78-Year-Old Woman With Fever, Weight Loss, and Rash
2003; Elsevier BV; Volume: 78; Issue: 5 Linguagem: Inglês
10.4065/78.5.635
ISSN1942-5546
AutoresTimothy B. Niewold, V. Santhi Swaroop,
Tópico(s)Autoimmune and Inflammatory Disorders Research
ResumoA 78-year-old woman with a lengthy history of seropositive rheumatoid arthritis (RA) presented to the emergency department with a 3-day history of nonproductive cough and low-grade fever, with self-measurement of temperature up to 38.5°C. The patient had chronic diarrhea over the past 6 months, the cause of which on extensive testing remained indeterminate with negative microbial cultures, normal findings on stool fat studies, and normal small bowel and large bowel biopsy specimens. She reported a 9-kg weight loss over the preceding 3 months, which she attributed to decreased appetite and persistent diarrhea. Also over the past 3 months, the patient noted a progressive, erythematous, macular rash (Figure 1) located bilaterally on her chest, back, and upper arms. The rash was not painful or pruritic, was nonpalpable, and blanched slightly with pressure. The patient had no rigors, chest pain, pleurisy, shortness of breath, nausea, vomiting, or urinary symptoms. She denied any recent joint pain or swelling and had not had active synovitis for years. The patient stopped taking methotrexate 2 years previously and took no disease-modifying antirheumatic agents since. She had received intramuscular gold therapy in the past but had never taken azathioprine or cyclophosphamide. On physical examination, the patient was frail and markedly kyphotic with numerous deformities due to longstanding RA, including bilateral boutonnière deformities of the fingers, ulnar deviation and subluxation of her digits, and evidence of tendon reconstruction surgeries in her hands and feet. Auscultation of the lungs revealed normal breath sounds with Velcro-like crackles at the bases bilaterally and no egophony. There was no dullness on percussion of the chest. Heart sounds were distant, with a regular rate and no murmurs. There was no organomegaly on abdominal examination, and neurologic examination findings were normal. 1.Considering the history and physical examination, which one of the following is the most likely cause of our patient's lung findings? a.Pleural effusionb.Methotrexate-induced interstitial pneumonitisc.Fungal pneumoniad.Interstitial fibrosise.Bacterial lobar pneumonia Pleural effusion, relatively common in patients with RA, has a prevalence of 5%; up to 50% of patients with RA have small pleural effusions at autopsy.1Bone RC Dantzker DR George RB Matthay RA Reynolds HY Pulmonary and Critical Care Medicine: Update 5. 6th ed. Mosby-Year Book, St Louis, Mo1998Google Scholar Clinical findings on examination of our patient's lungs are inconsistent with effusion. Methotrexate-induced interstitial pneumonitis usually presents as acute to subacute respiratory decompensation with nonproductive cough and fever. Although methotrexate-induced interstitial pneumonitis may occur weeks after methotrexate is discontinued, our patient had taken no methotrexate for years, and she had no shortness of breath, making this diagnosis unlikely. Our patient had taken no immunosuppressive agents in recent years and had no specific risk factors for fungal pneumonia; hence, this diagnosis is unlikely. Interstitial fibrosis is the most likely cause of her lung findings because of the classic dry or Velcro-like crackles. The prevalence of interstitial lung disease in patients with RA varies, depending on the investigation performed: 2% of cases are found on chest x-ray, and up to 40% of patients with RA have abnormalities on pulmonary function testing.1Bone RC Dantzker DR George RB Matthay RA Reynolds HY Pulmonary and Critical Care Medicine: Update 5. 