Abstract
Aggressive seropositive rheumatoid arthritis (RA) typically manifests with marginal joint erosions and periarticular osteopenia but rarely presents with diffuse osteolytic lesions mimicking malignancy. A 65-year-old woman presented with subacute back pain and incidentally discovered hypercalcemia (calcium 12.7 mg/dL). Imaging revealed multifocal lytic lesions of the axial and appendicular skeleton highly suggestive of multiple myeloma or metastatic disease, along with supraclavicular lymphadenopathy. Extensive evaluation including bone marrow biopsy demonstrated polyclonal plasmacytosis without evidence of hematologic malignancy. Lymph node excision revealed reactive follicular hyperplasia. Subsequent rheumatologic assessment identified symmetric inflammatory polyarthritis, rheumatoid nodules, rheumatoid factor 191 IU/mL, and anti-cyclic citrullinated peptide (anti-CCP) antibodies 2630 U/mL, establishing the diagnosis of aggressive seropositive RA. Bursectomy of a right elbow mass confirmed necrobiotic granulomatous inflammation consistent with a rheumatoid nodule. Treatment with methotrexate, leflunomide, and rituximab led to resolution of hypercalcemia, substantial improvement in joint symptoms, and radiographic stabilization of lytic lesions. This case highlights how RANKL-mediated osteoclast activation and anti-CCP antibody-driven bone resorption can, in rare instances, produce malignancy-mimicking diffuse osteolysis and hypercalcemia, and underscores the importance of considering RA in the differential diagnosis of diffuse lytic bone lesions. The diagnosis was supported by fulfillment of 2010 ACR/EULAR classification criteria, histologic confirmation of rheumatoid nodules, and dramatic response to disease-modifying antirheumatic therapy.
Introduction
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disorder characterized by symmetric inflammatory polyarthritis leading to progressive joint destruction.1,2 The typical skeletal manifestations include marginal bone erosions at the pannus-bone interface and periarticular osteopenia.3,4 Diffuse osteolytic lesions involving the axial skeleton are exceedingly rare and, when present, raise immediate concern for malignancy, particularly multiple myeloma or metastatic disease.5,6
Several case reports describe focal vertebral or long-bone lytic lesions in RA; however, cases with diffuse lytic involvement and true hypercalcemia prompting comprehensive myeloma workup remain infrequently reported. The pathophysiologic mechanisms underlying RA bone destruction—receptor activator of nuclear factor kappa-B ligand (RANKL)-mediated osteoclastogenesis, cytokine-driven inflammation, and anti-CCP antibody-induced osteoclast activation—typically produce localized erosions at joint margins.3,4,7 Extension of this inflammatory destruction to create diffuse osteolytic lesions throughout the skeleton represents an atypical disease phenotype that poses significant diagnostic challenges.
We present a clinicopathologic case of aggressive seropositive RA with diffuse osteolytic bone lesions, hypercalcemia, and lymphadenopathy that closely mimicked hematologic malignancy. This case emphasizes the necessity of systematic exclusion of alternative diagnoses and illustrates how integration of imaging, serologic, and pathologic findings with therapeutic response can resolve complex diagnostic dilemmas.
Case Presentation
Clinical History and Examination
A 65-year-old woman with a medical history of gout (managed with allopurinol 300 mg daily) presented to her primary care physician for routine follow-up. She reported a 3-month history of subacute, non-radiating mid-thoracic back pain without antecedent trauma. She denied fever, night sweats, or unintentional weight loss. Routine laboratory evaluation revealed hypercalcemia with total calcium 12.7 mg/dL (reference range 8.5-10.5 mg/dL), confirmed on repeat testing with ionized calcium 6.46 mg/dL (reference range 4.5-5.6 mg/dL). This unexpected finding prompted urgent evaluation for possible malignancy.
