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病例28-2024：一名75岁女性，患有水肿、关节炎和蛋白尿

发表人：京东医生

以下内容来源于新英格兰医学杂志。

Presentation of Case

Dr. Christine M. Parsons (Medicine): A 75-year-old woman was evaluated at this hospital because of arthritis, abdominal pain, edema, malaise, and fever.

Three weeks before the current admission, the patient noticed waxing and waning “throbbing” pain in the right upper abdomen, which she rated at 9 (on a scale of 0 to 10, with 10 indicating the most severe pain) at its maximal intensity. The pain was associated with nausea and fever with a temperature of up to 39.0°C. Pain worsened after food consumption and was relieved with acetaminophen. During the 3 weeks before the current admission, edema developed in both legs; it had started at the ankles and gradually progressed upward to the hips. When the edema began to affect her ambulation, she presented to the emergency department of this hospital.

A review of systems that was obtained from the patient and her family was notable for intermittent fever, abdominal bloating, anorexia, and fatigue that had progressed during the previous 3 weeks. The patient reported new orthopnea and nonproductive cough. Approximately 4 weeks earlier, she had had diarrhea for several days. During the 6 weeks before the current admission, the patient had lost 9 kg unintentionally; she also had had pain in the wrists and hands, 3 days of burning and dryness of the eyes, and diffuse myalgias. She had not had night sweats, dry mouth, jaw claudication, vision changes, urinary symptoms, or oral, nasal, or genital ulcers.

The patient’s medical history was notable for multiple myeloma (for which treatment with thalidomide and melphalan had been initiated 2 years earlier and was stopped approximately 1 year before the current admission); hypothyroidism; chikungunya virus infection (diagnosed 7 years earlier); seropositive erosive rheumatoid arthritis affecting the hands, wrists, elbows, and shoulders (diagnosed 3 years earlier); vitiligo; and osteoarthritis of the right hip, for which she had undergone arthroplasty. Evidence of gastritis was reportedly seen on endoscopy that had been performed 6 months earlier. Medications included daily treatment with levothyroxine and acetaminophen and pipazethate hydrochloride as needed for cough. The patient consumed chamomile and horsetail herbal teas. She had no known allergies to medications, but she had been advised not to take nonsteroidal antiinflammatory drugs after her diagnosis of multiple myeloma.

Approximately 5 months before the current admission, the patient had emigrated from Central America. She lived with her daughter and grandchildren in an urban area of New England. She had previously worked in health care. She had no history of alcohol, tobacco, or other substance use. There was no family history of cancer or autoimmune, renal, gastrointestinal, pulmonary, or cardiac disease.

On examination, the temporal temperature was 37.1°C, the heart rate 106 beats per minute, the blood pressure 152/67 mm Hg, and the oxygen saturation 100% while the patient was breathing ambient air. She had a frail appearance and bitemporal cachexia. The weight was 41 kg and the body-mass index (the weight in kilograms divided by the square of the height in meters) 15.2. Her dentition was poor; most of the teeth were missing, caries were present in the remaining teeth, and the mucous membranes were dry. She had abdominal tenderness on the right side and mild abdominal distention, without organomegaly or guarding. Bilateral axillary lymphadenopathy was palpable. Infrequent inspiratory wheezing was noted.

The patient had swan-neck deformity, boutonnière deformity, ulnar deviation, and distal hyperextensibility of the thumbs (Fig. 1). Subcutaneous nodules were observed on the proximal interphalangeal joints of the second and third fingers of the right hand and on the proximal interphalangeal joint of the fourth finger of the left hand. Synovial thickening of the metacarpophalangeal joints of the second fingers was noted. There was mild swelling and tenderness of the wrists. She had pain with flexion of the shoulders and right hip, and there was subtle swelling of the shoulders and right knee. Pitting edema (3+) and vitiligo were noted on the legs. No sclerodactyly, digital pitting, telangiectasias, appreciable calcinosis, nodules, nail changes (including pitting), or tophi were present. The remainder of the examination was normal.

Figure 1

Photograph of the Hands.

The blood levels of glucose, alanine aminotransferase, aspartate aminotransferase, bilirubin, globulin, lactate, lipase, magnesium, and phosphorus were normal, as were the prothrombin time and international normalized ratio; other laboratory test results are shown in Table 1. Urinalysis showed 3+ protein and 3+ blood, and microscopic examination of the sediment revealed 5 to 10 red cells per high-power field and granular casts. Urine and blood were obtained for culture. An electrocardiogram met (at a borderline level) the voltage criteria for left ventricular hypertrophy.

Table 1

Laboratory Data.

Dr. Rene Balza Romero: Computed tomography (CT) of the chest, abdomen, and pelvis, performed after the intravenous administration of contrast material, revealed scattered subcentimeter pulmonary nodules (including clusters in the right middle lobe and patchy and ground-glass opacities in the left upper lobe), trace pleural effusion in the left lung, coronary and valvular calcifications, and trace pericardial effusion, ascites, and anasarca. The scans also showed slight enlargement of the axillary lymph nodes (up to 11 mm in the short axis) bilaterally and a chronic-appearing compression fracture involving the T12 vertebral body.

Dr. Parsons: Morphine and lactated Ringer’s solution were administered intravenously. On the second day in the emergency department (also referred to as hospital day 2), the blood levels of haptoglobin, folate, and vitamin B₁₂ were normal; other laboratory test results are shown in Table 1. A rapid antigen test for malaria was positive. Wright–Giemsa staining of thick and thin peripheral-blood smears was negative for parasites; the smears also showed Döhle bodies and basophilic stippling. Antigliadin antibodies and anti–tissue transglutaminase antibodies were not detected. Tests for hepatitis A IgG and hepatitis C antibodies were positive. Tests for hepatitis B core and surface antibodies were negative. A test for human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) was negative.

Findings on abdominal ultrasound imaging performed on the second day (Fig. 2A and 2B) were notable for a small volume of ascites and kidneys with echogenic parenchyma. Ultrasonography of the legs showed no deep venous thrombosis. An echocardiogram showed normal ventricular size and function, aortic sclerosis with mild aortic insufficiency, moderate tricuspid regurgitation, a right ventricular systolic pressure of 39 mm Hg, and a small circumferential pericardial effusion. Intravenous hydromorphone was administered, and the patient was admitted to the hospital.

