancer (small-cell neuroendocrine carcinoma)

Renal cancer (sarcomatoid renal cell carcinoma) [36]

Liver carcinoma [37]

Lung cancer (bronchogenic carcinoma, mesothelioma of pleura, squamous cell carcinoma [38] )

Bronchial cancer

Laryngeal cancer

Ovarian cancer (medullary carcinoma, adenocarcinoma) [39]



Sarcoma (omentum, axilla)


Extramammary Paget disease [40]

Cancers of unknown primary

Because MRH is rare, a reporting bias exists in the literature toward those cases with underlying malignancy, especially previously unreported malignancies. Some of these associations may be a coincidence.

The activity of the arthritis and skin lesions in MRH may or may not be correlated with the eradication of the cancer, unlike some paraneoplastic disorders in which removal of the malignancy can produce improvement in the paraneoplastic findings.

Other conditions associated with MRH include the following:

Endocrinopathies (including diabetes mellitus and hypothyroidism)

Rheumatoid arthritis

Systemic lupus erythematosus

Sjögren syndrome

Primary biliary cirrhosis


One report of MRH in a patient with both Sjögren syndrome and systemic sclerosis [41]

Worldwide, MRH is very rare. The average dermatologist, rheumatologist, or orthopedist will see at most 1-2 cases in an entire career.

MRH affects all races, but about 88% of the reported cases have been in white patients. Like many other rheumatologic diseases, females are affected more often than men. The ratio of women to men for MRH has been reported as either 2:1 or 3:1.

Although MRH can occur at any age, but it has been reported primarily in middle-aged adults, with a mean age of 43 years. There are rare reports of MRH occurring during childhood.

MRH is not life threatening and, after an average course of 7-8 years, often goes into remission. The major morbidity of the disease is due to the associated arthritis, which primarily involves the interphalangeal joints. Although the arthritis may wax and wane, it can cause severe joint destruction known as arthritis mutilans in approximately 45% of cases. Therefore, even after the disease remits, some patients are left with deformed, crippled joints. In addition, skin lesions in MRH can result in disfigured, leonine facies.

The prognosis in MRH is also related to that of any associated malignancy. Pulmonary and cardiac involvement are other potential complications. Although these complications are rare, they may confer a poor prognosis.

If cytotoxic agents are used in the treatment of MRH, the patient should be monitored for subsequent development of a malignancy.

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Alisa N Femia, MD Assistant Professor, Ronald O Perelman Department of Dermatology, New York University Medical Center

Alisa N Femia, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, Society for Investigative Dermatology, Medical Dermatology Society, Rheumatologic Dermatology Society

Disclosure: Nothing to disclose.

Ruth Ann Vleugels, MD, MPH Assistant Professor of Dermatology, Harvard Medical School; Associate Physician, Department of Dermatology, Brigham and Women’s Hospital; Associate Physician, Department of Immunology and Allergy, Children’s Hospital Boston

Ruth Ann Vleugels, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Rheumatology, American Medical Association, Society for Investigative Dermatology, Medical Dermatology Society, Dermatology Foundation

Disclosure: Nothing to disclose.

Jeffrey P Callen, MD Professor of Medicine (Dermatology), Chief, Division of Dermatology, University of Louisville School of Medicine

Jeffrey P Callen, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, American College of Rheumatology

Disclosure: Received income in an amount equal to or greater than $250 from: Lilly; Amgen <br/>Received honoraria from UpToDate for author/editor; Received honoraria from JAMA Dermatology for associate editor; Received royalty from Elsevier for book author/editor; Received dividends from trust accounts, but I do not control these accounts, and have directed our managers to divest pharmaceutical stocks as is fiscally prudent from Stock holdings in various trust accounts include some pharmaceutical companies and device makers for i inherited these trust accounts; for: Allergen; Celgene; Pfizer; 3M; Johnson and Johnson; Merck; Abbott Laboratories; AbbVie; Procter and Gamble; Amgen.

Ronald P Rapini, MD Professor and Chair, Department of Dermatology, The University of Texas MD Anderson Cancer Center; Distinguished Chernosky Professor and Chair of Dermatology, Professor of Pathology, University of Texas McGovern Medical School at Houston

Ronald P Rapini, MD is a member of the following medical societies: American Academy of Dermatology, American Dermatological Association, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, American Society of Dermatopathology, Association of Professors of Dermatology, Society for Investigative Dermatology, Texas Dermatological Society

Disclosure: Book royalties from Elsevier publishers.

Herbert S Diamond, MD Visiting Professor of Medicine, Division of Rheumatology, State University of New York Downstate Medical Center; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital

Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Association, Phi Beta Kappa

Disclosure: Nothing to disclose.

Marcel E Conrad, MD Distinguished Professor of Medicine (Retired), University of South Alabama College of Medicine

Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, and Southwest Oncology Group

Disclosure: No financial interests None None

Rosalie Elenitsas, MD Herman Beerman Associate Professor of Dermatology, University of Pennsylvania School of Medicine; Director, Penn Cutaneous Pathology Services, Department of Dermatology, University of Pennsylvania Health System

Rosalie Elenitsas, MD is a member of the following medical societies: American Academy of Dermatology and American Society of Dermatopathology

Disclosure: Lippincott Williams Wilkins Royalty Textbook editor

Dirk M Elston, MD Director, Ackerman Academy of Dermatopathology, New York

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Bryan L Martin, DO Associate Dean for Graduate Medical Education, Designated Institutional Official, Associate Medical Director, Director, Allergy Immunology Program, Professor of Medicine and Pediatrics, Ohio State University College of Medicine

Bryan L Martin, DO is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology, American College of Osteopathic Internists, American College of Physicians, American Medical Association, and American Osteopathic Association

Disclosure: Nothing to disclose.

Lindsay T (Morgan) Bicknell, MD University of Texas Medical School at Houston

Lindsay T Morgan is a member of the following medical societies: American Medical Association

Disclosure: Nothing to disclose.

Takeji Nishikawa, MD Emeritus Professor, Department of Dermatology, Keio University School of Medicine; Director, Samoncho Dermatology Clinic; Managing Director, The Waksman Foundation of Japan Inc

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Richard P Vinson, MD Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Association of Military Dermatologists, Texas Dermatological Society, and Texas Medical Association

Disclosure: Nothing to disclose.

Multicentric Reticulohistiocytosis

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