Physical examination revealed stable vital signs with the patient appearing well. Musculoskeletal examination demonstrated mild tenderness over the thoracic spine, with prominent swelling and synovitis noted over the right elbow and left wrist (Figure 1). Firm subcutaneous nodules consistent with rheumatoid nodules were visible at both elbows. A firm, non-tender, mobile left supraclavicular lymph node measuring approximately 1.5 cm was palpated. No hepatosplenomegaly was appreciated. Clinical photographs demonstrating prominent soft tissue swelling at bilateral elbows and visible subcutaneous rheumatoid nodules, characteristic of extra-articular manifestations of aggressive seropositive RA
Laboratory Investigations
Key Laboratory Data at Presentation and Follow-Up
Anti-CCP, anti-cyclic citrullinated peptide; ANA, antinuclear antibody; BUN, blood urea nitrogen; IgG, immunoglobulin G; PTH, parathyroid hormone.
Serum protein electrophoresis demonstrated elevated immunoglobulin G at 1950 mg/dL but no monoclonal spike. Serum free light chains showed kappa 22.6 mg/L, lambda 7.86 mg/L, with kappa/lambda ratio 2.88 (reference 0.26-1.65). The laboratory report noted that elevated free light chain ratios between 1.66 and 3.00 may occur due to polyclonal hypergammaglobulinemia or impaired renal clearance. Twenty-four-hour urine protein was 92 mg/24 hours with no Bence Jones protein detected. Creatinine was 1.2 mg/dL (reference 0.6-1.2 mg/dL), indicating preserved renal function.
Comprehensive fungal serologies including Histoplasma, Blastomyces, Cryptococcus, and Coccidioides were negative. Lysozyme was mildly elevated at 13.4 mcg/mL (reference 4.0-13.0 mcg/mL), prompting consideration of sarcoidosis.
Imaging Studies
Whole-body computed tomography (CT) revealed multiple concerning findings: diffuse osteolytic lesions involving the scapula, ribs, and thoracic vertebral bodies (Figure 2). Additionally noted were small pulmonary micronodules, bilateral adrenal adenomas, and retropectoral lymphadenopathy. The cervicothoracic CT demonstrated erosion of the inferior aspect of the C6 spinous process. The radiographic pattern was highly suggestive of skeletal involvement from multiple myeloma or metastatic malignancy. Sagittal CT confirming erosion of C6 spinous process (arrow) and diffuse lytic lesions
Magnetic resonance imaging (MRI) of the spine demonstrated a nonspecific lytic lesion at the C6 vertebra, characterized by focal T1 hypointensity and short tau inversion recovery (STIR) hyperintensity (Figure 3). Post-contrast images revealed enhancement at the tip of the C6 spinous process and adjacent soft tissues (Figure 4), initially concerning for osteomyelitis or neoplastic involvement. (a) Sagittal T1-weighted MRI of the cervical spine demonstrating abnormal hypointense marrow signal and cortical erosion at the C6 spinous process (arrows). (b) Sagittal STIR MRI showing corresponding hyperintense marrow signal and surrounding soft-tissue abnormality at C6 (arrows). (a) Sagittal post‑contrast T1‑weighted MRI demonstrating enhancement of the C6 spinous process and adjacent paraspinal soft tissues (arrows). (b) Axial post‑contrast T1‑weighted MRI showing corresponding enhancing soft tissue surrounding the C6 spinous process (arrows).
A percutaneous biopsy of a representative lytic lesion was discussed with hematology-oncology and interventional radiology but, for the reasons outlined in the discussion, was ultimately not pursued.
Pathologic Findings
Bone marrow biopsy and aspiration from the left iliac crest demonstrated normocellular bone marrow with trilineage hematopoiesis and polyclonal plasmacytosis (Figure 5). CD138 immunohistochemistry and in situ hybridization for kappa and lambda light chains confirmed polyclonal plasma cells without clonal expansion. Flow cytometry revealed no diagnostic evidence of bone marrow involvement by a B-cell lymphoproliferative disorder, non-Hodgkin lymphoma, or plasma cell dyscrasia. Fluorescence in situ hybridization (FISH) for plasma cell disorders showed no abnormalities in 1q duplication, TP53 deletion, or IgH rearrangement. Reticulin staining showed only mild fibrosis, and no amyloid was identified. (A) Bone marrow core biopsy showing normocellular marrow with trilineage hematopoiesis and increased plasma cells; (B) bone marrow aspirate smear with numerous mature plasma cells; (C) CD138 immunostain highlighting scattered plasma cells; (D) kappa in situ hybridization and (E) lambda in situ hybridization demonstrating a polyclonal plasma cell population, excluding myeloma.