Figure 2

Imaging Studies of the Abdomen and Hands.

On the third day (also referred to as hospital day 3), nucleic acid testing for cytomegalovirus, Epstein–Barr virus, and hepatitis C virus was negative, and a stool antigen test for Helicobacter pylori was negative. An interferon-γ release assay for Mycobacterium tuberculosis was also negative. Oral acetaminophen and ivermectin and intravenous hydromorphone and furosemide were administered.

Dr. Balza Romero: Radiographs of the hands (Fig. 2C through 2F) showed joint-space narrowing of both radiocarpal joints and proximal interphalangeal erosions involving both hands. Radiographs of the shoulders showed arthritis of the glenohumeral joint and alignment suggestive of a tear of the right rotator cuff. A radiograph of the pelvis showed diffuse joint-space narrowing of the left hip, without osteophytosis, and an intact right hip prosthesis.

Dr. Parsons: Diagnostic tests were performed, and management decisions were made.

Differential Diagnosis

Dr. Beth L. Jonas: This patient is a 75-year-old woman who recently emigrated from Central America. She presented to this hospital with a multisystem disease involving the respiratory, gastrointestinal, renal, and musculoskeletal systems. Her medical history is notable for seropositive erosive rheumatoid arthritis and multiple myeloma, which had been treated with melphalan and thalidomide. Relevant clinical features on presentation include unintended weight loss and cachexia, axillary lymphadenopathy, serositis, cytopenia in two cell lines, hypocomplementemia, and elevated serum free kappa and lambda light-chain levels (with a normal free light-chain ratio) with no monoclonal spike. The white-cell count was elevated, but she had no eosinophilia. CT images of the chest showed scattered subcentimeter pulmonary nodules. With respect to the patient’s anemia, no schistocytes were present, the haptoglobin level was normal, and the iron studies were unremarkable. These findings, in combination with the elevated ferritin level, indicate anemia of chronic inflammation. The renal findings are most salient in the context of the patient’s hypertension, anasarca, elevated cystatin C level, active urinary sediment with proteinuria in the nephrotic range, and small, echogenic kidneys on ultrasonography.

In constructing a differential diagnosis, I will consider medication use, cancer, infectious disease, and autoimmune disease. Medications can be eliminated as the cause of this patient’s illness, since she was taking only levothyroxine, acetaminophen, and the antitussive agent pipazethate.

Cancer

The patient has a history of multiple myeloma, which may manifest with a multisystem disease involving the kidneys, but serum protein electrophoresis showed no monoclonal protein. Given the presence of nephrotic syndrome in the context of multiple myeloma, systemic immunoglobulin light-chain amyloidosis would be highest on the differential diagnosis with respect to cancer; however, the patient’s normal light-chain ratio makes this diagnosis unlikely. The development of myeloid neoplasms, such as acute myeloid leukemia, myelodysplastic syndromes, and myeloproliferative neoplasms, is important to consider in the context of previous treatment with alkylating agents,¹ which this patient had received. However, the peripheral-blood smear showed no findings that would indicate a hematologic cancer, and such a diagnosis would not explain the patient’s acute kidney injury with nephrotic-range proteinuria.

Infectious Disease

Several features of this patient’s case warrant special consideration, including her history of immunosuppression due to rheumatoid arthritis and to previously treated myeloma, along with the fact that she had emigrated from Central America, where certain infections may be prevalent. Infection with hepatitis A virus, hepatitis B virus, hepatitis C virus, HIV-1 and HIV-2, cytomegalovirus, Epstein–Barr virus, H. pylori, and M. tuberculosis can be ruled out on the basis of laboratory studies. A rapid antigen test for plasmodium species was reported to be positive, but this assay has a known cross-reactivity with rheumatoid factor.² Moreover, the thick and thin peripheral-blood smears were negative. Thus, malaria would be an unlikely diagnosis.

The patient has a history of infection with chikungunya virus, an arbovirus transmitted by a mosquito vector that has been responsible for large epidemics in the Americas since 2013.³ Acute symptoms include fever, rash, arthralgia, and myalgia. The development of a chronic arthritis that may meet the classification criteria for rheumatoid arthritis, as defined by the American College of Rheumatology and the European Alliance of Associations for Rheumatology, has been reported in up to 60% of patients infected with chikungunya virus.^4,5 In the context of this discussion, I considered whether chikungunya virus infection could be the cause of this patient’s symptoms, since this infection occurred before the diagnosis of rheumatoid arthritis. However, the degree of erosion and loss of joint space that was visible on radiographs would be most unusual for arthritis associated with chikungunya virus infection and would not explain the renal manifestations.

Strongyloidiasis is a helminth infection (caused by Strongyloides stercoralis) that is widespread in developing countries. Infection usually occurs through contact with soil, and most affected persons are asymptomatic. However, in immunosuppressed persons, strongyloides hyperinfection syndrome or a disseminated infection can develop as a consequence of accelerated autoinfection.⁶ The clinical presentation of strongyloides hyperinfection syndrome can include gastrointestinal symptoms (diarrhea, constipation, nausea, or vomiting), respiratory symptoms (cough, dyspnea, or wheezing), and rash due to migration of larvae through the subcutaneous tissues. Of note, only a minority of patients present with eosinophilia. Several case reports describe the development of nephrotic-range proteinuria, thrombotic microangiopathy, and IgA vasculitis in patients with strongyloides hyperinfection syndrome.^7-9 However, strongyloidiasis would not explain this patient’s cytopenias and hypocomplementemia.

Autoimmune Disease

The patient has a 3-year history of rheumatoid arthritis, although her clinical features of swan-neck deformity, boutonnière deformity, and joint instability suggest a longer duration of disease. We do not know whether she had received previous treatment with disease-modifying antirheumatic drugs or biologic agents, but the possible use of such treatments may be a consideration with respect to her progression of disease and overall degree of immunosuppression. The blood levels of rheumatoid factor and anti–cyclic citrullinated peptide antibodies were elevated, and radiographs of the hands showed erosive disease, although there was a relative paucity of metacarpophalangeal findings. A review of systems was negative for dry mouth, but her physical examination showed poor dentition and dry mouth — findings that make secondary Sjögren’s syndrome a consideration.

