Multicentric Reticulohistiocytosis

Synonyms and related keywords: multicentric reticulohistiocytosis, MRH, lipoid dermatoarthritis, destructive arthritis, multiple cutaneous nodules, histiocytic multinucleated giant cells, eosinophilic ground-glass cytoplasm, inflammatory arthropathy


INTRODUCTION

Background: Goltz and Laymon coined the term multicentric reticulohistiocytosis (MRH) in 1954 to describe patients with destructive arthritis and multiple cutaneous nodules histologically manifested by an infiltrate of histiocytic multinucleated giant cells with eosinophilic ground-glass cytoplasm. This is a rare condition, reported in fewer than 200 patients in the world literature. A variety of diseases have been associated with MRH, including malignancy.

Pathophysiology: The pathogenesis of this condition is unknown.

Frequency:

• In the US: This is a rare condition.

• Internationally: This is a rare condition.

Mortality/Morbidity: The disease is a debilitating process, but death is rare 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

History:

• The primary manifestations of multicentric reticulohistiocytosis (MRH) are joint and skin diseases.

• Inflammatory joint disease is a frequent presenting symptom, and it may be the sole symptom in 45% of patients.

• Skin disease occurs commonly, and it is the presenting manifestation in 30% of patients.

Physical:

• The joint disease usually is manifested by 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 may have a xanthelasma.

• The nodules grow slowly, and they rarely ulcerate.

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, 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

Dermatomyositis
Gout
Leprosy
Lymphoma, B-Cell
Lymphoma, Cutaneous T-Cell
Rheumatoid Arthritis
Sarcoidosis

Other Problems to be Considered:

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

WORKUP

Lab Studies:

• No specific laboratory studies are indicative of multicentric reticulohistiocytosis (MRH). Rheumatoid factor is negative.

Imaging Studies:

• X-ray of the affected joints will reveal destruction of bone disproportionate to loss of cartilage. Lesions may resemble gouty erosions.

• Mild osteopenia is noted.

• Often a marked resorption of subchondral bone is observed.

• The findings may develop rapidly and can resemble arthritis mutilans.

• Occasionally the cutaneous nodules may be seen as soft tissue swellings.

Other Tests:

• Findings on joint fluid analysis are variable. 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 stains are positive and are diastase resistant. Lipid stains may be positive. Acid phosphatase, nonspecific esterase, and lysozyme stains are usually positive. 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

Medical Care:

• No effective treatment is known for MRH.

• Therapy with nonsteroidal anti-inflammatory agents may help the arthritis.

• Systemic corticosteroids and/or cytotoxic agents, in particular cyclophosphamide, chlorambucil, or methotrexate, may affect the inflammatory response, prevent further joint destruction, and cause skin lesions to regress.

• Antimalarials also have been used.

• Alendronate and other bisphosphonates have been reported to be effective in an individual patient.

• Tumor necrosis factor-alpha antagonists have been reported to be effective in many, but not all, patients. Reports of both etanercept and infliximab have appeared in recent literature, and it would be reasonable to think that adalimumab might also be effective in an individual patient.

Surgical Care: Patients with burned out disease that has resulted in deformity may improve their function with joint replacement.

Consultations: Rheumatology and dermatology may be consulted.

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

MEDICATION

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 Name	Prednisone (Deltasone, Meticorten, Orasone) -- Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and also suppresses lymphocytes and antibody production. Regularly used, but not proven to be effective.
Adult Dose	1 mg/kg/d PO
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI disease
Interactions	Estrogens may decrease clearance; may cause digitalis (ie, digoxin) toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use

Drug Category: Cytotoxic/immunosuppressive agents -- These are steroid sparing. None have been documented to be effective, except in anecdotal reports.

Drug Name	Methotrexate (Folex PFS, Rheumatrex) -- 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.
Adult Dose	15-25 mg/wk PO/IM
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; alcoholism; hepatic insufficiency; documented immunodeficiency syndromes; preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia); renal insufficiency
Interactions	Coadministration with NSAIDs may be fatal Oral aminoglycosides may decrease absorption and blood levels of oral methotrexate (MTX); charcoal lowers levels; etretinate may increase hepatotoxicity; folic acid or its derivatives contained in some vitamins may decrease response Indomethacin and phenylbutazone can increase plasma levels; may decrease phenytoin serum levels Probenecid, salicylates, procarbazine, and sulfonamides, including TMP-SMX, may increase effects and toxicity; may increase plasma levels of thiopurines
Pregnancy	D - Unsafe in pregnancy
Precautions	Monitor CBCs monthly, and liver and renal function every 1-3 mo during therapy (monitor more frequently during initial dosing, dose adjustments, or when risk of elevated MTX levels, eg, dehydration); has toxic effects on hematologic, renal, GI, pulmonary, and neurologic systems Discontinue if significant drop in blood counts; aspirin, NSAIDs, or low-dose steroids may be administered concomitantly (possibility of increased toxicity with NSAIDs, including salicylates, has not been tested)

