Multicentric Reticulohistiocytosis

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Practice Essentials

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] 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).

Signs and symptoms

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:

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.

Diagnosis

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

Histiologic studies in MRH reveal the following:

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.

Management

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.

Image library


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Multiple erythematous nodules are present on the dorsal hands of this adolescent with an inflammatory arthropathy.

Background

Multicentric reticulohistiocytosis (MRH) is a rare disease in which papulonodular skin lesions containing a proliferation of true histiocytes (macrophages) are associated with arthritis.[1] 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.)


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Multiple erythematous nodules are present on the dorsal hands of this adolescent with an inflammatory arthropathy.


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Multiple erythematous to brown nodules on the fingers.

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.)

Patient education

For patient education resources, see the Arthritis Center.

Pathophysiology

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.[28, 29, 30] 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.[31]

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.[32] These findings may help explain the success of bisphosphonate treatment in some cases.[32, 33]

Etiology

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:

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:

Epidemiology

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

Race-, sex-, and age-related demographics

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.

Prognosis

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.

History

The primary manifestations of multicentric reticulohistiocytosis (MRH) are joint and skin involvement. Inflammatory joint disease is a presenting symptom in approximately 40% of cases and is the sole symptom in 45% of patients. Although the arthritis may wax and wane, it can rapidly become severe.

Approximately 30% of patients first develop skin papules and nodules, while another 25% of patients develop skin and joint manifestations at the same time. One tenth to one third of patients report pruritus.

Nonspecific pulmonary findings, such as pleural effusions and infiltrates, have been reported in association with MRH. Direct pulmonary involvement by MRH is extraordinarily rare but has been reported in 5 cases to date.[41]

Cardiac involvement is also extremely rare, but it has been reported in isolated cases and can manifest with myocardial involvement or pericardial disease.[42, 43, 44, 45]

There is one reported case of hepatic involvement in a patient with MRH and lung involvement.[46]

About one third of patients have constitutional symptoms, such as weakness, weight loss, and fever.

Physical Examination

Arthritis

MRH is a polyarthritis with a predilection for the distal interphalangeal joints but capable of affecting several others (see the image below). The rates of distribution are as follows:

Cutaneous lesions

Lesions vary from papules that are 1-2 mm in diameter to nodules that are 1 cm in diameter or larger. Papules and lesions may be isolated from one another, or they may be clustered, sometimes giving them a cobblestone appearance (see the image below). Clustering of papulonodules overlying the periungual areas may result in a characteristic “coral-bead” appearance. Nodules overlying extensor joints may resemble rheumatoid nodules.


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Cobblestone papules on the eyelid and papules on the forehead.

The lesions are usually nontender and may be skin colored, red, or yellowish. The nodules grow slowly and rarely ulcerate. Infiltrated plaques may resemble mucinosis.

The Koebner phenomenon has been reported, wherein trauma to the skin, including from ultraviolet (UV) radiation,[47] gives rise to new lesions.

Although MRH lesions have a predilection for the hands and face, they may occur on any surface of the body. Distribution rates are as follows:

In rare cases (9 reported to date), patients have a photodistribution of lesions simulating dermatomyositis, although it is possible that this manifestation is underrecognized. (See the images below.)[48, 49, 50]


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Erythematous to brown papules overlying the right dorsal hand and wrist and erythematous to violaceous patches over the right dorsal hand and fingers.....


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Erythematous to brown papules and erythematous to violaceous patches overlying the right dorsal hand and fingers, with a crusted erosion overlying the....

Malignancy is associated with MRH in approximately 25% of cases, similar to the observed frequency in dermatomyositis. Features mimicking dermatomyositis in a patient with MRH, however, do not appear to increase the risk of malignancy.