Renal disease can occur in patients with Sjögren’s syndrome. The two most typical presentations are tubulointerstitial nephritis and, less commonly, nephritic syndrome (membranoproliferative glomerulonephritis related to cryoglobulinemia). Tubulointerstitial nephritis may manifest with renal disease of varying severity, usually with a bland urinary sediment and often with abnormalities of tubular function such as distal renal tubular acidosis. Membranoproliferative glomerulonephritis caused by cryoglobulinemia is the most common glomerular disease associated with Sjögren’s syndrome. Although nephrotic-range proteinuria can occur with Sjögren’s syndrome, it is relatively uncommon.¹⁰ Renal disease is uncommon in patients with rheumatoid arthritis and is usually related to coexisting cardiovascular conditions. Medications used in the treatment of autoimmune disease — mainly nonsteroidal antiinflammatory drugs — may be associated with renal disease, but I would not expect the presence of an active urinary sediment, as was seen in this patient.

Amyloid A (AA) amyloidosis, a condition that is rare in the era of aggressive management of rheumatoid arthritis, has been described in patients with severe, long-standing seropositive erosive rheumatoid arthritis. Serum amyloid A (SAA) is a protein that is produced in the liver in response to chronic inflammation associated with interleukin-1, interleukin-6, and tumor necrosis factor α (TNF-α) in the context of chronic infections, autoimmune disease (classically rheumatoid arthritis), autoinflammatory disease, and cancers including renal cell carcinoma and non-Hodgkin’s lymphoma.¹¹ Signs and symptoms of AA amyloidosis are related to the deposition of the protein in organs, and patients often present with multisystem signs and symptoms. The kidney is the organ that is most often affected, but deposition can occur in the heart, gastrointestinal tract, nervous system, musculoskeletal system, and lungs. Proteinuria is the first clinical manifestation in almost 95% of patients with AA amyloidosis, and 50% of affected patients present with nephrotic syndrome.¹² The urinary sediment is generally bland, and complement levels in the blood are normal. AA amyloidosis remains on the differential diagnosis in this patient, but it would not completely explain her renal disease.

Hypocomplementemia

The key to this case is understanding the cause of this patient’s hypocomplementemia. Hypocomplementemia can be due to decreased complement production in the context of liver disease, congenital complement deficiency, or increased complement consumption resulting from activation of the innate immune system. This patient has no history of chronic liver disease and her laboratory test results indicated good hepatic synthetic function. Classical complement deficiency (including C4 deficiency) that begins early in life is associated with autoimmune disease, and early C3 deficiency is characterized by severe pyogenic infections. It would be unusual for a patient of this age to be deficient in both C3 and C4 without earlier clinical consequences. I therefore concluded that the hypocomplementemia in this case was related to complement consumption.

Rheumatic diseases that may be associated with prominent renal manifestations include antineutrophil cytoplasmic antibody–associated vasculitis, systemic sclerosis with renal crisis, cryoglobulinemic vasculitis, antiglomerular basement membrane disease, and systemic lupus erythematosus (SLE). Of those conditions, SLE would be the most likely to be manifested by an active urinary sediment and nephrotic-range proteinuria with consumption of both C3 and C4 in the context of fever, thrombocytopenia, and serositis. This patient’s fever, thrombocytopenia, and serositis also fit with this diagnosis.¹³

Because the patient has long-standing seropositive erosive rheumatoid arthritis, a diagnosis of AA amyloidosis is strongly suspected. Moreover, given the presence of thrombocytopenia, hypocomplementemia, and an active urinary sediment, I would recommend a kidney biopsy to evaluate for lupus nephritis and AA amyloidosis.

Dr. Beth L. Jonas’s Diagnosis

Overlap syndrome of rheumatoid arthritis and systemic lupus erythematosus with amyloid A amyloidosis.

Pathological Discussion

Dr. Claire Trivin-Avillach: Testing for autoimmune antibodies was performed. A test for antinuclear antibodies was positive at a titer of 1:5120 with a homogeneous pattern, and a test for anti–double-stranded DNA antibodies was positive at a titer of 1:2560.

The diagnostic procedure in this case was a core-needle biopsy of the kidney. Examination of the specimen with light microscopy revealed 20 glomeruli, 45% of which were globally sclerosed, along with fibrosis involving approximately 60% of the interstitium and tubular atrophy. Diffusely enlarged glomeruli with thickened capillary walls and an expanded mesangium were weakly positive on periodic acid–Schiff staining; the glomeruli stained pale blue on Masson’s trichrome staining. Congo red staining revealed metachromatic salmon-colored deposition involving the glomeruli, the blood-vessel walls, and the interstitium, which was associated with apple-green birefringence when viewed under polarized light (Fig. 3A). In addition, mesangial and endocapillary hypercellularity was identified in approximately 30% of the nonsclerosed glomeruli and was associated with karyorrhexis (Fig. 3B). One cellular crescent was also detected. These features are characteristic of active proliferative glomerulonephritis.

Figure 3

Biopsy Specimen of the Kidney.

Immunofluorescence microscopy revealed prominent granular staining for IgG (4+), IgM (4+), C3 (3+), C1q (3+), IgA (1+), kappa (3+), and lambda (3+) along the glomerular basement membranes and within the mesangium, as well as focal granular deposits of IgG and C3 along the tubular basement membrane (Fig. 3C and 3D). Additional immunofluorescence studies showed strong positivity (4+) for SAA within the glomeruli, the blood-vessel walls, and the interstitium (Fig. 3E), whereas staining for beta₂-microglobulin, transthyretin, and apolipoprotein A1 was faint.

Electron microscopy revealed the presence of subendothelial and mesangial electron-dense deposits (with no substructure identified) adjacent to randomly arranged fibrils (measuring 8.2 to 10.6 nm in diameter) within the glomerular basement membranes and the mesangium (Fig. 3F). Glomerular endothelial cells appeared reactive and contained tubuloreticular inclusions, features that were suggestive of interferon-mediated activation.