Drug Name	Cyclophosphamide (Cytoxan, Neosar) -- 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.
Adult Dose	1-2 mg/kg/d PO or IV
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; severely depressed bone marrow function
Interactions	Allopurinol may increase risk of bleeding or infection and exacerbate myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones Chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; high doses of phenobarbital may increase rate of metabolism and leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity
Pregnancy	D - Unsafe in pregnancy
Precautions	Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis

Drug Category: Antimalarial -- Derivatives of 4-aminoquinoline are active against a variety of autoimmune disorders.

Drug Name	Hydroxychloroquine (Plaquenil) -- Though not demonstrated to be effective in studies, anecdotal reports suggest possible effect. Inhibits chemotaxis of eosinophils, 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.
Adult Dose	200-400 mg/d PO
Pediatric Dose	less than 6.5 mg/kg/d PO
Contraindications	Documented hypersensitivity; psoriasis; retinal and visual field changes attributable to 4-aminoquinolones
Interactions	Cimetidine increases serum levels; magnesium trisilicate may decrease absorption
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in hepatic disease, G-6-PD deficiency, psoriasis, and porphyria; not recommended for long term in children; perform periodic (every 6 mo) ophthalmic examinations; test periodically for muscle weakness

Drug Category: TNF antagonists -- Individual case reports suggest a benefit.

Drug Name	Infliximab (Remicade) -- Neutralizes cytokine TNF-alpha and inhibits it from binding to TNF-alpha receptor. Consult rheumatologist for use.
Adult Dose	5 mg/kg single IV infusion
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; active infection; concurrent live vaccination
Interactions	None reported
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	TNF-alpha modulates cellular immune responses; anti-TNF therapies, such as infliximab, may adversely affect normal immune responses and allow development of superinfections; more cases of lymphoma were observed in TNF-alpha blockers compared with controlled groups; may increase risk of reactivation of tuberculosis in patients with particular granulomatous infections

Drug Name	Etanercept (Enbrel) -- Soluble p75 TNF receptor fusion protein (sTNFR-Ig). Inhibits TNF binding to cell surface receptors, which, in turn, decreases inflammatory and immune responses.
Adult Dose	25-50 mg SC qwk or 2 times/wk with or without concomitant administration of MTX
Pediatric Dose	less than 4 years: Not established 4-17 years: 0.4 mg/kg SC 2 times/wk (72-96 h apart); not to exceed 25 mg/dose >17 years: Administer as in adults
Contraindications	Documented hypersensitivity; active infection; sepsis; concurrent live vaccination
Interactions	None reported
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Serious infections may develop and therapy should be discontinued if they occur; possible adverse effects include injection site pain, redness and swelling at injection site, and headaches; rare cases of lupuslike symptoms and heart failure have been reported (discontinue treatment if symptoms develop)

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.

Drug Name	Alendronate (Fosamax) -- 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 less than 30 mL/min or CrCl >3 mg/dL, and, thus, its use in perirenal transplantation is limited.
Adult Dose	Treatment: 10 mg PO qd; alternatively, 70 mg PO qwk for osteoporosis prevention or treatment; no dose established in patients with MRH
Pediatric Dose	Not determined
Contraindications	Documented hypersensitivity; hypocalcemia; abnormalities of the esophagus; inability to stand upright for 30 min
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Must be taken at least 30 min before first food, beverage or medication of the day and should be taken with large amounts of water; caution in patients with renal impairment

FOLLOW-UP

Further Inpatient Care:

• Inpatient care often is not needed.

Further Outpatient Care:

• The patient 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. Referral to a medical center should occur on at least one occasion 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 it is not life threatening.

• If the patient has an associated malignancy, then the prognosis relates to that of the malignancy.

MISCELLANEOUS

Medical/Legal Pitfalls:

• Misdiagnosis

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