Excisional biopsy of the left supraclavicular lymph node revealed abundant small lymphocytes and reactive cells with mixed lymphocytosis (predominantly T cells over B cells) and polyclonal plasmacytosis (Figure 6). Histologic examination demonstrated reactive follicular hyperplasia consistent with a reactive or inflammatory process. No evidence of lymphoproliferative disorder or malignant transformation was identified. (A,B) Lymph node fine‑needle aspiration smears showing mixed lymphocytes and reactive cells, consistent with reactive lymphadenopathy.
Rheumatologic Evaluation and Diagnosis
Following exclusion of hematologic malignancy and granulomatous infection, the patient was referred to rheumatology. Upon detailed questioning, she reported persistent morning stiffness lasting 1-2 hours with progressive pain and swelling in the small joints of both hands over several months. Physical examination revealed symmetric synovitis involving the metacarpophalangeal (MCP), proximal interphalangeal (PIP), and distal interphalangeal (DIP) joints bilaterally. Prominent subcutaneous nodules were both palpated and visually apparent over both wrists and elbows, consistent with rheumatoid nodulosis (Figure 1).
Rheumatologic laboratory evaluation revealed markedly elevated rheumatoid factor at 191 IU/mL (reference <15 IU/mL) and anti-CCP antibodies at 2630 U/mL (reference <2.9 U/mL)—more than 900 times the upper limit of normal. Antinuclear antibody (ANA) was negative. Uric acid was 4.8 mg/dL (reference 2.4-5.7 mg/dL), within normal limits despite her history of gout.
The patient underwent bursectomy of a right elbow mass. Histopathologic examination revealed necrobiotic granulomatous inflammation consistent with a rheumatoid nodule. Periodic acid-Schiff diastase (PASD), Gomori methenamine silver (GMS), and acid-fast bacillus (AFB) special stains were negative for microorganisms, confirming a non-infectious, RA-related lesion.
The diagnosis of aggressive seropositive RA was established based on fulfillment of the 2010 ACR/EULAR classification criteria 8 : symmetric polyarticular involvement of small joints (≥10 joints), symptom duration >6 weeks, markedly elevated rheumatoid factor and anti-CCP antibodies, elevated acute-phase reactants, histologically confirmed rheumatoid nodules, and systematic exclusion of alternative diagnoses.
Treatment and Clinical Course
The patient was initiated on methotrexate 10 mg weekly with folic acid 1 mg daily and leflunomide 10 mg daily. Tumor necrosis factor (TNF) inhibitors were deliberately avoided during the prolonged malignancy workup. Given the severity of her disease—evidenced by exceptionally high anti-CCP antibody levels, diffuse skeletal involvement, and extra-articular manifestations—she was escalated to rituximab 1000 mg intravenously on days 1 and 15, repeated every 6 months.
Following rituximab therapy, the patient experienced significant clinical improvement with marked reduction in joint pain and swelling, complete resolution of morning stiffness, and normalization of serum calcium to 10.0 mg/dL. Methotrexate was increased to 15 mg weekly to optimize disease control given mild residual inflammation at the 3-month follow-up.
