A 62-year-old man presented to the rheumatology clinic with report of bilateral wrist and hand pain. His symptoms had begun several months before, and over the preceding 2 months had become so severe that he was unable to make a fist. The patient observed that he had begun “walking like an old man” and had difficulty getting out of his car. His joint symptoms were associated with morning stiffness of more than 1 hour. The patient also reported swelling in his hands and wrists.
Past medical history
His past medical history was notable for hypertension, hypercholesterolemia, prostatic hypertrophy, and fractures of the left tibia and fibula, which he had sustained in a skiing injury. Previous surgeries had included a vasectomy, removal of a basal cell cancer from his nose, and bilateral carpal tunnel release 2 years before presentation.
In addition, for at least 5 years, the patient had had persistent arthralgias of his shoulder and knees. He had taken ibuprofen, with some improvement. However, the medication caused lower extremity edema and was discontinued. He then began celecoxib.
The patient believed that his shoulder symptoms had been precipitated by lifting weights. He had undergone bilateral shoulder arthroscopies within 1 year of his presentation and received the diagnosis of degenerative joint disease. At arthroscopy, the patient had undergone debridement of both glenohumeral joints, as well as the reattachment of a torn left glenoid labrum. The operative report had indicated an unremarkable synovium.
Six months before presentation, the patient had developed chest pain without electrocardiogram changes. A cardiac catheterization had shown normal coronary arteries, and his symptoms were ascribed to gastroesophageal reflux. He had noted occasional bright red blood per rectum and dark stools. A colonoscopy 2 years before presentation had shown sigmoid diverticulosis and non-bleeding external hemorrhoids.
The patient's medications upon presentation to the rheumatology clinic were aspirin (81 mg/day), terazosin hydrochloride (5 mg at bedtime), carvedilol (20 mg/day), and celecoxib (100 mg twice daily). He had no known drug allergies.
Social and family history
The patient was a real estate developer. He lived with his wife and 2 children. He did not smoke and drank alcohol less than 1 to 2 times a week.
Review of systems
The patient denied skin rash, photosensitivity, alopecia, oral ulcers, weight loss, numbness or tingling in the extremities, and focal motor weakness. He also denied headaches, jaw claudication, vision changes, fevers, and cough.
The patient was afebrile, with a blood pressure of 124/70 mm Hg and a pulse of 80 beats/minute. His pulmonary, cardiac, and abdominal examination results were normal. There were no rashes or skin lesions. However, he had boggy swelling of his bilateral proximal interphalangeal and metacarpophalangeal joints and wrists. The areas were painful to palpation, with minimal warmth and no overlying erythema. Flexion and extension in the wrist were limited by pain. There were small effusions of both the ankles and knees.
Laboratory and radiologic evaluations
The initial evaluation revealed a normochromic anemia (hematocrit of 36.4%, normal range 41.0–53.0%), but the white blood cell and platelet counts were within normal limits. Results of the initial laboratory evaluation, including selected autoimmune disease serologies, are shown in Table 1. The patient's rheumatoid factor was negative, as was an assay for antibodies to cyclic citrullinated peptides (anti-CCP antibodies). Plain radiographs of the hands and wrists showed nonspecific soft tissue swelling that was most pronounced at the dorsum of the wrist. Mild osteopenia and scattered degenerative changes were present, but there were no bony erosions and no evidence of calcium pyrophosphate deposition.
The patient is a 62-year-old man with symmetric hand and wrist arthritis that had developed subacutely.
Synovitis of the hands and wrists comprises a classic rheumatic disease differential diagnosis.
Rheumatoid arthritis (RA) was the first consideration in our patient with persistent synovitis. Although his rheumatoid factor and anti-CCP antibody assays were negative, ∼20% of patients with RA have neither of these antibodies and are termed seronegative (1). The sensitivities of rheumatoid factor and anti-CCP antibody assays for RA are 64% and 62%, respectively (2, 3).
Given the patient's age and his bilateral shoulder symptoms, polymyalgia rheumatica (PMR) was another diagnostic possibility. Up to 50% of patients with PMR present with distal musculoskeletal manifestations (4–7). Many patients with PMR who have distal extremity synovitis are misdiagnosed as having seronegative RA (2). The patient denied symptoms of giant cell arteritis (GCA), but PMR occurs without clinically evident GCA in the majority of cases (3).
Remitting seronegative symmetrical synovitis with pitting edema
Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) is characterized by dramatic pitting edema of the hands, symmetric distal synovitis, tenosynovitis, and negative RA serologies (4). RS3PE mainly affects elderly men and has been associated with solid tumors, hematologic malignancies, PMR, and GCA (4). Although the patient had synovitis, his physical findings were not so impressive as to invoke the “boxing glove sign,” the diffuse dorsal hand edema characteristic of RS3PE (5, 6).