6th ed. Mosby-Year Book, St Louis, Mo1998Google Scholar Bacterial lobar pneumonia is more common in patients with RA than in the general population2Mikuls TR Saag KG Comorbidity in rheumatoid arthritis.Rheum Dis Clin North Am. 2001; 27: 283-303Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar; however, the lack of consolidation on our patient's physical examination and her history of nonproductive cough make this diagnosis less likely. The increased prevalence of bacterial lobar pneumonia in patients with RA is likely due to the impaired immune functioning caused by the disease itself and by the immunosuppressive agents used to treat RA. Chest x-ray films showed interstitial markings in the lower lobes bilaterally, which were unchanged from examinations performed 1 year previously, suggesting interstitial fibrosis as suspected clinically. The patient was admitted to the hospital for investigation of her symptoms of cough, fever, rash, and weight loss. She had become progressively weak for 2 weeks and was unable to care for herself at time of admission. Laboratory tests done on admission revealed the following (reference ranges shown parenthetically): hemoglobin, 9.1 g/dL (12.0-15.5 g/dL); white blood cell count, 4.5 × 109/L (3.5-10.5 × 109/L) with 98% neutrophils; creatinine, 0.4 mg/dL (0.6-0.9 mg/dL); erythrocyte sedimentation rate, 20 mm/h (0-29 mm/h); ferritin, 11,731 g/L (20-200 μg/L); glucose, 127 mg/dL; and albumin, 1.9 g/dL (3.5-5.0 g/dL). The reticulocyte count was lower than would be expected for the patient's degree of anemia, and her lactate dehydrogenase level was elevated to 1165 U/L (112-257 U/L). A peripheral smear showed a normochromic, normocytic anemia with mild anisopoikilocytosis but no helmet cells or schistocytes. Prothrombin time and activated partial thromboplastin time were both normal. Blood cultures were negative after 48 hours. 2.Which one of the following would be most helpful in establishing a diagnosis for our patient? a.Rheumatoid factor titerb.Skin biopsyc.Liver biopsy with iron staind.Echocardiographye.Bone marrow aspirate and biopsy Our patient has classic joint deformities associated with RA and has been seropositive in the past. No information about her rheumatic disease activity or the reason for her recent illness would be obtained from a rheumatoid factor titer. High-titer rheumatoid factor may accompany rheumatoid vasculitis, which is a legitimate concern for any patient with a history of RA who presents with a rash and systemic symptoms. However, this association is not sensitive or specific; therefore, the rheumatoid factor would not be helpful in the diagnosis of rheumatoid vasculitis.3Giersson AJ Sturfelt G Truedsson L Clinical and serological features of severe vasculitis in rheumatoid arthritis: prognostic implications.Ann Rheum Dis. 1987; 46: 727-733Crossref PubMed Scopus (72) Google Scholar Skin biopsy would be useful because the patient has a rash of uncertain etiology, and the differential diagnosis is wide. Vasculitis, atypical infections, and infiltrative processes should all be considered, and each can have characteristic findings on skin biopsy. Hemochromatosis possibly could explain the elevated serum ferritin level but not the fever, rash, and weight loss, and there was no evidence of diabetes or heart failure. Ferritin levels can be nonspecifically elevated in many inflammatory conditions; therefore, liver biopsy with iron stain would be inappropriate. Echocardiography may be useful because subacute bacterial endocarditis or atrial myxoma can present with generalized malaise, fevers, skin findings, and weight loss. However, our patient had no heart murmurs, negative blood cultures, and no classic skin findings of subacute bacterial endocarditis or arterial embolization; therefore, echocardiography would not be the best study. Bone marrow aspirate and biopsy may provide information regarding the patient's normocytic, normo-chromic anemia. Our patient has a relatively low reticulocyte count and elevated lactate dehydrogenase and ferritin levels; therefore, an infiltrating bone marrow process such as lymphoma, myeloma, leukemia, or metastatic carcinoma could be considered. Extremely high ferritin levels, as seen in our patient, can be found in hemophagocytic syndrome, a rare disease in which phagocytic cells aggressively ingest the patient's own blood cells. Hemophagocytic syndrome is sometimes associated with lymphoma. Bone marrow biopsy in hemophagocytic syndrome classically shows histiocytes phagocytosing red and white blood cells and platelets. Anemia of chronic disease could explain a normocytic anemia with a high ferritin level and low reticulocyte count and is likely, given our patient's lengthy history of RA. Findings compatible with anemia of chronic