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. This is a rare condition; approximately 200 cases have been reported in the world literature. Various diseases have been associated with MRH, including malignancy.
The pathogenesis of MRH is unknown but probably has an immunologic basis. Some studies have demonstrated increased levels of tumor necrosis factor (TNF)– α in the blood and in the tissue.[3, 4] Recently, a report of one patient with MRH describes overexpression of monocyte chemoattractant protein-1 (MCP-1), which is stimulated by TNF-α, in the serum and lesional epidermis. In this patient, serum levels of MCP-1 decreased with treatment. The authors hypothesize that MCP-1 may play a role in attracting histiocytes and giant cells in patients with MRH. 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. These findings may help explain the success of bisphosphonate treatment insome cases.[7, 6]
MRH is a very rare condition, and no studies have detailed the prevalence in the general population.
MRH is a rare condition.
The destructive arthritis of MRH is a debilitating process. MRH is also associated with malignancy. However, except for cases in which malignancy-related death occurs, MRH is rarely fatal.
MRH has been reported primarily in whites.
Women are affected more commonly than men, with a female-to-male ratio of 2:1.
MRH may occur at any age, but it has been reported primarily in middle-aged adults, with a mean age of 43 years.
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.
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.
The joint disease of MRH 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 which 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. This may give a characteristic “coral-bead” appearance, which is considered pathognomonic. The nodules grow slowly, and they rarely ulcerate. Infiltrated plaques may resemble mucinosis. Some patients also have associated xanthelasma.
Some patients appear to have a photodistribution of lesions simulating dermatomyositis. To date, 9 cases of MRH simulating dermatomyositis have been reported,[10, 11] and it is possible this entity is underrecognized. 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 do not appear to increase the risk of malignancy.
See the images below.
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.
Erythematous-to-brown papules overlying the right dorsal hand and wrist and erythematous-to-violaceous patches over the right dorsal hand and fingers.....
Erythematous-to-brown papules and violaceous-erythematous patches overlying the right dorsal hand and fingers, with a crusted erosion overlying the fo....
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 MRH and has been reported in multiple patients (perhaps as many as 25-33% of patients with MRH). No specific site or type of malignancy has been identified as most commonly occurring with MRH. Reported malignancies include melanoma, sarcoma, leukemia, lymphoma, bladder and renal cancer, squamous cell carcinoma of the lung, liver carcinoma, and carcinomas (usually adenocarcinoma) of the breast, 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.
No laboratory studies are specific for multicentric reticulohistiocytosis (MRH). Serum rheumatoid factor is usually negative.
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.
Findings on joint fluid analysis vary. The effusions may demonstrate polymorphonuclear leukocytes or mononuclear cells.
Early skin lesions demonstrate a lymphohistiocytic infiltrate. 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. Results of S100 protein and alpha-1-antitrypsin are negative. 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. See the slides below.
Histopathology of multicentric reticulohistiocytosis (MRH) skin lesions.
Histopathology of multicentric reticulohistiocytosis (MRH) skin lesions. Higher power demonstrating multinucleated giant cells with eosinophilic groun....
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,[16, 17] chlorambucil, or methotrexate,[18, 19, 17, 20] may affect the inflammatory response, prevent further joint destruction, and cause skin lesions to regress. Azathioprine[21, 22] and cyclosporine have also been reported as effective for MRH.
Antimalarials have also been used.
Alendronate and other bisphosphonates have been reported to be effective in individual patients.[24, 25]
TNF-alpha antagonists have been reported to be effective in many, but not all, patients. Etanercept,[3, 4] infliximab,[26, 27] and adalimumab in combination with methotrexate and minocycline have been reported as effective in recent literature.
Several reports have suggested that the combination of methotrexate with a tumor necrosis factor antagonist is more effective than either alone.
Joint replacement may improve function in patients with burned-out disease that has resulted in deformity.
A rheumatologist and a dermatologist may be consulted.
Activity may be limited by the severity of the disease. Physical therapy may prevent deformities and relieve symptoms.
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, chlorambucil, or a tumor necrosis factor-α antagonist.
Clinical Context: Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and suppresses lymphocytes and antibody production. Regularly used but not proven to be effective.
These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.
Clinical Context: Unknown mechanism of action in treatment of inflammatory reactions; may affect immune function. Ameliorates symptoms of inflammation (eg, pain, swelling, stiffness).
Adjust dose gradually to attain satisfactory response.
Clinical Context: Chemically related to nitrogen mustards. As alkylating agent, mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.
These are steroid sparing. None have been documented to be effective, except in anecdotal reports.
Clinical Context: Although not demonstrated to be effective in studies, anecdotal reports suggest possible effect. 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.
Derivatives of 4-aminoquinoline are active against various autoimmune disorders.
Clinical Context: Recombinant human IgG1 monoclonal antibody specific for human TNF. Indicated to reduce inflammation and inhibit progression of structural damage in moderate-to-severe rheumatoid arthritis. Reserved for those who experience inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs). Can be used alone or in combination with methotrexate (MTX) or other DMARDs. Binds specifically to TNF-alpha and blocks interaction with p55 and p75 cell-surface TNF receptors.
Clinical Context: Neutralizes cytokine TNF-alpha and inhibits it from binding to TNF-alpha receptor. Consult rheumatologist for use.
Clinical Context: Soluble p75 TNF receptor fusion protein (sTNFR-Ig). Inhibits TNF binding to cell surface receptors, which, in turn, decreases inflammatory and immune responses.
Individual case reports suggest a benefit.
Clinical Context: Inhibits bone resorption via actions on osteoclasts or osteoclast precursors. Used to treat osteoporosis in both men and women. May reduce bone resorption and incidence of fracture at spine, hip, and wrist by approximately 50%. Should be taken with large glass of water at least 30 min 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, it is not recommended in patients with moderate-to-severe renal insufficiency, ie, CrCl < 30 mL/min or CrCl >3 mg/dL, and, thus, its use in perirenal transplantation is limited.
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.
Inpatient care is rarely necessary.
Patients with multicentric reticulohistiocytosis (MRH) should be monitored at regular intervals to track the activity of the disease and response to therapy.
MRH is a rare condition. The patient should be referred to a medical center at least once following diagnosis.
MRH can cause deformities of the joints and disfigurement due to the skin lesions.
Malignancy, and rarely, pulmonary involvement, may be associated with MRH.
If cytotoxic agents are used, the patient should be monitored for development of a malignancy in the future.
MRH is debilitating but is not life threatening. If the patient has an associated malignancy, the prognosis relates to that of the malignancy.