Anti-HMGCR antibody-positive immune-mediated necrotizing myopathy associated with rectal adenocarcinoma: a case description

Introduction

Immune-mediated necrotizing myopathy (IMNM) is a distinct subtype of idiopathic inflammatory myopathy (IIM), characterized by predominant myofiber necrosis, proximal muscle weakness, and markedly elevated serum creatine kinase (CK) levels (1). Anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) antibodies define one of the two major IMNM subtypes and are classically associated with statin exposure, although a substantial proportion of patients are statin-naïve (2,3). The association between IIMs and malignancy is well established in dermatomyositis (DM), particularly in patients positive for anti-transcriptional intermediary factor 1-γ (anti-TIF1-γ) antibodies (4,5). In contrast, the relationship between anti-HMGCR-positive IMNM and cancer remains poorly characterized (6). Several cohort studies have reported a possible malignancy risk in anti-HMGCR-positive patients, predominantly involving upper gastrointestinal, colonic, pulmonary, and breast cancers (2,7), yet to the best of our knowledge, anti-HMGCR-positive IMNM specifically associated with rectal adenocarcinoma has not been individually reported.

In this report, we describe a 66-year-old statin-naïve male who was diagnosed with anti-HMGCR-positive IMNM (strongly positive, +++) with concurrent anti-Ro-52 positivity. During the diagnostic workup, rectal adenocarcinoma was incidentally discovered. The patient underwent surgical resection followed by combined immunotherapy over 22 months. This case expands the known spectrum of anti-HMGCR-associated malignancies and highlights the importance of comprehensive malignancy screening in statin-naïve patients with anti-HMGCR antibodies.

Case presentation

Medical history and initial evaluation

A 66-year-old man was admitted to our hospital in May 2024 with a 3-month history of progressive proximal limb weakness, muscle soreness, and bilateral upper eyelid erythema. Manual muscle testing (MMT) at initial evaluation revealed proximal weakness with Medical Research Council (MRC) grade 4/5 in bilateral shoulder abductors, hip flexors, and knee extensors; distal strength was preserved at MRC grade 5/5. Neck flexion strength was intact (MRC 5/5), and no isolated neck weakness was observed. The eyelid erythema did not exhibit features characteristic of a heliotrope rash, and no Gottron papules or other DM-specific cutaneous findings were observed. The patient had no history of statin or other lipid-lowering agent use. His past medical history included a right humeral fracture treated with internal fixation and hardware removal on 20 November 2022, at which time serum CK was normal (130 U/L; reference: 38–174 U/L). No family history of autoimmune disease or malignancy was reported.

Laboratory findings

On admission, serum muscle enzymes were markedly elevated: CK 8,732 U/L (reference: 38–174 U/L), aspartate aminotransferase (AST) 234 U/L (reference: 15–40 U/L), alanine aminotransferase (ALT) 223 U/L (reference: 5–40 U/L), lactate dehydrogenase (LDH) 1,663 U/L (reference: 110–240 U/L), creatine kinase-MB isoenzyme (CK-MB) 294.26 ng/mL (reference: 0–5 ng/mL), and myoglobin 1,197.70 ng/mL (reference: 0–70 ng/mL). C-reactive protein (CRP) was mildly elevated at 18.9 mg/L (reference: 0–5 mg/L). Antinuclear antibodies (ANA), extractable nuclear antigen (ENA) panel, anti-neutrophil cytoplasmic antibodies (ANCA), and rheumatoid factor were all negative. Immunoglobulin levels and complement levels were unremarkable. Myositis-specific antibody (MSA) testing by commercial line immunoassay revealed strongly positive anti-HMGCR antibodies (+++ on a semiquantitative scale) and positive anti-Ro-52 antibodies (+), with all other MSAs negative [including anti-signal recognition particle (anti-SRP), anti-Mi-2, anti-melanoma differentiation-associated protein 5 (anti-MDA5), anti-TIF1-γ, anti-nuclear matrix protein 2 (anti-NXP2), anti-small ubiquitin-like modifier activating enzyme (anti-SAE), and anti-histidyl-tRNA synthetase (anti-Jo-1)]. A clinical diagnosis of IMNM was established according to the 2017 European Neuromuscular Centre (ENMC) seropositive criteria (8), based on elevated CK, proximal muscle weakness, and positive anti-HMGCR antibodies.