disease on bone marrow examination would not help to establish a diagnosis for our patient, and skin biopsy would probably provide more information. Our patient continued to be febrile over the next few days, and all cultures and investigations for infection were negative. Skin biopsy from the area of the rash showed extensive deep dermal and perivascular infiltration of monotonous-appearing cells expressing CD3 and granzyme B. 3.Which one of the following is the most likely diagnosis for our patient, given the biopsy findings? a.Langerhans cell histiocytosisb.Multicentric reticulohistiocytosis (MR)c.Cutaneous T-cell lymphoma (CTCL)d.Metastatic adenocarcinomae.Hypersensitivity dermatitis Langerhans cell histiocytosis is a disease of abnormal proliferation of mononuclear phagocytic cells involving many organ systems, including bone, lung, central nervous system, and skin. Our patient's rash could be compatible with Langerhans cell histiocytosis, but biopsy findings are not. Langerhans cell histiocytosis produces granulomatous lesions composed of histiocytes, mature eosinophils, and lymphocytes. Multicentric reticulohistiocytosis is also an infiltrating mononuclear phagocytic cell disease. Destructive arthritis is a common feature, and skin involvement typically is thickened nodules or papules. The arthritis and nodules seen in MR may sometimes mimic RA; however, involvement of the distal interphalangeal joints is common in MR and is extremely rare in RA. Biopsy specimens of MR show large foamy macrophages and giant cells, which were not seen in our patient. Our patient's biopsy specimen showed monotonous infiltration of cells positive for CD3, indicating T-cell origin, and granzyme B, one of the components of cytotoxic granules present in cytotoxic T cells. The most likely diagnosis based on the biopsy is CTCL. Metastatic adenocarcinoma is not the most likely diagnosis because our patient's lesions are of T-cell origin. Hypersensitivity eruptions can appear extremely similar to macular or plaque-type cutaneous lymphoma. Our patient's lack of new exposures, progression of disease, and systemic manifestations make hypersensitivity less likely, and the biopsy specimen is not suggestive of this diagnosis. For cases in which further clarification is necessary, T-cell gene rearrangement studies can be performed, which show a monoclonal population in CTCL. Clinically, our patient's condition continued to deteriorate while she was in the hospital. She had a history of coronary disease and had a non-ST-elevation myocardial infarction, which presented as an episode of shortness of breath. She was extremely frail and wanted no invasive interventions. Medical therapy for coronary artery disease was augmented, and further studies were conducted to establish the extent of her CTCL. 4.Which one of the following should be done next to stage the disease in our patient? a.Peripheral blood flow cytometry and biopsy of any enlarged lymph nodesb.Epstein-Barr virus testing of abnormal cellsc.Colonoscopy with biopsyd.Measurement of depth of invasion of skin lesionse.Chromosomal studies of abnormal cells Traditional methods used to stage CTCL are based on the TNM method developed in 1979 by Bunn and Lamberg.4Bunn Jr, PA Lamberg SI Report of the Committee on Staging and Classification of Cutaneous T-Cell Lymphomas.Cancer Treat Rep. 1979; 63: 725-728PubMed Google Scholar The amount of skin involved, percentage of abnormal circulating T cells, and presence of involved lymph nodes are important for staging and prognosis; hence, peripheral blood flow cytometry and biopsy of any enlarged lymph nodes would be the next step. Epstein-Barr virus is found frequently in non-Hodgkin lymphomas arising in immunosuppressed patients and often is related to a more aggressive phenotype and a poorer prognosis. Our patient had received no immunosuppressive therapy recently, and data about the presence of the Epstein-Barr virus in CTCL are limited. Visceral organ involvement is a poor prognostic sign in CTCL, but our patient recently had a colonoscopy with biopsies that showed no neoplastic T cells. A second colonoscopy with biopsies would likely be of low yield. Although depth of invasion of skin lesions is an important prognostic factor in melanoma, it is not a useful variable in staging CTCL. Chromosomal abnormalities are incorporated into some of the newer staging systems for CTCL; however, determination of the nodal status and other variables in the TNM staging system is more important and should be done first. Our patient had no detectable neoplastic cells in the peripheral blood, no palpable lymph nodes that could be cbiopsied, no adenopathy or masses on computed tomographic scans of the chest, abdomen, and pelvis, and less than 10% involvement of her skin surface area. According to the TNM criteria, our patient had T1N0M0 disease. 