Parvovirus B19, a common cause of viral arthritis, can mimic RA. Adults with joint manifestations of parvovirus B19 infections present with symmetric small joint arthralgias or frank synovitis, myalgias, an evanescent rash, and fever (7). Although the “slapped cheek” rash is the most characteristic finding in children, cutaneous findings in adults are more common on either the upper or lower extremities (8). Up to 80% of patients infected with parvovirus B19 develop joint symptoms. However, the majority of arthropathies associated with parvovirus B19 resolve within 2 months. The duration of symptoms in this case makes parvovirus unlikely.
Calcium pyrophosphate deposition disease
Calcium pyrophosphate deposition disease (CPDD) can masquerade as RA. Although most patients with CPDD are asymptomatic, some develop a chronic, progressive disorder that resembles osteoarthritis, neuroarthropathy, or even RA (9). CPDD can affect the hands, wrists, elbows, shoulders, knees, ankles, and feet in a symptomatic manner. The symmetric polyarthritis can be combined with morning stiffness and fatigue and synovial thickening (9). Laboratory and radiographic evaluations along with synovial fluid examination help distinguish CPDD from RA. CPDD can be associated with a variety of underlying conditions, including hemochromatosis, hypothyroidism, hyperparathyroidism, and acromegaly. The patient had no subtle findings to suggest any of these disorders, and his radiographs did not reveal chondrocalcinosis.
In the elderly, gout can present more often with upper extremity involvement, fewer gouty episodes, and a more indolent course (10–12). However, the number of joints involved in our patient's case, the symmetric joint involvement, and the absence of an acute gouty episode (particularly podagra) argue against gout as the etiology of the patient's symptoms. A uric acid level was not checked in this case.
The patient was substantially older than the mean age of presentation of individuals with ankylosing spondylitis, which normally appears before the age of 30 years (13). The symmetric nature of his arthritis makes psoriatic and reactive arthritis unlikely, although up to one-third of patients with psoriatic arthritis do not have skin disease at presentation (13).
Erosive osteoarthritis is characterized by bony proliferation and at least mildly destructive joint lesions. The disorder is associated with a female predominance and is associated with pain, swelling, warmth, and erythema. The proximal and distal interphalangeal joints are involved most often (14). Although the patient's radiographs showed some degenerative changes, there was no evidence of a periosteal reaction or erosive disease.
A variety of miscellaneous conditions can also cause synovitis of the hands and wrists. A complete list of such conditions is lengthy, but would include Whipple's disease, systemic vasculitides, sarcoidosis, and amyloidosis. However, at this juncture, few (if any) clues implicated one or more of these disorders.
Following his initial evaluation, the patient was diagnosed as having seronegative RA. He was prescribed treatment with prednisone (10 mg/day), methotrexate (15 mg/week), and folic acid (1 mg/day). Because his symptoms improved quickly on prednisone, he elected not to begin the methotrexate.
THE PATIENT'S COURSE
Four months after his initial evaluation, the patient began to have both shortness of breath and dyspnea on exertion. He also experienced edema of his lower extremities and gained 25 pounds. An echocardiogram revealed an ejection fraction of 30–35%. His primary care provider started him on furosemide (40 mg/day), carvedilol (3.125 mg/day), captopril (112.5 mg 3 times daily), fish oil, cod liver oil, and iron. Following a worsening of his symptoms, he was admitted for further evaluation.
Physical examination revealed a right conjunctival hemorrhage and bilateral ecchymoses of the eyelids. He had decreased bibasilar breath sounds. On cardiac examination, the point of maximal impulse was diffuse. S3 and S4 heart sounds were present, as was a 1/6 holosystolic murmur along the left sternal border. Examination of his extremities revealed pitting edema of the lower extremities up to the knees, swelling within the right popliteus consistent with a Baker's cyst, and synovial thickening of both wrists without tenderness or warmth.
An electrocardiogram found a normal sinus rhythm, left axis deviation, and a left bundle branch block. These findings were new compared with his electrocardiogram obtained 5 years ago and 6 months prior to the current presentation. A cardiac catheterization revealed normal coronary arteries. His pulmonary artery pressure was elevated at 46/18 mm Hg. The pulmonary capillary wedge pressure was 22 mm Hg, and the left ventricular end-diastolic pressure was 21 mm Hg.
A transesophageal echocardiogram showed thickening of the aortic, pulmonary, and tricuspid valve leaflets, with mild insufficiency of all 3 valves. The left ventricle was noncompliant, symmetrically hypertrophic, and diffusely hypokinetic, with an ejection fraction of 26%. The right ventricle was also symmetrically hypertrophic. Results of laboratory tests are shown in Table 1.