Repeat MRI of the spine 10 months after initiating RA treatment demonstrated complete resolution of the erosive process at C6, with normalization of bone marrow signal and resolution of soft tissue enhancement (Figure 7). Other lytic lesions remained stable without features suggestive of malignancy or progression. Serial imaging studies confirmed radiographic stabilization on immunosuppressive therapy, providing retrospective confirmation of the diagnosis. Follow-up STIR MRI 10 months post-treatment showing resolution of C6 abnormality (arrow)
Discussion
This case illustrates an infrequently reported but clinically important presentation of aggressive seropositive RA manifesting with diffuse osteolytic bone lesions, hypercalcemia, and lymphadenopathy that closely mimicked hematologic malignancy. Although marginal erosions and periarticular osteopenia are characteristic skeletal manifestations of RA, diffuse lytic lesions involving the axial and appendicular skeleton represent an atypical disease phenotype requiring systematic exclusion of malignancy and infection.5,6
Pathophysiology of Bone Destruction in RA
Bone destruction in RA is mediated by inflammatory cytokines and osteoclast activation at the pannus-bone interface.3,4 Synovial fibroblasts produce RANKL, which binds to RANK receptors on osteoclast precursors, stimulating differentiation and activation.9,10 Pro-inflammatory cytokines including TNF-α, interleukin-1β (IL-1β), and interleukin-6 (IL-6) amplify this process while simultaneously inhibiting osteoblast function.3,4 Activated osteoclasts create an acidic microenvironment and secrete cathepsin K to degrade the mineralized bone matrix. 9
Anti-CCP antibodies, particularly at very high titers, can directly stimulate osteoclastogenesis through Fc receptor activation on macrophages and osteoclasts, independent of synovial inflammation.7,11 This direct osteoclastogenic effect of anti-CCP antibodies, combined with systemic inflammatory cytokine production, likely contributed to the unusually aggressive bone destruction in this patient.7,11
Hypercalcemia in RA
Several series in RA have reported hypercalcemia, but in most patients this has been attributable to concomitant conditions, most commonly primary hyperparathyroidism, malignancy, medications, or other systemic diseases, rather than RA itself.12-14 Hypercalcemia is therefore considered uncommon as a direct manifestation of RA, and its presence should generally prompt evaluation for alternative or coexisting etiologies.
In malignancy-associated hypercalcemia, predominant mechanisms include humoral hypercalcemia (PTH-related peptide-mediated) and local osteolytic hypercalcemia from extensive bone metastases or multiple myeloma, as described in endocrine literature. 15 By analogy with malignancy-related osteolytic hypercalcemia, we suspected that the patient’s extensive lytic bone involvement led to excess osteoclastic resorption and calcium release. This patient’s suppressed PTH, negative PTH-related peptide, and normal vitamin D metabolites pointed toward osteolytic bone resorption as the mechanism.
The extensive bone involvement likely generated sufficient calcium release to overwhelm renal clearance mechanisms, analogous to local osteolytic hypercalcemia in malignancy. 15 Complete resolution of hypercalcemia following immunosuppressive therapy strongly supports RA-driven bone resorption as the underlying cause and demonstrates that aggressive disease-modifying therapy can reverse even severe metabolic complications.
Lymphadenopathy in RA
Lymphadenopathy occurs in approximately 40% of RA patients and reflects chronic immune activation. 16 However, given the established increased risk of lymphoproliferative disorders in RA patients, particularly those with long-standing, highly seropositive disease, lymph node biopsy was essential to exclude malignant transformation.16,17 The finding of reactive follicular hyperplasia with polyclonal plasmacytosis, rather than clonal proliferation, supported a diagnosis of RA-associated reactive lymphadenopathy. 16
Diagnostic Approach and Limitations
When diffuse osteolytic lesions are encountered, the differential diagnosis appropriately prioritizes multiple myeloma, metastatic disease, osseous sarcoidosis, Langerhans cell histiocytosis, and granulomatous infections.5,6,18 In our patient, multiple myeloma was strongly considered because of the combination of hypercalcemia and diffuse lytic lesions, but serum protein electrophoresis showed no monoclonal spike, 24-hour urine was negative for Bence Jones protein, and bone marrow biopsy demonstrated polyclonal rather than clonal plasmacytosis, arguing against myeloma. Metastatic carcinoma was evaluated with whole-body CT, which failed to identify a primary tumor, and the lytic lesions remained radiographically stable over 10 months without new systemic symptoms, making metastatic disease unlikely. Osseous sarcoidosis was considered in light of lytic lesions, lymphadenopathy, and mildly elevated lysozyme, but lymph node and bone marrow histology did not show noncaseating granulomas. Langerhans cell histiocytosis was also in the differential, yet bone marrow and lymph node specimens lacked the characteristic Langerhans cell infiltrates. Finally, endemic fungal and mycobacterial infections were excluded by negative fungal serologies and the absence of granulomatous inflammation on lymph node and bone marrow biopsy.