The findings on Congo red staining were characteristic of amyloidosis with typical birefringent material. The strong positivity of SAA within the deposits as compared with the faint staining of other reactants identified the type of amyloid as SAA, which is consistent with the patient’s history of rheumatoid arthritis. The biopsy also showed an immune complex–mediated proliferative glomerulonephritis with a “full house” pattern (defined as positivity for the three immunoglobulin classes IgG, IgM, and IgA and the two complement components C3 and C1q, in reference to the “full house” hand in a poker game). Immune complex–mediated proliferative glomerulonephritis has been reported in patients with rheumatoid arthritis who were receiving anti–TNF-α therapy,¹⁴ which was not the case in this patient. The positive test for hepatitis C antibodies prompted consideration of hepatitis C–related membranoproliferative glomerulonephritis. However, taken together, the negative nucleic acid test for hepatitis C virus, the full house pattern on immunofluorescence, the tubular basement membrane deposits, and the positive test for anti–double-stranded DNA antibodies favor a diagnosis of lupus nephritis of at least class III (defined as focal proliferative glomerulonephritis), according to the criteria of the International Society of Nephrology and the Renal Pathology Society, superimposed on AA amyloidosis.

Pathological Diagnosis

Proliferative lupus nephritis of International Society of Nephrology and Renal Pathology Society class III, superimposed on amyloid A amyloidosis.

Discussion of Management

Dr. Pui W. Cheung: On the basis of the finding of echogenic kidneys on ultrasonography and the findings of extensive interstitial fibrosis and tubular atrophy on kidney biopsy, we know that this patient has advanced chronic kidney disease that is unlikely to be reversible. The patient is also noted to have a markedly lower glomerular filtration rate (GFR) than that predicted by the blood creatinine level owing to the presence of cachexia, and this is substantiated by the cystatin C–based GFR and a 24-hour creatinine clearance of 22 ml per minute per 1.73 m² of body-surface area. The typical induction therapy for stage III or IV lupus nephritis consists of high-dose glucocorticoids and either mycophenolate mofetil or cyclophosphamide. Other reasonable alternatives for initial therapy include mycophenolate mofetil in combination with either a calcineurin inhibitor or belimumab, or cyclophosphamide in combination with belimumab.¹⁵ Hydroxychloroquine is also recommended as part of the therapy, since it has shown benefits in improving the response to treatment and reducing disease flare.¹⁶ Mycophenolate mofetil and cyclophosphamide have similar efficacy with respect to clinical response, which includes a reduction in proteinuria and either an improvement in renal function or stabilization of renal function; the risks of infections and adverse events associated with these medications are also similar.^17,18

Given the severity of the lupus nephritis with overlying AA amyloidosis from active rheumatoid arthritis, the treatment options proposed were high-dose glucocorticoids and rituximab with either mycophenolate mofetil or cyclophosphamide.¹⁹ After discussions with multidisciplinary consultants from rheumatology, infectious diseases, and nephrology, lingering concerns were raised about infection and patient frailty; ultimately, the decision was made to initiate high-dose glucocorticoid therapy in combination with mycophenolate mofetil, rituximab, and hydroxychloroquine.

The patient’s mycophenolate mofetil dose regimen was inconsistent owing to gastrointestinal side effects, and the treatment was eventually withheld because of pancytopenia and fever. Unfortunately, her kidney function worsened, and renal replacement therapy was initiated within 3 weeks after the start of the induction therapy. The cause of her renal failure was thought to be disease progression, compounded by hemodynamically mediated tubular injury in the context of infection. While the administration of mycophenolate mofetil was stopped, treatment with rituximab was continued, with slow tapering of the glucocorticoid dose at the direction of the rheumatologist. She remained dependent on dialysis and was deemed to have end-stage kidney disease after 3 months of dialysis.

Dr. Lisa G. Criscione-Schreiber: The patient has SLE with nephritis, seropositive erosive rheumatoid arthritis, and systemic AA amyloidosis. AA amyloidosis is rare owing to the availability of effective therapies for rheumatoid arthritis and is managed through aggressive treatment of inflammation due to rheumatoid arthritis. Reports addressing the management of rheumatoid arthritis–induced AA amyloidosis generally cite stability of end-organ damage caused by AA amyloid as evidence of effective management of the condition (through treatment of the inflammation of rheumatoid arthritis). Methotrexate, the cornerstone of treatment for rheumatoid arthritis, is contraindicated in this case owing to the presence of kidney disease. The alkylating agent cyclophosphamide has been reported to be effective for the treatment of AA amyloidosis from rheumatoid arthritis²⁰ and has known efficacy in patients with lupus nephritis, both of which make it a viable treatment option. Rituximab has also been reported to be effective for managing rheumatoid arthritis–induced AA amyloidosis,²¹ is approved for the treatment of rheumatoid arthritis, and is used for manifestations of SLE, including thrombocytopenia and nephritis. Although anti–TNF-α agents, abatacept, and Janus kinase inhibitors are reported to be effective for the treatment of AA amyloidosis in patients with rheumatoid arthritis,²² recent publications have coalesced on the ability of anti–interleukin-6 therapy to block interleukin-6–induced hepatic production of SAA.^23-25

The overlap of seropositive erosive rheumatoid arthritis and SLE (sometimes termed “rhupus”) usually resembles rheumatoid arthritis more than SLE; manifestations include thrombocytosis, leukocytosis, an elevated erythrocyte sedimentation rate, an elevated blood level of C-reactive protein, and the presence of marginal erosions on radiographs.²⁶ In contrast, SLE without seropositive erosive rheumatoid arthritis characteristically manifests with thrombocytopenia, leukopenia, and an elevated erythrocyte sedimentation rate but usually not an elevated C-reactive protein level; in addition, nonerosive inflammatory arthritis with reversible deformities is commonly observed. This patient had a mixed laboratory profile, on the basis of the results of antinuclear antibody and anti–double-stranded DNA antibody tests. The challenge of treating an overlap syndrome of rheumatoid arthritis and SLE is choosing disease-modifying antirheumatic drugs that are effective and safe in both conditions. This patient’s most severe disease manifestation is lupus nephritis; therefore, the treatment regimen must target nephritis along with the AA amyloidosis and inflammatory arthritis.