Electrophysiological studies

Electromyography (EMG) and nerve conduction studies performed on 29 May 2024 revealed no myopathic changes on needle examination of six muscles (right first dorsal interosseous, abductor pollicis brevis, tibialis anterior, gastrocnemius, deltoid, and vastus medialis) despite the markedly elevated CK.

Imaging findings and tumor discovery

Abdominal contrast-enhanced computed tomography (CT) on 2 June 2024 revealed eccentric wall thickening of the upper rectum with serosal surface irregularity and marked enhancement on contrast, suggestive of a neoplastic lesion (Figure 1A). Positron emission tomography/computed tomography (PET/CT, 4 June 2024) confirmed a hypermetabolic rectal mass, consistent with malignancy. Pelvic magnetic resonance imaging (MRI, 7 June 2024) demonstrated eccentric rectal wall thickening (1.1 cm thick, extent 3.2 cm) with restricted diffusion and marked enhancement (Figure 1B,1C).

Figure 1.

Multimodal imaging of rectal adenocarcinoma in a 66-year-old male. (A) Contrast-enhanced axial CT shows eccentric thickening of the upper rectal wall (red arrow) with an irregular serosal surface and marked enhancement. (B,C) Contrast-enhanced MRI reveals slightly hyperintense signal on T2-Fs sequence, restricted diffusion on DWI, an irregular serosal surface, and marked enhancement of the lesion (red arrows). (D) Colonoscopy demonstrates a polypoid/elevated mass (black arrow). CT, computed tomography; DWI, diffusion-weighted imaging; MRI, magnetic resonance imaging; T2-Fs, T2-weighted fat-suppressed.

Colonoscopy and biopsy

Colonoscopy (3 June 2024) identified a mass in the upper rectum (Figure 1D). Biopsy (5 June 2024) confirmed adenocarcinoma (Figure 2A). Immunohistochemistry showed intact mismatch repair (MMR) protein expression: MSH6(+), MSH2(+), MLH1(+), PMS2(+); P53 (70% weak to moderate positive), Ki-67 (60%), C-erbB-2/human epidermal growth factor receptor 2 (HER2, 1+).

Figure 2.

Histopathological features of rectal adenocarcinoma (H&E stain). (A) Colonoscopic biopsy specimen reveals moderately to poorly differentiated adenocarcinoma (original magnification, ×20). (B) Surgical specimen confirms invasive adenocarcinoma (original magnification, ×20). H&E, hematoxylin and eosin.

Surgical treatment and pathology

Laparoscopic radical rectal resection with temporary ileostomy was performed on 11 June 2024. Surgical pathology revealed a moderately differentiated tubular adenocarcinoma (3.0 cm × 2.5 cm × 1.3 cm) with invasion to the subserosa (Figure 2B). Upper, lower, and circumferential resection margins were all negative. No lymphovascular invasion or perineural invasion was identified. Tumor budding grade was Bd2 (intermediate, 6 buds/0.785 mm²). All 17 perirectal lymph nodes were free of metastasis. The American Joint Committee on Cancer (AJCC) 8th edition stage was pT3N0Mx.

Immunohistochemistry of the surgical specimen showed CDX2(+), CK20(+), CK7(−), P53 (wild type), C-erbB-2/HER2 (3+), Ki-67 (60%), MLH1(+), MSH2(+), MSH6 (partial loss of expression), PMS2(+). High-resolution melting curve analysis (16 July 2024) of 8 microsatellite loci confirmed microsatellite stability (MSS), consistent with a proficient mismatch repair (pMMR) phenotype. Ileostomy reversal with ileal anastomosis was performed on 24 October 2024, without complications.

IMNM treatment and clinical course

Following tumor resection, serum CK declined substantially from 6,688 U/L (preoperative) to 2,611 U/L (postoperative day 2), supporting a paraneoplastic contribution to the myopathy. However, CK did not normalize completely, suggesting that the autoimmune process had become partially independent of tumor-derived antigenic stimulation. Methylprednisolone 40 mg daily was initiated. The patient developed prerenal acute kidney injury (AKI), which resolved with conservative management without dialysis. During this period, CK transiently rose to 3,384 U/L before gradually declining with continued treatment. Muscle biopsy was recommended but declined by the patient.

