8 Things Rheumatologists Should Know About Heavy Chain Disease

October 22, 2014

The rare diseases that prevent immunoglobulin molecules from forming properly can present with symptoms typical of rheumatic disease: rashes, joint swelling, and stiffness.

The heavy chain diseases are a group of three rare B-cell neoplasms that are clinically and morphologically distinct from one another, but that have in common the production of an abnormal immunoglobulin heavy chain incapable of binding light chains. The altered heavy chains contain deletions, insertions, and point mutations that are acquired during somatic hypermutation, typically resulting in loss of the constant domain of the immunoglobulin heavy chain molecule responsible for light chain binding. 

This gives rise to three different diseases, each with unique clinical presentations and clinical and laboratory findings. All of these are rare, but the two least frequent can  cause clinical manifestations that also occur in rheumatic disease, as described below.

1.  Alpha (or α) heavy chain disease, the most common of these rare disorders (more than 400 cases described in the literature) typically infects the gastrointestinal system and presents as a malabsorption syndrome. Rare cases of respiratory and lymphomatous forms have been reported.1

2. Gamma (or γ) heavy chain disease (also called Franklin disease, after the physician who first described it in 1964)2 is uncommon, with approximately 130 cases reported in the literature. In recent series, the median age at diagnosis is 51 to 68 years, and there is a clear female predominance.3,4

While its pathogenesis is unknown, an autoimmune disease (see below) is present in about 25% of patients. Manifestations of the auotimmune disease often precede gamma chain disease by many years.

3.Rheumatoid arthritis is the most common autoimmune condition associated with gamma heavy chain disease. Sjögren syndrome, systemic lupus erythematosus, and vasculitis, have also been reported, as well as myasthenia gravis and autoimmune cytopenias, including idiopathic thrombocytopenic purpura. 5

4. Most patients with gamma heavy chain disease (83% to 91%) have an underlying systemic or localized lymphoplasmacytic neoplasm. Disseminated lymphoma (57-66% of patients) typically presents with constitutional symptoms, including fever, malaise, and weight loss, which are associated in 50% of cases with generalized lymphadenopathy; splenomegaly; and, less commonly, hepatomegaly.3,5

5.In 9% to 17% of patients, most of whom have pre-existing autoimmune disease, no lymphoplasmacytic neoplasm is present at diagnosis. Clinical manifestations are mainly those of the autoimmune disease, including rheumatoid nodules, rashes, synovitis, and joint deformities.

6. Clinical and laboratory distinction of gamma heavy chain disease from an infectious or inflammatory process is sometimes difficult due to the protean clinical presentations, with constitutional symptoms and a history of autoimmune disease seen in a large proportion of patients overall. Diagnosis of gamma heavy chain disease requires the demonstration of abnormal immunoglobulin protein consisting solely of gamma heavy chain, without associated light chains, by serum or urine immunofixation studies. Supporting laboratory findings include elevation in serum immunoglobulin G (IgG), without accompanying elevation in serum free light chains.

7.There is no standardized treatment for gamma heavy chain disease.  Typically, treatment is tailored to the symptomatology and to the presence of an accompanying autoimmune disease or overt lymphoma. Patients with no overt lymphoma or who are asymptomatic can be followed expectantly without therapy. Autoimmune disease should be treated according to usual guidelines.

Patients presenting with disseminated lymphoma or with symptomatic disease limited to the bone marrow, chemotherapy is recommended. Successful treatment of localized extranodal disease with surgical resection or radiation therapy has also been reported.5 Adequate infectious disease prophylaxis and surveillance are critical, particularly in patients receiving immunosuppressive treatments. In view of the heterogeneity of the disease and treatment, the prognosis is highly variable.

8. Mu (or μ) heavy chain disease, the rarest in this family of conditions (with only 30-40 cases in the literature) was first described in 1970.6,7 The first two cases were both men in their late fifties, presenting with unremitting joint pain or stiffness. The disease occurs predominantly in Caucasian men, with a median age of 58 years at diagnosis.8

The cause is not known, but most patients have a lymphoid neoplasm resembling chronic lymphocytic leukemia/small lymphocytic lymphoma.9 Splenomegaly is almost universally present, with hepatomegaly in three-quarters of patients.8 Palpable, superficial lymphadenopathy is identified in 40% of patients.

The literature contains a single case report of mu heavy chain disease associated with systemic lupus erythematosus, as well as reports of association with other conditions including myelodysplastic syndrome and systemic amyloidosis, each with clinical features reflecting the accompanying disorder.9,10 Lytic bone lesions have been reported in about 20% of patients. Carpal tunnel syndrome and amyloid deposition in the rectal mucosa were also present in the first two patients with mu heavy chain disease.11

Because of its rarity, data regarding treatment and prognosis of this disease are limited. Detectable monoclonal mu heavy chain in a patient who is otherwise asymptomatic requires only observation
without therapy.12

Adapted from The Heavy Chain Diseases: Clinical and Pathological Features, a longer review in Oncology (Jan 15, 2014)

The Heavy Chain Diseases: Clinical and Pathologic Features - See more at: http://www.cancernetwork.com/authors/giada-bianchi-md#sthash.7EuJwHs6.dpufThe Heavy Chain Diseases: Clinical and Pathologic Features - See more at: http://www.cancernetwork.com/authors/giada-bianchi-md#sthash.7EuJwHs6.dpuf

References:

1. Seligmann M, Danon F, Hurez D, et al. Alpha-chain disease: a new immunoglobulin abnormality. Science. (1968) 162:1396-1397.

2. Franklin EC, Lowenstein J, Bigelow B, Meltzer M. Heavy chain disease-a new disorder of serum gamma-globulins: report of the first case. Am J Med. (1964) 37:332-350

3. Wahner-Roedler DL, Witzig TE, Loehrer LL, Kyle RA. Gamma-heavy chain disease: review of 23 cases. Medicine (Baltimore). (2003) 82:236-250

4. Bieliauskas S, Tubbs RR, Bacon CM, et al. Gamma heavy-chain disease: defining the spectrum of associated lymphoproliferative disorders through analysis of 13 cases. Am J Surg Pathol. (2012) 36:534-543

5. Fermand JP, Brouet JC, Danon F, Seligmann M. Gamma heavy chain “disease”: heterogeneity of the clinicopathologic features. Report of 16 cases and review of the literature. Medicine (Baltimore). (1989) 68:321-335

6. Forte FA, Prelli F, Yount WJ, et al. Heavy chain disease of the gamma (gamma M) type: report of the first case. Blood. (1970) 36:137-144

7. Ballard HS, Hamilton LM, Marcus AJ, Illes CH. A new variant of heavy-chain disease (mu-chain disease). N Engl J Med. (1970) 282:1060-1062

8. Wahner-Roedler DL, Kyle RA. Heavy chain diseases. Best Pract Res ClinHaematol. (2005) 18:729-746

9. Wahner-Roedler DL, Kyle RA. Mu-heavy chain disease: presentation as a benign monoclonal gammopathy.Am J Hematol. (1992) 40:56-60

10. Iwasaki T, Hamano T, Kobayashi K, Kakishita E. A case of mu-heavy chain disease: combined features of mu-chain disease and macroglobulinemia.Int J Hematol. 1997 66:359-365

11. Kinoshita K, Yamagata T, Nozaki Y, et al. Mu-heavy chain disease associated with systemic amyloidosis. Hematology. (2004) 9:135-137.

12. Witzig TE, Wahner-Roedler DL. Heavy chain disease. Curr Treat Options Oncol. (2002) 3:247-254