About one third of patients have been reported to have xanthelasma, but whether this is related to MRH is unclear.[48]

Approach Considerations

No laboratory studies are specific for multicentric reticulohistiocytosis (MRH). Findings, however, are as follows:

Imaging Studies

Radiography

Routine radiographs of joints may be helpful. Changes, which may develop rapidly, are most commonly seen in the proximal or distal interphalangeal joints. Findings can include the following:

Other modalities

Magnetic resonance imaging (MRI)[52] and computed tomography (CT) scanning[53] have been reported to be helpful, but they are not needed in most cases.

Gallium scans and bone scans have been used in the past; however, recommending them routinely is difficult because of their nonspecificity.

Histologic Findings

When the skin lesions are present, skin is the easiest site from which to obtain a biopsy specimen. Histiologic studies in MRH reveal the following (see the images below):

In addition to macrophage properties, the histiocytes may have osteoclastic properties. Those of the osteoclast phenotype express osteoclast selective markers, tartrate-resistant acid phosphatase, and cathepsin K, and they respond to treatment with bisphosphonates.[3]

Stains

The cytoplasm of the histiocytes stains with the periodic acid-Schiff (PAS) stain. Although positive staining with Sudan black B and scarlet red indicates the presence of lipid within these cells, they are not usually foamy to the degree found in many other histiocytic disorders.

The cells stain with the usual macrophage markers, such as lysozyme (see the image below), CD68, MAC387, and human alveolar macrophage-56 (HAM-56), as well as CD10 (multinucleated giant cells only).[3] Staining results for S-100, CD1a, CD34, factor XIIIa, or alpha-1-antitrypsin are typically negative.


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Brown immunoperoxidase staining for lysozyme in histiocytes.

Approach Considerations

Because some patients with multicentric reticulohistiocytosis (MRH) may have an underlying malignancy, evaluation for this is important. Patients ought to have at least a good review of systems to direct appropriate additional studies.

No therapy consistently improves MRH. After an average course of 7-8 years, patients often go into remission, but considerable joint destruction may have already occurred. Many different drugs have been used in MRH, but patient response to therapy is difficult to determine because of the rarity of the disease, lack of controlled studies, and tendency for the remission to complicate evaluation of treatment efficacy.

Surgical care

Joint replacement may improve function in patients with burned-out disease that has resulted in deformity. Recently, a case of mutilating arthritis of the small joints of the hands due to MRH was reported as having been successfully managed with arthrodesis of the metacarpophalangeal joints.[54]

In the case of internal malignancies, adequate tumor removal may result in the resolution of histiocytosis.[37]

Mahajan et al reported on the case of a patient with MRH in whom confluent, disfiguring papules on the scalp, forehead, nasolabial folds, retroauricular region, and chin were successfully treated with carbon dioxide laser therapy. According to the authors, complete ablation was achieved, with no recurrence seen over an 8-month follow-up period.[27]

Activity

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

Consultations

The following consultations may be necessary:

Monitoring

Patients with MRH should be monitored at regular intervals to track the activity of the disease and response to therapy.

Pharmacologic Therapy

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[12, 13] and cyclosporine[14] are also reportedly effective in MRH.

Individual patients have reportedly responded to treatment with alendronate and other bisphosphonates.[15, 16] Antimalarials have also been used in MRH.

Several reports have suggested that combining methotrexate with a tumor necrosis factor (TNF) ̶ alpha antagonist—such as etanercept, infliximab, or adalimumab—is more effective than the use of either alone.[10, 11, 17, 18, 19, 20]

Tocilizumab, an interleukin-6 (IL-6) receptor inhibitor, reportedly caused remission of cutaneous and articular symptoms in a 35-year-old woman whose MRH was refractory to a combination of prednisone and methotrexate.[26]

Medication Summary

No drug of choice is known for multicentric reticulohistiocytosis (MRH). Most patients are treated with oral prednisone, with or without a cytotoxic/immunosuppressive agent, such as methotrexate, cyclophosphamide, or chlorambucil, or a TNF-alpha antagonist. Most of the previously reported therapies are as listed below.