Because of persistently elevated CK (4,503 U/L upon readmission in August 2024), treatment was intensified with intravenous methylprednisolone 80 mg daily combined with intravenous immunoglobulin (IVIG) 20 g daily for three consecutive days. At discharge, CK had decreased to 1,645 U/L and muscle strength improved to grade 5/5 in all extremities. Repeat EMG (August 2024) demonstrated partial myogenic changes in the right biceps brachii, confirming subclinical myopathic involvement. High-resolution CT of the chest revealed bilateral pulmonary interstitial fibrosis with pleural thickening.

Follow-up

The subsequent outpatient course (Table 1) demonstrated a biphasic pattern. During the initial steroid taper phase, CK declined progressively from 1,612 U/L (September 2024) to a nadir of 350 U/L (November 2024) on prednisone 10 mg daily. 
However, upon further steroid reduction to 7.5 mg daily with addition of methotrexate (MTX) 10 mg weekly, CK rose to 705 U/L (January 2025) and subsequently rebounded to 1,552 U/L (February 2025), prompting dose escalation of both prednisone (to 15 mg daily) and MTX (to 12.5 mg weekly). Despite this intensification, CK remained elevated (1,503–1,933 U/L) through May 2025, prompting a regimen switch to methylprednisolone 12 mg daily plus mycophenolate mofetil (MMF) 0.5 g twice daily in July 2025. CK persisted at 1,412–2,100 U/L through November 2025, causing further escalation to triple immunotherapy (methylprednisolone 8 mg daily, MMF 0.5 g twice daily, and MTX 15 mg weekly). At the latest follow-up (March 2026, approximately 22 months post-surgery), CK remained elevated at 2,715 U/L. Throughout the follow-up period, the patient remained ambulatory. He was independent in all activities of daily living. MMT showed transient mild proximal weakness (MRC grade 4/5) between April and August 2025, after which strength recovered to grade 5/5 and remained stable through the most recent assessment.

Table 1. Serial creatine kinase levels, muscle strength assessments, treatment adjustments, and key clinical events during the 22-month disease course.

No.	Date	CK (U/L)	MRC grade	Treatment	Clinical event
1	20 Nov 2022	130	–	None	Baseline (orthopedic admission)
2	28 May 2024	8,732	4/5	None	Initial presentation
3	31 May 2024	6,105	4/5	None	Hospital day 3
4	6 Jun 2024	6,688	4/5	None	Preoperative
5	13 Jun 2024	2,611	4/5	None	POD 2
6	2 Jul 2024	3,384	4/5	MP 40 mg qd	Prerenal AKI
7	4 Jul 2024	3,351	4/5	MP 40 mg qd	Continued treatment
8	13 Aug 2024	4,503	4/5	MP 80 mg IV qd + IVIG 20 g $\times$3 d	2nd admission
9	22 Aug 2024	1,645	5/5	Pred 50 mg qd	Discharge
10	16 Sep 2024	1,612	5/5	Pred 35 mg qd	Steroid taper
11	18 Oct 2024	532	5/5	Pred 20 mg qd	Steroid taper
12	15 Nov 2024	350	5/5	Pred 10 mg qd	CK nadir
13	13 Jan 2025	705	5/5	Pred 7.5 mg + MTX 10 mg/wk	Adding MTX
14	17 Feb 2025	1,552	5/5	Pred 10 mg + MTX 12.5 mg/wk	Disease flare
15	17 Mar 2025	1,801	5/5	Pred 15 mg + MTX 12.5 mg/wk	Dose escalation
16	21 Apr 2025	1,933	4/5	Pred 15 mg + MTX 12.5 mg/wk + IVIG	Adding IVIG
17	19 May 2025	1,503	4/5	Pred 15 mg + MTX 12.5 mg/wk	None
18	23 Jun 2025	1,746	4/5	Pred 15 mg + MTX 12.5 mg/wk	None
19	21 Jul 2025	2,100	4/5	MP 12 mg + MMF 0.5 g bid + IVIG	Switch to MMF
20	18 Aug 2025	2,099	4/5	MP 12 mg + MMF 0.5 g bid	None
21	22 Sep 2025	1,501	5/5	MP 12 mg + MMF 0.5 g bid	None
22	21 Nov 2025	1,412	5/5	MP 8 mg + MMF 0.5 g bid	Steroid taper
23	23 Jan 2026	2,275	5/5	MP 8 mg + MTX 10 mg/wk + MMF 0.5 g bid	Triple therapy
24	20 Mar 2026	2,715	5/5	MP 8 mg + MTX 15 mg/wk + MMF 0.5 g bid	Latest follow-up