As noted earlier, current induction therapy for lupus nephritis includes either mycophenolate mofetil or cyclophosphamide. Mycophenolate mofetil may provide inadequate treatment of the rheumatoid arthritis and amyloidosis, whereas cyclophosphamide would treat the lupus nephritis, has possible efficacy for treatment of the AA amyloidosis, and would treat the rheumatoid arthritis. Rituximab could be added to cyclophosphamide or mycophenolate mofetil to treat the rheumatoid arthritis and resultant AA amyloidosis and could also possibly help treat the lupus nephritis. The addition of anti–interleukin-6 therapy to mycophenolate mofetil or cyclophosphamide is an intriguing option that may effectively treat the rheumatoid arthritis and subsequent AA amyloidosis. The addition of belimumab to mycophenolate mofetil or cyclophosphamide has been reported to improve renal response in patients with lupus nephritis,²⁷ as has the addition of voclosporin to mycophenolate mofetil.²⁸ However, belimumab is ineffective for the treatment of rheumatoid arthritis, and voclosporin has not been studied in patients with rheumatoid arthritis or in those with a GFR of 45 milliliters per minute or less. The high-dose glucocorticoids that are used in induction therapy for lupus nephritis will effectively manage this patient’s inflammatory arthritis and probably also the subsequent AA amyloidosis. Finally, it is important that every patient with lupus nephritis receive hydroxychloroquine, which improves the treatment response to induction therapy.²⁹

Follow-up

Dr. Parsons: The patient’s hospital course was further complicated by suspected immune-mediated thrombocytopenia, for which she received intravenous immune globulin. Her pancytopenia and arthritis ultimately abated. Unfortunately, she did not have renal recovery and continues to receive hemodialysis. After a prolonged hospital course, she was discharged home.

Final Diagnosis

Overlap syndrome of rheumatoid arthritis and systemic lupus erythematosus complicated by proliferative lupus nephritis, superimposed on amyloid A amyloidosis.

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最近接诊了一例比较典型的胃气受损，气机紊乱的病例。患者5+年前因为喝了鹿茸酒后，导致自觉“上火”，长期体内燥热难安，舌红苔黄厚腻，经常自觉烧心。

遂长期自服“菊花茶”、“莲子心”，及服用各种凉药调理。20+天前，就诊于当地中医院，给予生地30克，玄参30克，牡丹皮30克，黄柏10克，知母15克，龙胆草15克，黄芩10克，柴胡15克，制大黄6克，郁金10克，泽泻30克，葛花25克，青黛（包煎）10克，竹叶10克治疗。经治疗，上症稍缓解。

患者遂又饮酒，饮酒后胃胀闷不适，于是吃了一些生白萝卜，服用后，胃部不适加重。恰好下午洗澡，看到下腹部有红色细疹若干，自以为是“蜘蛛痣”，联想到“肝硬化”，心中一惊，晚上便开始吃不下东西。

患者第二天强迫自己吃了一些馒头、西红柿，依然没有食欲，开始自觉心悸、头晕，遂就诊于当地医院，给予输液治疗，药物有庆大霉素，泮托拉唑等。

输液后，上症仍未好转，遂换了一家医院就诊，诊断为“功能性消化不良”，予“莫沙必利，阿莫西林，健胃消炎颗粒”治疗，并检查了“乙肝两对半”及“肝功能”，以上项目未见明显异常。

患者仍自觉恶心，食欲不振，遂就诊于我处，舌黯红，舌苔黄白相间，黄多白少，脉微弦，诊断为胃气受损，寒热错杂，气机紊乱症。

方则予“甘草泻心汤”加减，方药如：姜半夏6克、黄连6克、黄芩12克、干姜6克、炙甘草12克、党参12克、生姜10克、大枣12克、蒲公英20克、醋香附10克、陈皮12克、竹茹12克、木香6克。中药配方颗粒，5剂，每日两次，每次一袋，开水冲服。患者用药后，恶心，呕吐感逐渐消失，食欲缓慢恢复，遂叮嘱患者不要暴饮暴食，吃饭吃七分饱，先吃一些面条。

患者长期身体燥热难安，一直用莲子心，菊花等清凉之品泡茶饮用，之后又喝了大黄，黄柏，玄参等寒凉中药，接着又不忌口，开始喝白酒，胃气因此受损，脾胃气机紊乱，脾胃气机升降失常，脾气不能升清，胃气不能降浊，气机紊乱后，又衍生各种变证。

在中医理论中，脾胃是人体气机升降的枢纽，通过脾升举清气，胃气肃降浊气，升降相依，生生不息，维持着人体气机升降的平衡，当平衡被破坏后，人体的脾胃和身体就会出现一系列不适。辛开苦降法则是应对脾胃气机紊乱的中正之法。

所谓辛开苦降法，就是辛温和苦寒药物并举，两类药物互相配合使用的一种方法。辛能散，能升，苦能泄，能降，辛温之品可以温运脾阳，益气升清，苦寒燥湿之品可以肃降浊气，祛除有形之邪——如此，清气升，浊气降，脾胃的升、降、出、入恢复正常，人体又恢复了动态平衡。

辛开苦降法的代表方剂就是“半夏泻心汤”，“生姜泻心汤”，“甘草泻心汤”三大泻心汤，在这三个经典方子中，温药半夏可散结消痞，干姜/生姜可温中散寒，人参，大枣，甘草健脾和中，镇守中焦；凉药黄连，黄芩，苦寒肃降，泄热逐邪。辛温药物和寒凉药物搭配在一起后，脾气能升，胃气能降，胃部痞满不适，恶心，腹胀，食欲不振等气机紊乱之症就此消弭。

在三大泻心汤中，从比例分析，半夏泻心汤重用半夏，故消痞之力最强；生姜泻心汤，干姜之外，加用生姜，故温阳化饮的力量最强；甘草泻心汤，重用甘草，故补胃气的功效最强。

在这个病例中，由于患者长期服用寒凉药物，同时又喝酒，所以选用甘草泻心汤为基础方。患者的病情因“受惊吓”而加重，故加陈皮，香附以疏肝解郁，理气宽中。

香附和蒲公英是我非常喜欢搭配使用的一对药对，两者相伍既能疏肝气，清郁热，又能泻胃火，化湿热，同时既无燥热伤阴之忧，又无苦寒败胃之弊。所以我用香附必用蒲公英，用蒲公英必佐香附。

患者同时伴有些许恶心感，胃部不适感，遂稍加竹茹以化痰止呕，木香以行气、健脾、止痛。

总之，仲景开创的辛开苦降法乃调理脾气气机升降，恢复气机正常运行的首选方法，遇到此类病例，均可斟酌使用。

本文由作者原创，文章内容仅供参考。转载及合作事宜可联系jdh-hezuo@jd.com 。
身体没有劲，一活动就喘，是心衰还是哮喘？怎样缓解？

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老年人一活动就喘，大体上有几种可能，但怎样缓解，需要根据是什么疾病来判断！咱们一起来看看一活动就喘的可能性都有那些？