First-line therapies

These include the following agents:

Second-line therapies

Prednisone (Rayos)

Clinical Context:  Prednisone is an immunosuppressant for treatment of autoimmune disorders. It may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear cell activity. It stabilizes lysosomal membranes and suppresses lymphocytes and antibody production. Although prednisone is regularly used, it has not been proven to be effective.

Prednisolone (Millipred, Orapred, Orapred ODT, Prelone)

Clinical Context:  Corticosteroids act as potent inhibitors of inflammation. They may cause profound and varied metabolic effects, particularly in relation to salt, water, and glucose tolerance, in addition to their modification of the immune response of the body.

Dexamethasone acetate (Baycadron)

Clinical Context:  This agent decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reducing capillary permeability. Dosage varies with the degree of inflammation and the size of the affected area.

Triamcinolone (Kenalog-10, Kenalog-40, Aristospan)

Clinical Context:  Triamcinolone can be used topically or injected intralesionally. It decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing capillary permeability.

Class Summary

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

Indomethacin (Indocin)

Clinical Context:  Indomethacin is rapidly absorbed; metabolism occurs in the liver by demethylation, deacetylation, and glucuronide conjugation. This agent inhibits prostaglandin synthesis.

Ibuprofen (I-Prin, Advil, Motrin)

Clinical Context:  Ibuprofen is the drug of choice for mild to moderately severe pain. It inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.

Naproxen (Anaprox, Naprelan, Naprosyn)

Clinical Context:  Naproxen is used for relief of mild to moderately severe pain. It inhibits inflammatory reactions and pain by decreasing the activity of cyclooxygenase, which is responsible for prostaglandin synthesis.

Ketoprofen

Clinical Context:  Ketoprofen is used for the relief of mild to moderate pain and inflammation. Small doses are indicated initially in patients with small body size, elderly patients, and persons with renal or liver disease. Doses of over 75 mg do not increase therapeutic effects. Administer high doses with caution, and closely observe the patient for response.

Flurbiprofen

Clinical Context:  Flurbiprofen may inhibit cyclooxygenase, thereby inhibiting prostaglandin biosynthesis. These effects may result in analgesic, antipyretic, and anti-inflammatory activities.

Diclofenac (Voltaren XR, Cataflam, Cambia)

Clinical Context:  This is one of a series of phenylacetic acids that has demonstrated anti-inflammatory and analgesic properties in pharmacological studies. It is believed to inhibit the enzyme cyclooxygenase, which is essential in the biosynthesis of prostaglandins. Diclofenac can cause hepatotoxicity; hence, liver enzymes should be monitored in the first 8 weeks of treatment. It is absorbed rapidly; metabolism occurs in the liver by demethylation, deacetylation, and glucuronide conjugation. The delayed-release, enteric-coated form is diclofenac sodium, and the immediate-release form is diclofenac potassium.

Class Summary

These agents have analgesic, anti-inflammatory, and antipyretic activities. Their mechanism of action may be inhibition of cyclo-oxygenase (COX) activity and prostaglandin synthesis. Other mechanisms, such as inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell membrane functions, may also exist.

Methotrexate (Rheumatrex, Trexall)

Clinical Context:  Methotrexate has an unknown mechanism of action in the treatment of inflammatory reactions; it may affect immune function. This agent ameliorates symptoms of inflammation (eg, pain, swelling, stiffness). Adjust the dose gradually to attain a satisfactory response.

Cyclophosphamide

Clinical Context:  Cyclophosphamide is chemically related to nitrogen mustards. As an alkylating agent, its mechanism of action may involve cross-linking of DNA, which may interfere with the growth of normal and neoplastic cells.

Azathioprine (Imuran, Azasan)

Clinical Context:  Azathioprine is a purine analog that inhibits the synthesis of deoxyribonucleic acid (DNA), RNA, and proteins. It may decrease the proliferation of immune cells, resulting in lower immunologic activity.

