Multicentric Reticulohistiocytosis 

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.[11, 12] 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 ^[36]
• Renal cancer (sarcomatoid renal cell carcinoma) ^[37]
• Liver carcinoma ^[38]
• Lung cancer (bronchogenic carcinoma, pleural mesothelioma, squamous cell carcinoma ^[39] )
• Bronchial cancer
• Laryngeal cancer
• Ovarian cancer (medullary carcinoma, adenocarcinoma) ^[40]
• Lymphoma
• Leukemia
• Sarcoma (omentum, axilla)
• Melanoma
• Extramammary Paget disease ^[41]
• Thymic carcinoma ^[42]
• 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 correlate 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
• Pregnancy

MRH has been reported in a patient with both Sjögren syndrome and systemic sclerosis.[43]

Worldwide, MRH is very rare and there is no published data on incidence and prevalence. MRH has largely been reported in single case studies, mostly in Western countries and Japan.[43] 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.

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 (see images below), while another 25% of patients develop skin and joint manifestations at the same time. One tenth to one third of patients report pruritus.

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

Multiple erythematous to brown nodules on the fingers.

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.[44]

Cardiac involvement is also extremely rare, but it has been reported in isolated cases and can manifest with myocardial involvement or pericardial disease.[45, 46, 47, 48]

There is one reported case of hepatic involvement in a patient with MRH and lung involvement.[49]

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

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:

• Hands (76%)
• Knees (73%)
• Shoulders (64%)
• Wrists (64%)
• Hips (61%)
• Ankles (58%)
• Elbows (58%)
• Feet (58%)
• Spine (52%)

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

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.

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,[50] 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:

• Face (ears, nose, paranasal areas) and hands (90%): Several miscellaneous nail changes have also been described, but most are due to adjacent arthritis.
• Ears (76%)
• Forearms (55%), as shown below

   

  Swollen elbow and nodules on the forearm.
• Elbows (40%)
• Scalp (40%)
• Mucosal surfaces (eg, lips, tongue, gingiva, nasal septum) (50%)

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.)[51, 52, 53]

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.

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

About one third of patients have been reported to have xanthelasma, but whether this is related to MRH is unclear.[51]

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

• Elevated erythrocyte sedimentation rate (ESR) or anemia: In about 50% 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 been reported to be 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.

Because some patients with 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.

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:

• Destruction of bone in affected joints is disproportionate to cartilage loss
• Lesions may resemble gouty erosions
• Mild osteopenia is notedMarked resorption of subchondral bone is common
• Cutaneous nodules may be seen as soft tissue swellings
• Findings on joint fluid analysis vary; effusions may contain polymorphonuclear leukocytes or mononuclear cells
• Bilaterally symmetrical, sharply circumscribed erosions spread from the margins to the joint surfaces
• Separation of the bone ends often occurs, but no subchondral sclerosis and little or no periosteal reaction are seen
• Osteoporosis is mild or absent
• Erosions in osteoarthritis begin centrally rather than at the joint margins
• In psoriatic arthritis and reactive arthritis, erosions are asymmetrical and have poorly defined margins; the erosions are also associated with periosteal new bone formation

Other modalities

Magnetic resonance imaging (MRI)[56] and computed tomography (CT) scanning[57] have been reported to be helpful, but they are not needed in most cases.

Fluorodeoxyglucose positron emission tomography (FDG-PET)/CT may be useful for identifying the characteristic features of MRH, in addition to screening for a possibly associated malignancy.[58, 59, 60]

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):

• 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 (PAS) 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 ^[3]
• 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. 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 ^[4]
• 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 ^[5]

  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.

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.[4]

Stains

The cytoplasm of the histiocytes stains with 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).[4] Staining results for S-100, CD1a, CD34, factor XIIIa, or alpha-1-antitrypsin are typically negative.

Brown immunoperoxidase staining for lysozyme in histiocytes.

No therapy consistently improves multicentric reticulohistiocytosis (MRH). After an average course of 7-8 years, MRH often goes 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.

Depending on its severity, MRH may limit activity. Physical therapy may prevent deformities and relieve symptoms.

Consultations with dermatologists and rheumatologists may be necessary. If internal malignancy occurs, consult with oncologists or surgeons as needed.

Patients with MRH should be monitored at regular intervals to track the activity of the disease and response to 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,[6, 7]  chlorambucil,[6]  and methotrexate,[8, 9, 7, 10]  may also affect the inflammatory response, as well as prevent further joint destruction and cause skin lesions to regress. Azathioprine[13, 14]  and cyclosporine[15]  are also reportedly effective in MRH.

Individual patients have reportedly responded to treatment with alendronate and other bisphosphonates.[16, 17]  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.[11, 12, 18, 19, 20, 21]

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.[27]

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.[61]

In the case of internal malignancies, adequate tumor removal may result in the resolution of histiocytosis.[39]

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.[28]

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 tumor necrosis factor (TNF)–alpha antagonist. Most of the previously reported therapies are as listed below.

First-line therapies include the following agents:

• Methotrexate ^{[7, 10, 22, 62]}
• Systemic corticosteroids (eg, prednisone, prednisolone, dexamethasone high-dose pulse)
• Intralesional corticosteroids (eg, triamcinolone acetonide)
• Nonsteroidal anti-inflammatory drugs (NSAIDs; eg, aspirin, indomethacin)

Second-line therapies include the following:

• Psoralen plus ultraviolet light (PUVA)
• Antimalarials (eg, chloroquine, hydroxychloroquine ^[22] )
• Cyclophosphamide ^[7]
• Chlorambucil
• Azathioprine
• Vincristine
• Topical nitrogen mustard
• Leflunomide ^[23]
• TNF-alpha antagonists ^[24] (eg, etanercept, ^[12] infliximab ^{[18]   [63]} ): TNF-alpha has been found to be increased in the synovium of patients with MRH, providing a rationale for this therapy ^[25]
• Bisphosphonate drugs (eg, alendronate, zoledronic acid ^[26] )
• Concomitant combinations of several of the above therapies ^[22]

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.

Prednisone (Rayos)

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)

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)

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)

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 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.

Indomethacin (Indocin)

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)

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)

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

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

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

Diclofenac (Voltaren XR, Cataflam, Cambia)

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

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.

Methotrexate (Rheumatrex, Trexall)

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

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)

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

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

Leflunomide (Arava)

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

Class Summary

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

Hydroxychloroquine (Plaquenil)

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

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

Vincristine (Vincasar PFS)

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)

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)

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

Etanercept (Enbrel)

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

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.

Alendronate (Fosamax)

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)

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)

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

Tiludronate (Skelid)

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

Zoledronate (Reclast, Zometa)

Zoledronate inhibits bone resorption. It inhibits osteoclastic activity and induces osteoclastic apoptosis