一、心功能不全

心衰病人，尤其是左心功能不全以及全心功能不全的病人，会出现一活动就喘，也就是我们常说的活动耐量下降的情况。而鉴别是否是心功能不全，除外症状以后，还需要有心脏彩超的支持，以及BNP的升高，可以诊断心功能不全。心功能不全的治疗，主要是改善症状及改善预后治疗。

二、肺动脉高压

各种原因引起的肺动脉高压的患者，会出现活动后就喘的情况，诸如先天性心脏病引起的，肺栓塞后引起的，原发性肺动脉高压的，肺动脉高压的诊断需要结合胸部x线或者胸部CT等发现肺动脉增宽，心脏彩超证实肺动脉压力升高，才能诊断。肺动脉高压的治疗，主要是降低肺动脉高压以及延缓肺动脉高压患者的预后。

三、慢性阻塞性肺疾病

慢阻肺的患者，到肺功能严重受损的情况下，也会出现活动后就喘的情况，而慢阻肺的诊断，需要肺部CT以及肺功能的测定才能诊断，而诊断后的治疗，需要氧疗以及改善肺功能预后及对症处理。

四、严重肺部感染

严重的肺部感染，因为感染较重，也会出现活动后就喘的情况，此时诊断主要依据感染学的相关指标，比如血常规、C反应蛋白、血沉、降钙素原、肺部影像学检查等诊断。治疗主要是抗感染以及对症处理，注意相关并发症。

五、哮喘

哮喘会出现活动后就喘，但哮喘的病人有明确的发作性的规律，诊断需要有肺功能测定以及影像学检查来诊断。治疗主要是缓解气道痉挛，以及相关并发症。

六、神经官能症

神经官能症也会出现活动后就喘，因为神经官能症可以表现为各种各样的表现，其诊断主要是排除器质性疾病才能确诊，治疗也主要是心理疏导、心理治疗以及药物治疗。

其他疾病也会出现活动后就喘的症状，比如甲亢，比如严重的恶病质，比如电解质紊乱等等，需要综合考虑，根据证据做出正确判断，并给以对症处理，才能达到意想不到的治疗效果。

活动后就喘，也需要因病试治。

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购买膏贴需要医生的处方吗？

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在日常生活中，我们经常会遇到各种轻微的疼痛和不适，如肌肉酸痛、关节疼痛等。膏贴作为一种方便快捷的外用药物，因其使用简单、直接作用于疼痛部位而受到许多人的青睐。然而，很多人在选择购买膏贴时，常常会有这样的疑问：购买膏贴需要医生的处方吗？

膏贴的分类

首先，我们需要了解膏贴的分类。膏贴按照成分和用途可以大致分为两类：非处方膏贴和处方膏贴。

- 非处方膏贴：这类膏贴主要用于缓解轻微的肌肉疼痛、关节疼痛、扭伤等。它们通常含有辣椒素、薄荷脑、冰片等成分，通过刺激皮肤产生热感或冷感，达到缓解疼痛的目的。非处方膏贴因其成分相对温和，一般认为在正确使用的情况下，风险较低，因此可以在药店直接购买，不需要医生的处方。

- 处方膏贴：这类膏贴含有更强效的药物成分，用于治疗特定的疾病，如慢性关节炎、神经痛等。因其含有较强效的药物，可能会有一定的副作用，需要在医生的指导下使用。因此，购买这类膏贴需要医生的处方。

如何选择膏贴

在选择膏贴时，需要根据自己的实际情况来决定是否需要咨询医生：

1. 了解自己的症状：如果您只是遇到了轻微的肌肉拉伤或扭伤，可以尝试使用非处方膏贴进行自我缓解。但如果疼痛持续不减或伴有其他症状，如肿胀、发热等，应及时就医。

2. 阅读说明书：购买任何膏贴前，务必仔细阅读其说明书，了解其成分、适应症、使用方法及可能的副作用。特别是对某些成分过敏的人，更应注意成分表。

3. 咨询专业人士：当您对是否适合使用某种膏贴有疑问时，咨询药师或医生是一个不错的选择。他们可以根据您的具体情况，提供专业的建议。

总的来说，购买膏贴是否需要医生的处方，取决于膏贴的类型及您的具体需求。非处方膏贴通常可以直接在药店购买，而处方膏贴则需要医生的处方。在使用任何膏贴之前，正确了解自己的症状、仔细阅读说明书并在必要时咨询专业人士，是保障使用安全的关键。
心脏下方隐隐作痛应该如何处理？

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心脏下方隐隐作痛有可能是生理性导致的，通常休息片刻即可缓解，但也有可能是外伤或骨折、胃食管反流病、胃炎等疾病等病理性因素导致的，一般可以采取物理治疗、药物治疗、手术治疗等。

1.生理性因素：长时间保持同一姿势或局部软组织损伤也可能导致心脏下方隐隐作痛，通常避免长时间保持同一姿势，如久坐、长时间站立等，休息片刻即可自行缓解。

2.病理性因素：（1）外伤或骨折：如果您的疼痛是由外伤或骨折引起的，应尽快就医，进行伤口处理和骨折固定。同时，需要按照医生的建议进行康复训练和避免剧烈运动，以促进身体的恢复。（2）胃食管反流病、胃炎等疾病：这些疾病也可能导致心脏下方隐隐作痛，需要积极治疗原发病。例如，胃食管反流病患者需要避免高脂、辛辣等刺激性食物，胃炎患者需要使用抗生素等药物治疗。疼痛症状较轻时也可采取热敷或冷敷缓解疼痛，如果是由于局部软组织损伤引起的，可以尝试一些物理治疗方法，如按摩、针灸、理疗等，如果疼痛症状加重，还可在医生的指导下使用布洛芬、阿司匹林等缓解疼痛。总之，心脏下方隐隐作痛的原因有很多种，在排除生理性原因后，如果症状持续或加重应及时就医，明确病因后，积极治疗。
如何巧用药膳调节失眠，帮助快速入睡？

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作者 | 于晓云
文章首发于 | 中医美容产后调养于大夫微博