Class Summary

Cytotoxic/immunosuppressive agents inhibit key factors in the immune system that are responsible for inflammatory responses. None have been documented to be effective in MRH, except in anecdotal reports.

Leflunomide (Arava)

Clinical Context:  Leflunomide is an immunomodulatory agent. It inhibits pyrimidine synthesis, which, in turn, results in antiproliferative and anti-inflammatory effects.

Class Summary

Disease-modifying antirheumatic drugs (DMARDs) can retard or prevent disease progression and, thus, joint destruction and subsequent loss of function.

Hydroxychloroquine (Plaquenil)

Clinical Context:  Although this agent has not been demonstrated to be effective in studies, anecdotal reports suggest a possible effect. Hydroxychloroquine inhibits chemotaxis of eosinophils and locomotion of neutrophils and impairs complement-dependent antigen-antibody reactions.

Hydroxychloroquine sulfate 200 mg is equivalent to 155 mg hydroxychloroquine base and 250 mg chloroquine phosphate.

Class Summary

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

Vincristine (Vincasar PFS)

Clinical Context:  The mechanism of action of vincristine is uncertain. It may involve a decrease in reticuloendothelial cell function or an increase in platelet production.

Class Summary

Individual case reports suggest a benefit from the use of TNF-antagonists in MRH.

Adalimumab (Humira)

Clinical Context:  Adalimumab is a recombinant human immunoglobulin G1 (IgG1) monoclonal antibody specific for human TNF. It is indicated for the reduction of inflammation and the inhibition of structural damage progression in moderate to severe rheumatoid arthritis. This agent is reserved for patients who experience an inadequate response to 1 or more disease-modifying antirheumatic drugs (DMARDs).

Adalimumab can be used alone or in combination with methotrexate or other DMARDs. It binds specifically to TNF-alpha and blocks interaction with p55 and p75 cell-surface TNF receptors.

Infliximab (Remicade)

Clinical Context:  Infliximab neutralizes the cytokine TNF-alpha and inhibits it from binding to the TNF-alpha receptor. Consult a rheumatologist concerning its use.

Etanercept (Enbrel)

Clinical Context:  Etanercept is a soluble p75 TNF-receptor fusion protein (sTNFR-Ig). It inhibits TNF binding to cell-surface receptors, thereby decreasing inflammatory and immune responses.

Class Summary

Individual case reports suggest a benefit from the use of TNF-antagonists in MRH.

Alendronate (Fosamax)

Clinical Context:  Alendronate inhibits bone resorption via actions on osteoclasts or osteoclast precursors. Used to treat osteoporosis in men and women, it may reduce bone resorption and the incidence of fracture in the spine, hip, and wrist by approximately 50%.

Alendronate should be taken with a large glass of water at least 30 minutes before eating and drinking, to maximize absorption. Because of possible esophageal irritation, patients must remain upright after taking the medication. Since it is renally excreted, alendronate is not recommended for use in patients with moderate to severe renal insufficiency, ie, creatinine clearance (CrCl) below 30 mL/min or above 3 mg/dL. Consequently, its use in perirenal transplantation is limited.

Pamidronate (Aredia)

Clinical Context:  Pamidronate's main action is to inhibit the resorption of bone. The mechanism by which this inhibition occurs is not fully known. The drug is adsorbed onto calcium pyrophosphate crystals and may block the dissolution of these crystals, also known as hydroxyapatite, which are an important mineral component of bone. There is also evidence that pamidronate directly inhibits osteoclasts.

Risedronate (Actonel, Atelvia)

Clinical Context:  Risedronate is a potent aminobisphosphonate that principally acts by inhibiting osteoclastic bone resorption.

Tiludronate (Skelid)

Clinical Context:  Tiludronate is a sulfur-containing bisphosphonate of intermediate potency between etidronate and newer nitrogen-containing bisphosphonates.