This report has limitations. A targeted biopsy of one of the lytic skeletal lesions was considered during the initial oncology evaluation but was deferred because bone marrow and lymph node biopsies, serum and urine protein studies, and cross-sectional imaging did not demonstrate clonal or infiltrative malignancy, and there was no single dominant lesion that could be safely targeted with an acceptable risk-benefit profile. After rheumatology evaluation established seropositive RA and subsequent imaging showed stability and then improvement of the lesions on immunosuppressive therapy, the multidisciplinary team felt that an additional osseous biopsy would be unlikely to change management. Nevertheless, the absence of direct biopsy of a lytic lesion remains a limitation; the diagnosis rests on the convergence of imaging features, serologic findings, histologically confirmed rheumatoid nodules, clinical phenotype, and dramatic response to RA-directed therapy. The resolution of C6 erosive changes and stabilization of other lytic lesions on serial imaging provides strong evidence that these skeletal abnormalities represented RA-mediated bone destruction rather than an alternative process.
Clinical Implications
This case underscores several important lessons. First, RA should be considered in the differential diagnosis of diffuse lytic bone lesions when accompanied by serologic evidence of autoimmunity and clinical features of inflammatory arthritis. Second, very high anti-CCP antibody levels (>1000 U/mL) serve as both diagnostic markers and prognostic indicators of aggressive, erosive disease phenotypes with potential for extra-articular manifestations.7,11 Third, multidisciplinary collaboration among rheumatology, hematology-oncology, infectious disease, pathology, and radiology remains essential for navigating diagnostically complex presentations. 18
Finally, aggressive immunosuppressive therapy can effectively control even severe bone-destructive phenotypes of RA, highlighting the importance of early diagnosis and treatment initiation.1,2,19 The dramatic clinical and biochemical response to rituximab validates the diagnosis and demonstrates that timely immunosuppression can reverse metabolic complications and stabilize skeletal disease. 19
Conclusion
Aggressive seropositive rheumatoid arthritis can rarely present with diffuse osteolytic bone lesions, hypercalcemia, and lymphadenopathy that closely mimic hematologic malignancy or metastatic disease. This case emphasizes the necessity of comprehensive evaluation to systematically exclude alternative diagnoses through bone marrow biopsy, lymph node histology, infectious studies, histologic confirmation of rheumatoid nodules, and serial imaging. The pathophysiologic mechanisms underlying RA bone destruction—RANKL-mediated osteoclastogenesis and anti-CCP antibody-induced osteoclast activation—can in exceptional cases extend beyond typical marginal erosions to produce extensive skeletal involvement. Very high anti-CCP antibody levels serve as both diagnostic markers and prognostic indicators of aggressive disease. The dramatic response to disease-modifying antirheumatic therapy, including rituximab, validates the diagnosis and demonstrates that even severe bone-destructive RA responds to timely immunosuppression. Maintaining RA in the differential diagnosis of diffuse lytic bone lesions, particularly when accompanied by serologic evidence of autoimmunity, can prevent diagnostic delay and ensure appropriate therapeutic intervention.
Footnotes
Ethical Considerations
Our institution does not require ethical approval for reporting individual cases or case series.
Consent to Participate
Verbal informed consent was obtained from the patient for their anonymized information to be published in this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.