莲子百合瘦肉汤

功效：益气调中，补虚损，交心肾，安神，益智，清心。

适应症：神经衰弱，心悸失眠，病后体弱等。

莲子性味甘、涩、平，入心、脾、肾经，能养心、益肾、补脾、涩肠；百合性味甘、微苦、平，入心、肺经，有润肺止咳、养阴清热、清心安神、益气调中等功效．莲子50克，百合50克，猪瘦肉250克切块，加水煲汤。

柏子仁炖猪心

功效：养心，安神，补血，润肠。

适应症：心悸，怔忡，失眠，肠燥便秘等。

柏子仁性味甘、辛、平，可宁心安神，润肠通便，止汗；猪心性味甘、咸、平，入心经，可补血养心。用柏子仁适量，放入猪心内，加水炖熟服食。

合欢花蒸猪肝

功效：清风明目，舒郁理气，养肝安神。

适应症：失眠，胁痛等。

合欢花性味甘、平，入心、肝、脾经，能舒郁，理气，安神，活络：猪肝性味甘、苦、温，入肝经，能补肝，养血，明目。每次用合欢花(干品)10克，加水少许，泡浸4～6小时，猪肝100～150克切片，同放碟中，加食盐少许调味，隔水蒸熟，食猪肝。

甘草小麦红枣汤

功效：和中缓急，养心安神，补脾和胃。

适应症：癔病、神经衰弱、失眠、盗汗等。

甘草性味甘、平，入脾、肺经，能和中缓急，润肺，解毒：小麦性味甘、凉，入心、脾、肾经，能养心、益肾、除热、止渴：红枣性味甘、温，入脾、胃经，能补脾和胃、益气生津、调和营卫。每次用甘草10克，小麦30克，红枣5枚，清水两碗，煎至一碗，去渣饮汤。

本文转载自其他网站，不可二次转载。文章内容仅供参考，具体治疗请咨询医生或相关专业人士。如有问题，可联系jdh-hezuo@jd.com。
胆结石会遗传？它是怎样形成的？

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胆结石是临床中比价常见的一类疾病，尤其在中老年人中，胆结石是由于胆汁中胆固醇、胆红素含量增加，导致聚集形成结石，存在与胆囊中，称为胆结石。胆结石形成的原因有很多，胆结石的患者并不是单一因素导致的，是由于多个因素长期的作用下，是一个慢性的过程。

很多胆结石的患者平常可以没有任何症状，由于结石数量少，体积小，只有在体检的时候可能被发现。临床中常见的比较典型的症状为右上腹或者肋骨下的疼痛、同时伴有恶心、呕吐消化系统的症状，并且在进食油腻的食物后会减重。因为脂肪的消化是在胆汁的作用下进行，结石的存在会导致胆汁的分泌受阻，所以进食油腻的食物后会出现症状。

胆结石形成的原因中有一些不可改变的因素，例如遗传因素，家庭成员中有该患者，会使胆结石的患病率明显增加。年龄是很重要的一个因素，年龄越大，胆结石的患病率越高，临床中胆结石的患者多为中老年人。由于老年人控制胆囊收缩的肌肉功能下降，或者激素的分泌失调，导致胆汁排泄不畅，从而使患病率增加。也有部分患者为年龄较小的儿童，可能是由于先天的溶血性疾病或者黄疸导致胆结石的形成。

据调查，胆结石的女性患者是男性患者的2倍。女性患病率增加的原因与雌激素影响胆汁分泌有关系，女性体内雌激素明显高于男性。因此，患病率增加，另外在可控的影响因素中，饮食习惯占有重要地位，爱吃油腻食物。

高热量食物的人容易的胆结石，由于血液中胆固醇是形成胆结石的主要成分，所以进食过多的胆固醇吸收入血后，增加了血液中胆固醇的浓度，胆固醇主要存在于胆汁中，胆汁中胆固醇的浓度增加所以容易沉积形成结石。由于胆汁的分泌是在食物的刺激下发动的，饮食不规律，不吃早餐，长期禁食，胆汁积聚在胆囊中，浓度增加，容易沉积，进而增加患病率。

患有糖尿病、高血脂、肥胖等代谢性疾病的人，由于物质代谢的紊乱，三大营养成分比例失调，胆固醇的排泄主要通过胆汁，所以代谢性紊乱的病人胆结石的患病率增加。吸烟、饮酒、熬夜，也是患病率增加的原因。妊娠期间的妇女，由于此时雌激素、黄体酮的增加，影响胆囊的收缩及胆汁的分泌，多次妊娠的妇女患病率明显增加。

以上都是胆结石的患病原因，现在人们对健康的越来越重视，以及疾病一级预防的积极倡导下，很多人坚持每年进行体检，提高了疾病的早期检出率，在及时的治疗下，明显提高了疾病预后。

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预防癌症要趁早，拥有正确饮食习惯

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癌症对于人类来说，可以说是一种很可怕的疾病，主要是由于身体内部某一抗体或免疫功能的缺失与损坏，使得体内的正常细胞发生病变形成癌细胞，其还具有细胞分裂的特性，随血液以极快的方式在体内进行再次分裂，所以极易发生转移，且在临床中无法及时的被发现，隐藏性极好，病发表现出一定的症状时基本已经不可控了。在进行化疗时，人们也遭受苦难，所以不仅对身体造成了伤害，对患者的心理也是一种折磨。

一般的癌症都与个人的生活习惯有关，俗话说，病从口入，所以饮食习惯对于癌症的预防也有很重要的作用，下面我们就来了解怎样通过饮食预防癌症。

第一、养成一日三餐的好习惯

对于很多上班族来说，早餐很容易被忽略，其实早餐是必须要吃的，好的早餐可以补充人体在夜晚所消耗的营养，并且可以给予上午人体所需要的能量，一日之计在于春，不仅可以使人们有充足的精力面对早上的工作，还可以提高大脑的记忆功能。午餐同样需要重视，午餐是一天能量的再次补给，不仅可以补充上午营养的流失，还可以为下午的生活与工作提供充足的营养。晚餐不宜吃太多，在保证睡眠的同时，为人体在夜间的睡眠提供充足可吸收的营养。

第二、多吃一些无添加的食物

在日常生活中，腌制酸菜是每家必备的食物，但是腌制食物中的含盐量很高，过量食用后，会导致体内局部渗透压的异常，导致细胞坏死，这时体内为了补充这部分的细胞，就会加速细胞的分裂，进行补偿性的增生，在此过程中细胞癌变的风险就会增加，最终会导致胃癌的出现。所以我们应该选择一些天然的食物，当天只做当天的饭，不吃长时间放置的剩饭剩菜。

第三、做一个素食主义者

肉类当中多多少少会含有寄生虫，在烹饪的过程中，有些寄生虫可能没有被高温杀死，进入人体后就会影响身体各个器官的正常工作，导致人体出现疾病，并且过多的食用肉质，会给消化系统造成负担，长时间甚至会导致癌变。所以在生活中以素食为主，其内含有大量的膳食纤维可以促进体内不良物质尽快代谢出体外，减小肠胃的压力，缩短肠胃排空的时间，降低癌症发生的风险。
麻甘颗粒治什么咳嗽?