Zoledronate (Reclast, Zometa)

Clinical Context:  Zoledronate inhibits bone resorption. It inhibits osteoclastic activity and induces osteoclastic apoptosis

Class Summary

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

Author

Alisa N Femia, MD, Clinical Fellow in Dermatology-Rheumatology, Brigham and Women's Hospital, Harvard Medical School

Disclosure: Nothing to disclose.

Coauthor(s)

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

Disclosure: Auxillium Honoraria Consulting; Stiefel, a GSK company Honoraria Consulting; UpToDate Honoraria author/editor; JAMA Dermatology Honoraria Associate editor and intermittent author; Elsevier Royalty Book author/editor; Stock holdings in various trust accounts include some pharmaceutical companies and device makers I do not control these accounts, but have directed our managers to divest pharmaceutical stocks as is fiscally prudent I inherited these trust accounts

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

Disclosure: Nothing to disclose.

Chief Editor

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

Disclosure: Nothing to disclose.

Additional Contributors

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 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.

Ronald P Rapini, MD Josey Professor and Chair, Department of Dermatology, Professor of Pathology, University of Texas Medical School at Houston and MD Anderson Cancer Center

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, Society for Investigative Dermatology, and Texas Medical Association

Disclosure: Elsevier publishers Royalty Independent contractor; FDA panel Consulting fee Consulting

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.

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Multiple erythematous nodules are present on the dorsal hands of this adolescent with an inflammatory arthropathy.

Multiple erythematous nodules are present on the dorsal hands of this adolescent with an inflammatory arthropathy.

Multiple erythematous to brown nodules on the fingers.

Nodules on a hand with deformed joints from arthritis due to multicentric reticulohistiocytosis.

Cobblestone papules on the eyelid and papules on the forehead.

Swollen elbow and nodules on the forearm.

Erythematous to brown papules overlying the right dorsal hand and wrist and erythematous to violaceous patches over the right dorsal hand and fingers. The cutaneous changes are in a photodistributed pattern and mimic the changes of dermatomyositis.

Erythematous to brown papules and erythematous to violaceous patches overlying the right dorsal hand and fingers, with a crusted erosion overlying the fourth metacarpophalangeal joint. These cutaneous changes can be easily confused with dermatomyositis.

Histopathology of multicentric reticulohistiocytosis (MRH) skin lesions.

Histopathology of multicentric reticulohistiocytosis (MRH) skin lesions. Higher power demonstrating multinucleated giant cells with eosinophilic ground-glass cytoplasm.

Low-power view of a biopsy sample of large histiocytes and multinucleated giant cells in the dermis.

High-power view of large histiocytes in the dermis.

Brown immunoperoxidase staining for lysozyme in histiocytes.

Multiple erythematous nodules are present on the dorsal hands of this adolescent with an inflammatory arthropathy.

Multiple erythematous to brown nodules on the fingers.

Erythematous, poikilodermatous, mamillated plaque on the anterior chest.

Histopathology of multicentric reticulohistiocytosis (MRH) skin lesions.

Histopathology of multicentric reticulohistiocytosis (MRH) skin lesions. Higher power demonstrating multinucleated giant cells with eosinophilic ground-glass cytoplasm.

Erythematous to brown papules overlying the right dorsal hand and wrist and erythematous to violaceous patches over the right dorsal hand and fingers. The cutaneous changes are in a photodistributed pattern and mimic the changes of dermatomyositis.

Erythematous to brown papules and erythematous to violaceous patches overlying the right dorsal hand and fingers, with a crusted erosion overlying the fourth metacarpophalangeal joint. These cutaneous changes can be easily confused with dermatomyositis.

Nodules on a hand with deformed joints from arthritis due to multicentric reticulohistiocytosis.

Swollen elbow and nodules on the forearm.

Cobblestone papules on the eyelid and papules on the forehead.

Low-power view of a biopsy sample of large histiocytes and multinucleated giant cells in the dermis.

High-power view of large histiocytes in the dermis.

Brown immunoperoxidase staining for lysozyme in histiocytes.