CK reference range: 38–174 U/L (entries 1–7); $<$164 U/L (entries 8–24, updated laboratory reference). AKI, acute kidney injury; bid, twice daily; CK, creatine kinase; IV, intravenous; IVIG, intravenous immunoglobulin; MMF, mycophenolate mofetil; MP, methylprednisolone; MRC, Medical Research Council muscle strength grade; MTX, methotrexate; POD, postoperative day; Pred, prednisone; qd, once daily.

Throughout the follow-up period, all tumor markers remained within normal limits [carcinoembryonic antigen (CEA) 1.79 ng/mL, CA19-9 6.68 U/mL, CA72-4 8.46 U/mL, alpha-fetoprotein (AFP) 3.79 ng/mL, CA125 14.85 U/mL, CA242 3.00 IU/mL, CA50 4.00 IU/mL]. Abdominal contrast-enhanced CT scans (September 2024, April 2025, June 2025, October 2025) showed no evidence of tumor recurrence or distant metastasis. Follow-up colonoscopy with biopsy (July 2025) demonstrated chronic mucosal inflammation with focal erosion at the terminal ileum and ileocecal valve, without malignancy.

All procedures in this study were performed in accordance with the ethical standards of the relevant institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was provided by the patient for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

Although anti-HMGCR antibody-positive IMNM associated with colon cancer has been previously described (2,7), to the best of our knowledge, this is the first individually detailed case of specifically rectal adenocarcinoma-associated anti-HMGCR IMNM. Anti-HMGCR antibodies are detected in approximately 6–12% of patients with IIMs (3,9). Although initially identified in statin-exposed patients, anti-HMGCR-positive IMNM also occurs in statin-naïve individuals, particularly those of Asian descent (10). The association between anti-HMGCR antibodies and malignancy has been explored in several cohort studies. Allenbach et al. (7) reported that malignancy risk in anti-HMGCR-positive patients was elevated compared to the general population. Kadoya et al. (2) described a high cancer incidence among anti-HMGCR-positive patients, with a predominance of gastrointestinal malignancies. Such patients tend to be older and statin-naïve. HMGCR expressed by the tumor may serve as the initial antigenic trigger (11).

A paraneoplastic contribution in our case is likely. Symptoms began just 3 months before the cancer diagnosis, and a normal CK 18 months prior argues strongly against chronic myopathy. Notably, CK fell from 6,688 U/L preoperatively to 2,611 U/L by postoperative day 2. This decline was far too rapid to be a result of the concurrently initiated steroids. However, the relationship is not purely paraneoplastic. Despite 22 months of cancer remission, CK levels remained persistently elevated on multi-agent immunotherapy, pointing to a likely direct pathogenic role of anti-HMGCR antibodies (12).

Several diagnostic considerations in this case merit comment. The initial working diagnosis was cancer-associated inflammatory myopathy, with DM and other IIM subtypes considered pending MSA results. The eyelid erythema initially suggested DM, but there was no heliotrope rash or Gottron papules, and DM-specific antibodies were negative. Notably, although anti-HMGCR-positive IMNM has traditionally been regarded as a predominantly muscle-limited disease, recent studies have reported that skin manifestations, including eyelid erythema, are relatively common in anti-HMGCR myopathy (13,14). The cutaneous findings in our patient are consistent with these emerging observations. The strongly positive anti-HMGCR result then reframed the diagnosis from a syndromic label (“paraneoplastic myositis”) to an immunopathologic one (anti-HMGCR-positive IMNM with a paraneoplastic contribution). This sequence illustrates a broader point: cancer-associated myositis is not a single disease but an umbrella that requires MSA-based subtyping for accurate prognosis and treatment planning, and the MSA panel should be sent at first presentation rather than after initial empirical management. The first EMG was normal despite the very high CK; this can happen in early IMNM when necrosis outpaces inflammation, and a repeat EMG 3 months later showed myopathic changes, underscoring the value of serial studies. Finally, anti-Ro-52 positivity together with bilateral pulmonary fibrosis suggests an overlap phenotype, and long-term lung monitoring is warranted given the known Ro-52/interstitial lung disease (ILD) link across IIM subtypes (15). Moreover, recent evidence suggests that isolated anti-Ro-52 antibody positivity is associated with increased cancer risk and distinct malignancy patterns (16), although a specific association with colorectal carcinoma has not been established.