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麻甘颗粒这里指小儿麻甘颗粒。小儿麻甘颗粒可治疗风热感冒引起的咳嗽。

小儿麻甘颗粒是一味中成药，具有利咽祛痰、止咳平喘等作用，可用于治疗小儿风热侵犯肺部所引起的肺炎喘咳、咳嗽痰稠、呼吸急促等多种症状。

小儿麻甘颗粒用药后可出现腹泻、恶心、呕吐、皮肤发红、皮肤发炎等不良反应，长期用药可产生药瘾，对成分过敏者禁用。用药期间避免吃生冷、辛辣刺激、油炸、腌制等类型的食物，阴虚肺热、肺脾气虚者慎用。

如咳嗽者需要使用小儿麻甘颗粒等药物，需要专业医生指导。
接种流感疫苗的最佳时间，快来了解一下

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最近流感疫苗上市了，流感疫苗是预防流感的最佳方式。

但不是说打了流感疫苗就不会得流感了，接种流感疫苗，能将因为该病就诊的几率降低40-60%。对儿童而言，还有更大的好处是能显著降低因流感导致的死亡率。

根据美国儿科学会（AAP）与美国感染病学会（IDSA）在2017年9月发布的儿童流感预防与控制建议显示：流感的危害主要体现为其可怕的传染性和极高的变异能力，儿童及婴幼儿免疫系统发育尚不完善，很容易被流感病毒盯上，应及早预防。

什么是流感疫苗？

流感疫苗大多数是灭活疫苗，不是减毒疫苗，有效成分是流感病毒的抗原成分：血凝素。

在打完流感疫苗后，就会对人体内的少量流感病毒抗原成分产生一定的免疫抗体。而当人体遭到流感病毒的大规模侵袭后，流感疫苗刺激人体所产生的大量抗体就会迅速启动，从而发挥抗流感病毒的作用，达到杀灭病毒、抵抗流感的目的。

什么时候接种？

流感高发期通常在1-2月（南方4-6月，中纬度地区是1-2月和6-8月）。从高发季前接种疫苗，可以赶在高发期前形成保护。

什么人应该要接种？

6个月以上的所有人都应该接种流感疫苗。

尤其是属于免疫相对弱的人群，建议优先接种：5岁以下儿童（尤其是2岁以下）；患有某些特定疾病的人，包括心脏病、哮喘、糖尿病和慢性肺病等；孕妇；60岁以上老人。

有的人会问，接种了流感疫苗，是不是就不会感冒了？

事实上，感冒和流感不是一种疾病，流感是流感病毒引起的，而感冒是由感冒的病毒引起的。它们的症状虽然有些相似，但是，他们是不同的两种病！

普通感冒通常就持续3-7天，常见的症状是喉咙痛、咳嗽、打喷嚏和流鼻涕，可能会有发烧，但体温通常不会很高。自愈，不容易出现并发症。

流感通常症状更严重，会出现发烧、喉咙痛、咳嗽、头痛、肌肉疼痛，流鼻涕，全身乏力等症状，也更容易出现严重的并发症，甚至导致死亡，特别是小朋友、老人、孕妇、有慢性病的人。

哺乳期可以接种吗？

可以的。

一般来说我们都会推荐6个月以上的孩子包括成人都可以打流感疫苗，包括孕妇。

中国疾病预防控制中心曾今不建议孕妇接种。但在最新的流感疫苗应用技术指南中，中国的专家综述了国际上其他权威机构的意见和最新的研究证据，如今也建议孕期任何阶段都可以接种，并应尽早安排孕妇接种。

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扁桃体炎多久能好 4个护理加速扁桃体康复

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扁桃体炎通常由细菌、病毒感染引起，一般好发于春秋季节，很多青少年都受过扁桃体炎的痛苦。扁桃体炎为不仅是常见病，更是多发病，一旦发病除了常规的治疗外，对扁桃体炎的护理也非常关键，很多患者都不太清楚扁桃体炎的日常护理，下面我们来简单介绍一下。

急性扁桃体炎发作非常迅速，伴有发热，扁桃体充血，咽喉疼痛，吞咽困难等症状，一般及时就医，病情很快就能得到控制。通常从扁桃体炎发作到彻底治愈，一般需要10-15天时间。

扁桃体炎好转过程中，要做好日常护理，才能加速扁桃体炎的康复。

1、保证每日的饮水量。急性扁桃体炎是因为细菌感染造成，在进行抗生素治疗后，要多饮水，每天保证足量饮水，有利于身体排毒。

2、加强身体锻炼。扁桃体炎虽然是细菌感染，但与自身抵抗力低下有很大关系。急性扁桃体炎患者，一定要加强身体锻炼，提高免疫力，才能帮助身体更快康复。

3、密切注意身体变化。很多扁桃体炎患者在进行了一段时间治疗后，会出现一些身体不适的改变，有的会伴有发热，呼吸急促等症状，一定要及时就医，防止病情反复。

4、积极预防并发症。扁桃体炎最大的危害，不是咽喉疼痛，吞咽困难等症状，而是容易引起心肌炎，肾炎、关节炎等疾病，所以患者要在医生的指导下，预防这类并发症的发生。

扁桃体炎虽然不是大病，但是对于患者来说非常痛苦，所以一定要做好日常护理，多喝水，不要吃刺激性食物，注意防止感冒及其他疾病的发生，在治疗过程中有任何问题，要及时听取医生的建议，不要擅做主张。扁桃体炎恢复期，要积极锻炼身体，这样才能更快康复健康。