Reformulating the case
The patient's new cardiac findings suggested an infiltrative cardiomyopathy. The major additional possibilities to consider were sarcoidosis, amyloidosis, hemochromatosis, and giant cell myocarditis. Sarcoidosis can affect any part of the heart and present with conduction abnormalities, an infiltrative cardiomyopathy, congestive heart failure, pericarditis, and in rare cases, involvement of the valves (15, 16). Older echocardiographic techniques often revealed a “snowstorm” pattern to the myocardium in cardiac sarcoidosis (similar to the “ground glass” appearance described in cardiac amyloidosis) (17–19). However, newer echocardiogram technology does not reveal this finding, which is an artifact of older echocardiogram technology. Although sarcoidosis could have caused the patient's cardiac picture, the likelihood of cardiac sarcoidosis in the absence of more classic features of that disease (e.g., respiratory tract disease) is low.
Cardiac manifestations in hemochromatosis are uncommon, but arrhythmias can be an early manifestation of a cardiomyopathy caused by iron overload (20). Giant cell myocarditis is a rare and frequently fatal disorder that can be characterized by arrhythmias and congestive heart failure (21). Amyloidosis can cause conduction blocks, congestive heart failure, systolic dysfunction, changes in diastolic filling, valve thickening, and thickening of the posterior interventricular septum (22, 23).
A diagnostic test was performed.
The patient's serum protein electrophoresis revealed a marked decrease in normal immunoglobulins and 2 high-concentration bands present in the β region. The serum IgG level was high (1,660 mg/dl, normal range 614–1,295). In contrast, both the IgM and IgA levels were low (15 mg/dl, normal range 53–334 and 10 mg/dl, normal range 69–309, respectively). On immunofixation, one of the bands was identified as an IgG λ M component. The second band was identified as λ Bence Jones protein. The serum level of β2-microglobulin was 3.01 mg/liter (normal value <1.85). Urine analysis was negative for albumin. A urine protein electrophoresis was positive for λ Bence Jones protein.
A bone marrow biopsy confirmed the diagnosis of multiple myeloma. A skeletal survey was negative for lytic lesions. The marrow had increased cellularity (40%), with an increased myeloid to erythroid ratio. Numerous plasma cells were present in small and large clusters (Figure 1). Immunohistochemical stains revealed that 60% of the marrow's cellularity was comprised of CD138-positive plasma cells, which exhibited monotypic λ light chain restriction.
The patient underwent an endomyocardial biopsy, which revealed an acellular, eosinophilic substance with cracking, especially around the blood vessels (Figure 2). Congo red staining and examination of the cardiac tissue deposits by polarized microscopy revealed “apple-green” birefringence (Figure 3). Trichrome staining demonstrated a “dishwater blue” appearance (Figure 4). Immunofluorescence studies showed amyloid deposition, with selective reactivity for λ light chains as opposed to κ light chains, apolipoprotein A-I, transthyretin, and serum amyloid A (Figure 5). These findings confirmed the diagnosis of primary AL amyloidosis.
Amyloidosis is a systemic disease in which the clinical symptoms are caused by the replacement of normal tissue with insoluble amyloid fibrils (24). Despite heterogeneous structures and functions, the proteins responsible for the different amyloidosis syndromes are morphologically indistinguishable. Therefore, the deposition of amyloid fibrils represents a final common pathway of varied etiologic starting points. The major types of amyloid disease include primary or light chain (AL) amyloidosis, reactive (AA) amyloidosis, dialysis-associated (β2-microglobulin) amyloidosis, and amyloidosis associated with transthyretin (Table 2). With the use of newer dialysis membranes, β2-microglobulin amyloidosis has become rarer. In addition, a host of less common forms of amyloidosis exists (25). This discussion focuses on our patient's disorder, AL amyloidosis.
The annual incidence of AL amyloidosis, the most common form of amyloid disease, is 1 case per 100,000 person-years (25). AL amyloidosis is always associated with an underlying plasma cell dyscrasia, which in many cases progresses rapidly and is associated with a poor prognosis (26). AL amyloidosis can be difficult to diagnose due to its insidious onset, vague symptomatology, and varied manifestations. Systemic symptoms can include fatigue, dyspnea, edema, paresthesias, weight loss, peripheral neuropathy, and autonomic dysfunction (27, 28).
Only a short portion of the amyloid light chain can fit within the β-pleated sheet. In addition, the tight fibril packing characteristic of amyloidosis imposes certain constraints on the light chains. The polypeptide incorporated into the β-pleated sheet generally includes at least part of the variable region of the light chain. Therefore, only a small fraction of light chains contributes to the formation of amyloid fibrils. Because the variable region is commonly involved, the protein constituent of the fibril is likely unique for each patient. Hence, the clinical distribution and consequences of AL amyloidosis are unpredictable, and the disease can be highly heterogeneous from patient to patient.