5.Which one of the following therapies would be most appropriate for our patient? a.Excision of her skin lesionsb.Cyclophosphamide, hydroxydaunomycin (doxorubicin), Oncovin (vincristine), and prednisone (CHOP)c.Rituximabd.Bone marrow transplantatione.Topical nitrogen mustard and phototherapy with ultraviolet (UV) light There is no role for excision of our patient's lesions because excision is not curative and our patient's lesions were extensive. Although commonly used for non-Hodgkin lymphoma, CHOP therapy has limited efficacy in CTCL and high toxicity; it should be considered only for patients with systemic involvement for whom multiple treatment regimens have failed. Rituximab is a monoclonal antibody to CD20, a B-cell marker, and is used in therapy for B-cell lymphomas. CD20 is not expressed on T cells; hence, rituximab would not help our patient. Bone marrow transplantation is done extremely rarely in CTCL and is usually reserved for the most advanced cases. Autologous bone marrow transplantation has not resulted in improved outcomes in CTCL. Although allogeneic transplantation may offer the chance for a cure, the risk of graft-vs-host disease is considerable, and our patient likely could not withstand the toxicity. For limited CTCL, as found in our patient, common first-line therapies include topical nitrogen mustard and phototherapy with UV B, or PUVA, which is a combination of topical psoralen (a chemotherapeutic agent that enhances the efficacy of UV light) and UV A. The patient declined active therapy for her CTCL because her general state of health was precarious, and she decided to pursue hospice care at home. The patient died 2 weeks after discharge from the hospital. In many studies, hematologic malignancies have been reported in increased frequency in patients with RA. The largest study describing this association is by Isomaki et al in 1978,5Isomaki HA Hakulinen T Joutsenlahti U Excess risk of lymphomas, leukemia and myeloma in patients with rheumatoid arthritis.J Chronic Dis. 1978; 31: 691-696Abstract Full Text PDF PubMed Scopus (397) Google Scholar in which data from more than 45,000 patients with RA were compared with Finnish national cancer registry data and revealed a 2-fold increased risk of hematologic malignancy. This association is controversial and has not been shown in all studies. In a retrospective study of the Mayo Clinic RA patient cohort from 1950 to 1975, the risk of developing multiple myeloma was increased compared with the general population, but there was no significant difference in the risk for other hematologic malignancies.6Katusic S Beard CM Kurland LT Weis JW Bergstralh E Occurrence of malignant neoplasms in the Rochester, Minnesota, rheumatoid arthritis cohort.Am J Med. 1985; 78: 50-55Abstract Full Text PDF PubMed Scopus (96) Google Scholar The strongest link between hematologic malignancy and RA was shown in the subset of patients with RA who have Felty syndrome (splenomegaly, neutropenia, and recurrent infections). A group of 906 patients with RA and Felty syndrome was shown to have a 12-fold higher risk of non- Hodgkin lymphoma than the general population.7Gridley G Klippel JH Hoover RN Fraumeni Jr, JF Incidence of cancer among men with the Felty syndrome.Ann Intern Med. 1994; 120: 35-39Crossref PubMed Scopus (86) Google Scholar Numerous hypotheses have been proposed to explain the link between RA and hematologic malignancy, including decreased immune surveillance due to long-term immuno- suppressive therapies, increased mutation rates due to cytotoxic therapies, or possibly increased activation and proliferation of immune cells due to autoimmunity. There are at least 4 prior reports of CTCL developing in patients with RA.8Chakravarty K Goyal M Scott DG McCann BG Malignant ‘angioendotheliomatosis’—(intravascular lymphomatosis) an unusual cutaneous lymphoma in rheumatoid arthritis.Br J Rheumatol. 