The therapeutic course illustrates the challenges of managing cancer-associated IMNM. Despite sequential escalation through corticosteroids, IVIG, MTX, and MMF over 22 months, CK remained persistently elevated (2,715 U/L at latest follow-up). This treatment resistance is consistent with the challenging therapeutic course of anti-HMGCR-positive IMNM, which the 2017 ENMC workshop recognized as requiring a dedicated escalation strategy including early IVIG addition and prolonged maintenance therapy (8). In retrospect, the initial dose of methylprednisolone (40 mg daily) may have been suboptimal, as anti-HMGCR-positive IMNM often requires aggressive combination immunosuppressive therapy from the outset. The steroid taper from 10 mg to 7.5 mg daily between November 2024 and January 2025 may have been too rapid, and a slower reduction (e.g., 0.5–1 mg decrements) might have mitigated the subsequent disease flare. Upon relapse, a more aggressive re-induction strategy, such as repeat high-dose intravenous methylprednisolone and IVIG, could also have been considered. Notably, despite persistent CK elevation, the patient maintained largely stable muscle strength (MRC grade 5/5, apart from a transient dip to grade 4/5 between April and August 2025) and functional independence throughout follow-up, a clinically important dissociation previously described in anti-HMGCR-positive IMNM (17). Additionally, no tumor recurrence was observed despite prolonged immunosuppression, suggesting that carefully monitored immunotherapy may be feasible following complete tumor resection. A meta-analysis has shown that rituximab is effective in approximately 60–65% of patients with refractory IIM and may represent a future therapeutic option for this patient (18), although data specific to anti-HMGCR-positive IMNM remain limited.

This case underscores the importance of comprehensive malignancy screening in patients newly diagnosed with anti-HMGCR-positive IMNM, particularly in statin-naïve individuals. We recommend thorough age-appropriate malignancy evaluation for all newly diagnosed anti-HMGCR-positive IMNM patients over 50 years of age, especially those without prior statin exposure.

A few limitations deserve mention. First, a muscle biopsy was lacking, which might have refined the phenotypic diagnosis. Second, muscle MRI of the extremities was not performed; given its established utility in the diagnosis, prognostic assessment, and monitoring of inflammatory myopathies, serial MRI examination correlated with CK level fluctuations would have provided valuable complementary information. Third, anti-HMGCR testing was only semiquantitative. Fourth, the use of multiple immunotherapies precludes assigning causality to any single agent. Fifth, discrepancies in P53 and MSH6 staining between biopsy and resection specimens likely reflect sampling heterogeneity. Sixth, HER2 was 3+ on the surgical specimen, but fluorescence in situ hybridization (FISH) confirmation was not performed, which is worth noting given HER2’s rarity in colorectal cancer. Seventh, the eyelid erythema was not biopsied. Although emerging evidence suggests that skin manifestations may be more common in anti-HMGCR IMNM than previously recognized (13,14,19), histological confirmation would have clarified whether the eyelid erythema was directly related to the myopathy. Finally, this remains a single case; broader cohorts are needed to define the anti-HMGCR-malignancy link more precisely.

Conclusions

This case represents the first individually detailed report of anti-HMGCR antibody-positive IMNM associated with rectal adenocarcinoma in a statin-naïve patient. The initial post-surgical decline in CK levels, followed by persistent elevation despite prolonged cancer remission, supports a dual pathogenesis involving both paraneoplastic triggering and antibody-mediated autoimmune perpetuation. Comprehensive malignancy screening is warranted in all statin-naïve patients over 50 years of age newly diagnosed with anti-HMGCR-positive IMNM. MSA-based subtyping at initial presentation is essential for accurate diagnosis and treatment planning in cancer-associated myositis.

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Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this article and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.