The kidneys are the most commonly involved organ. Renal involvement can include nephrotic-range proteinuria and renal failure (27). The second most commonly involved organ is the heart. In a series of male patients with a mean age of 53 years, cardiac disease was apparent in 83% (22). The features of cardiac amyloidosis include abnormal electrocardiographic findings, particularly conduction blocks (86%), impaired left ventricular systolic function (27%), and mitral or aortic thickening (13%) (22). Our patient had a variety of features classic for AL amyloidosis: left axis deviation, left bundle branch block, congestive heart failure, right ventricular hypertrophy, valve dysfunction, and leaflet thickening.
Biopsy is the definitive test for amyloidosis. This becomes more difficult when the affected organ is the brain or heart. Studies have found that only cases that are very characteristic of cardiac amyloidosis were diagnosed in life (29). In a large series of endomyocardial biopsies that were performed to establish the cause of cardiomyopathies, cardiac amyloidosis was found in 18% of the cases without previous clinical identification of the disease (30).
Oral manifestations occur in up to 39% of patients with AL amyloidosis (31). There can be enlargement of the submandibular structures, macroglossia, submandibular lymphadenopathy, and purpura, especially around the eyes (28, 32). Purpura can occur from minor trauma such as rubbing the eyes. In our patient, it occurred after an episode of coughing. Factor X deficiency in amyloidosis is due to the adsorption of factor X to amyloid fibrils within the vasculature (33). The acquired factor X deficiency heightens the risk of bleeding from already friable vessels (34). The macroglossia in amyloidosis, which leads to a firm, dry, ulcerated, fissured, and painful tongue, can be associated with indentations from the teeth (31). Organomegaly can also occur in the liver and spleen (28).
Musculoskeletal and articular manifestations stem from the infiltration of skeletal and periarticular structures by the amyloid protein. This leads to complications such as muscle hypertrophy, carpal tunnel syndrome, trigger finger, flexor tendon contracture, and spontaneous tendon rupture (28, 32, 35). Bony involvement and vertebral collapse due to amyloid infiltration are unusual manifestations of AL amyloidosis and need to be distinguished from the lytic bone lesions seen in multiple myeloma (36). The most common symptom is severe joint pain without radiographic changes of arthritis. The shoulder is affected most often (35). Our patient had surgery for bilateral carpal tunnel and bilateral shoulder arthroscopy for his reports of shoulder pain.
Studies have found that cervical adenopathy and muscle hypertrophy have been observed only in patients with multiple myeloma (32). The risk of dominant soft tissue and bone involvement is approximately 4 times higher in patients with AL amyloidosis with multiple myeloma than those with AL amyloidosis alone (32).
Patients with AL amyloidosis can have a mixed sensory and motor peripheral neuropathy or an autonomic neuropathy. Those with a peripheral neuropathy can present with numbness, tingling, and pain. Compression of the peripheral nerves, as in compression of the median nerve in carpal tunnel, can cause localized symptoms. At diagnosis, 17% of patients with AL amyloidosis have peripheral neuropathy. The neuropathy associated with amyloidosis is painful and progressive and can be accompanied by autonomic dysfunction (37).
Amyloidosis should be suspected in a patient with multiorgan dysfunction, especially if the nephrotic syndrome, cardiomyopathy, or peripheral neuropathy are present. The diagnosis is made by tissue biopsy. Aspiration of abdominal fat, the least invasive method, has a sensitivity of up to 80% with a single aspiration (38, 39). The specificity of subcutaneous abdominal fat aspiration is 99%, with a positive predictive value of 98% and a negative predictive value of 76% (38). If results are negative but suspicion of amyloidosis persists, biopsy of the dysfunctional organ is high in yield. Sites that are commonly chosen include the rectum, stomach, heart, kidney, and liver.
Under polarized light, amyloid-infiltrated tissues stained with Congo red classically demonstrate apple-green birefringence. All subtypes of amyloidosis demonstrate this finding. Once the diagnosis of amyloidosis is made, the particular type of amyloid must be defined. The course and prognosis of amyloidosis are dependent upon the particular organs involved and the degree of organ involvement.
Our patient was treated with dexamethasone, thalidomide, and colchicine. In addition, a dual-chamber pacemaker with an intracardiac device was placed. Six months into treatment, the patient had complete remission of his multiple myeloma, with a decrease in his λ free light chains from approximately 2,200 mg/liter to 18.4 mg/liter (normal range 9.7–28.3), and the plasma cell population in his bone marrow was less than 1%.
λ light chain (AL) amyloidosis associated with multiple myeloma.
It has been 4 years since the diagnosis, and the patient has been doing well. He continues to take daily thalidomide and has been receiving infusions of zoledronate every 3 months. There have been no cardiac issues and his disease has been in full remission.
Dr. Setty 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. Setty.
Acquisition of data. Setty.
Analysis and interpretation of data. Setty, Robinson.