Primary or AL amyloidosis is a plasma cell disorder characterized by the overproduction and tissue deposition of a monoclonal Ig light chain or fragments containing the light-chain variable region (VL). The deposits form amyloid fibrils that can be identified by Congo red staining. Light chain deposition produces tissue damage and eventually organ failure, leading to death in untreated patients within 1–1.5 years (1). A variety of effective treatments are now available for patients with AL amyloidosis, including dose-intensive intravenous melphalan followed by autologous stem cell support (2) and dexamethasone-based regimens (3, 4). The immunomodulatory drugs thalidomide (5, 6) and lenalidomide (7) have also been found to be effective.
One of the most important determinants of outcome is early diagnosis, since severe amyloid organ disease may preclude the use of potentially effective treatment regimens. Amyloid cardiomyopathy can rapidly lead to diastolic dysfunction, heart failure, and arrhythmias that can complicate use of chemotherapy and steroids. Amyloid kidney disease can alter drug clearance and make the kidney highly susceptible to nephrotoxic insults. In the liver, amyloid involvement can produce cholestatic liver disease, and alter drug metabolism. Involvement of the gastrointestinal tract itself alters oral absorption and can lead to malnutrition.
AL amyloidosis can also present with symptoms and signs that mimic a variety of rheumatic conditions. Skin thickening due to amyloid deposits may simulate scleroderma (8). Amyloid infiltration into periarticular and synovial tissue can produce stiffness and multiple joint swelling resembling rheumatoid arthritis (9, 10). Xerostomia caused by amyloid deposition in salivary glands can be mistaken for Sjögren's syndrome (11, 12). Such symptoms and signs of a systemic disorder may bring patients to the attention of rheumatologists, and must be distinguished from authentic rheumatic diseases. This study was undertaken to characterize features of such involvement in a large group of patients with AL amyloidosis, analyze the VL gene sequences associated with this type of disease, and assess the impact of these manifestations on survival.
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- PATIENTS AND METHODS
- AUTHOR CONTRIBUTIONS
Soft tissue is 1 of 7 sites of organ involvement in AL amyloidosis that have been identified by international consensus. Soft tissue involvement has been described as including macroglossia, submandibular swelling, amyloid lymphadenopathy, vascular amyloid manifested by claudication or bruising, muscle involvement, and painful periarticular amyloid deposition (13). In the present study, we focused on those features that might bring a patient with AL amyloidosis to the attention of a rheumatologist. For this reason, bone lesions were also included in the analysis.
In our group of 191 patients with AL amyloidosis, 82 (42.9%) had evidence of soft tissue and bone involvement. Soft tissue and bone involvement tended to occur in the setting of multiple organ involvement; the median number of involved organ systems was 4, compared with 2 in the group of patients without soft tissue and bone involvement. Such involvement consisted of submandibular gland enlargement in almost one-third of the patients and macroglossia in almost one-quarter of the group. CTS, common in patients with rheumatic diseases (22, 23), occurred in 13.1% of the patients with AL amyloidosis.
The frequency of amyloid arthropathy, which can mimic seronegative rheumatoid arthritis (9), was relatively low in our series (3.7%), as was amyloid deposition in unusual subcutaneous sites including breast, eyelid, lower lip, and skin nodules (2.6%). Muscle involvement was even rarer, with a frequency of 1.6%, comparable with the frequency reported in other studies (24, 25). Peripheral lymphadenopathy due to amyloid deposition was observed in 1% of patients. Only 6 case reports of peripheral lymphadenopathy in AL amyloidosis have been published (26–31). Bony involvement and vertebral collapse due to amyloid infiltration is an unusual manifestation of AL amyloidosis and should be distinguished from the lytic bone lesions seen in multiple myeloma (24). In the present study, we observed this in 1% of the patients with AL amyloidosis without evidence of multiple myeloma.
The incidence of soft tissue and bone involvement identified in this study was higher than that shown in our previous studies (32, 33), primarily because those studies did not include submandibular gland involvement in the soft tissue and bone involvement category. In this analysis, submandibular gland enlargement and CTS occurred with equal frequency in patients with dominant soft tissue and bone involvement and patients with dominant involvement of other organs. Thus, these manifestations were not exclusively part of the rheumatic syndrome. Dominant soft tissue and bone involvement occurred in 9.4% of patients, similar to the frequencies found in 2 other cohort series (7.3% and 9%) (34, 35).