1993; 32: 932-934Crossref PubMed Scopus (14) Google Scholar, 9Levy Y George J Abraham A Afek A Livneh A Shoenfeld Y Subcutaneous T-cell lymphoma in a patient with rheumatoid arthritis not treated with cytotoxic agents.Clin Rheumatol. 1997; 16: 606-608Crossref PubMed Scopus (13) Google Scholar, 10Fam AG Perez-Ordonez B Imrie K Primary cutaneous B cell lymphoma during methotrexate therapy for rheumatoid arthritis.J Rheumatol. 2000; 27: 1546-1549PubMed Google Scholar, 11Tournadre A D'Incan M Dubost J-J et al.Cutaneous lymphoma associated with Epstein-Barr virus infection in 2 patients treated with methotrexate.Mayo Clin Proc. 2001; 76: 845-848Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar In 2 of these reports,10Fam AG Perez-Ordonez B Imrie K Primary cutaneous B cell lymphoma during methotrexate therapy for rheumatoid arthritis.J Rheumatol. 2000; 27: 1546-1549PubMed Google Scholar, 11Tournadre A D'Incan M Dubost J-J et al.Cutaneous lymphoma associated with Epstein-Barr virus infection in 2 patients treated with methotrexate.Mayo Clin Proc. 2001; 76: 845-848Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar patients were being treated for RA with methotrexate, and withdrawal of the methotrexate resulted in regression of the CTCL. The phenomenon of reversible lymphoma associated with methotrexate use has been described more frequently in patients with RA who have noncutaneous non-Hodgkin lymphoma, and a review of this literature was published recently.12Georgescu L Paget SA Lymphoma in patients with rheumatoid arthritis: what is the evidence of a link with methotrexate?.Drug Saf. 1999; 20: 475-487Crossref PubMed Scopus (66) Google Scholar The lymphomas found in patients with RA who receive methotrexate therapy are most frequently of the large B-cell type, the same histologic type seen with high frequency in other immunosuppressed patients such as those with acquired immunodeficiency syndrome and those who undergo transplantation.12Georgescu L Paget SA Lymphoma in patients with rheumatoid arthritis: what is the evidence of a link with methotrexate?.Drug Saf. 1999; 20: 475-487Crossref PubMed Scopus (66) Google Scholar Cutaneous T-cell lymphoma is a rare disease with a variable clinical course. Many elderly patients with limited CTCL die of causes unrelated to their CTCL because 10- year survival rates greater than 80% are commonly reported.13Kashani-Sabet M McMillan A Zackheim HS A modified staging classification for cutaneous T-cell lymphoma [published correction appears in J Am Acad Dermatol. 2002;46:250].J Am Acad Dermatol. 2001; 45: 700-706Abstract Full Text PDF PubMed Scopus (47) Google Scholar Once systemic involvement is discovered, however, 10-year survival rates are close to 20%.13Kashani-Sabet M McMillan A Zackheim HS A modified staging classification for cutaneous T-cell lymphoma [published correction appears in J Am Acad Dermatol. 2002;46:250].J Am Acad Dermatol. 2001; 45: 700-706Abstract Full Text PDF PubMed Scopus (47) Google Scholar In one prior report, CTCL involved a patient's gastrointestinal tract and caused watery diarrhea14Cohen MI Widerlite LW Schechter GP et al.Gasterointestinal involvement in the Sezary syndrome.Gasteroenterology. 1977; 73: 145-149PubMed Google Scholar; in this patient, rectal, colonic, and small bowel biopsies revealed infiltrating malignant T cells. Our patient's normal small bowel and large bowel biopsy specimens argue against CTCL infiltration of the bowel as a cause of her chronic diarrhea. Correct answers: 1. d, 2. b, 3. c, 4. a, 5. e CorrectionMayo Clinic ProceedingsVol. 78Issue 8PreviewIncorrect term: In the Residents’ Clinic article by Niewold and Swaroop entitled “78-Year-Old Woman With Fever, Weight Loss, and Rash,” published in the May 2003 issue of Mayo Clinic Proceedings (Mayo Clin Proc. 2003;78:635-638), in the first 2 sentences of the first paragraph in the Discussion section on page 638, the abbreviation “CTCL” was used incorrectly for the phrase “cutaneous lymphoma.” The 2 sentences should read: “There are at least 4 prior reports of cutaneous lymphoma developing in patients with RA. Full-Text PDF
Referência(s)