The majority of soft tissue, joint, and bone manifestations of AL amyloidosis are nonspecific and may frequently be attributed to various rheumatic diseases. Similar to previously published case reports, soft tissue and bone involvement in our group of patients with AL amyloidosis was misdiagnosed as seronegative rheumatoid arthritis (9, 10), scleroderma (8), Sjögren's syndrome (11, 12), and polymyalgia rheumatica (36). Although AL amyloidosis is a rare condition, it should be considered in the differential diagnosis of atypical symptoms in patients believed to have rheumatic diseases.
There was no significant difference in light-chain families or subfamilies associated with soft tissue and bone involvement. In contrast, dominant soft tissue and bone involvement was found to be associated with VLκ and VLκI families in unadjusted models; however, the significance of this association was reduced after adjusting for possible confounders. A trend toward an association of VLκI gene usage and primary soft tissue disease has previously been reported (37). In another study, VLκIII protein was isolated from the shoulder tissue of a patient with dominant soft tissue and bone involvement (14). None of the VL sequences in our group of patients with dominant soft tissue and bone involvement and articular involvement were of the VLκIII type (Table 3), and the predicted protein sequences did not encode the amino acids at positions 32, 34, 59, and 95 that were present in the VLκIII protein.
In this study, the major confounding variable was a history of multiple myeloma, which was found to be a significant risk factor for dominant soft tissue and bone involvement in both the VLκ and VLκI models. The risk of having dominant soft tissue and bone involvement was 3.9–4.3 times higher in patients with AL amyloidosis with multiple myeloma than in patients with AL amyloidosis without multiple myeloma. Interestingly, the risk of developing soft tissue and bone involvement was not associated with the presence of multiple myeloma. AL amyloidosis may occur in 7–15% of patients with multiple myeloma (38), and a variety of soft tissue and bone manifestations in patients with AL amyloidosis with multiple myeloma have previously been reported. While CTS (24), macroglossia (24, 39, 40), arthropathy (41–43), and myopathy (25, 44, 45) were common soft tissue findings, lymphadenopathy (24, 46), submandibular gland enlargement (40), and amyloid bone lesions (47, 48) were rarely reported in multiple myeloma–associated AL amyloidosis.
In the analysis of soft tissue and bone involvement, the major confounding variable was male sex in both the VLκ and VLκI models. In our cohort, the risk of developing soft tissue and bone involvement was 2-fold higher in men than in women. Male predominance has been reported for various amyloid musculoskeletal and soft tissue manifestations, such as arthropathy (41, 49), myopathy (25, 44, 45), bone lesions (50), and lymphadenopathy (31).
Dominant soft tissue and bone involvement has been thought to be a relatively indolent presentation of AL amyloidosis (14). Our survival data did demonstrate an improved median survival time and higher rate of early survival among patients with dominant soft tissue and bone involvement compared with those with other dominant organ involvement. However, over time, the Kaplan-Meier survival curve for patients with dominant soft tissue and bone involvement converged with the curve for patients with other dominant organ involvement. This result suggests that, eventually, patients with dominant soft tissue and bone involvement either developed significant morbidity and mortality from their soft tissue and bone involvement or developed life-threatening involvement of other organ systems. Indeed, both of these outcomes were observed in patients in the present study. Two other variables associated with an increased risk of death in this analysis were male sex and history of multiple myeloma, consistent with the findings of a previous study (37).
In conclusion, AL amyloidosis can present with symptoms mimicking a variety of rheumatic syndromes. Patients with symptoms or signs of an infiltrative process involving soft tissue, joints, periarticular structures, or bones, without a clear rheumatic disease diagnosis, should be screened for AL amyloidosis, so that effective treatment can be instituted in a timely manner.
- Top of page
- PATIENTS AND METHODS
- AUTHOR CONTRIBUTIONS
Dr. Prokaeva had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study design. Prokaeva, Seldin.
Acquisition of data. Prokaeva, Spencer, Kaut, Skinner, Seldin.
Analysis and interpretation of data. Prokaeva, Connors, Skinner, Seldin.
Manuscript preparation. Prokaeva, Seldin.
Statistical analysis. Prokaeva, Ozonoff, Doros, Seldin.