Rheumatoid Arthritis Associated With Anti-Signal Recognition Particle Immune-Mediated Necrotizing Myopathy: A Case Report

Abstract

Immune-mediated necrotizing myopathy (IMNM) is a rare subtype of idiopathic inflammatory myopathy that is characterized by severe subacute proximal weakness, myofiber necrosis, and significantly elevated serum creatine kinase. Anti-signal recognition particle (SRP) and anti-3-hydroxy-3-methylglutaryl-coenzyme-A reductase autoantibodies have been found in about two-thirds of patients with IMNM. This myopathy is usually idiopathic and there is a scarce literature concerning its association with connective tissue diseases. Herein, we report an unusual case of a young woman who presented with both rheumatoid arthritis and severe anti-SRP IMNM. Thankfully to a therapeutic protocol combining rituximab and cyclophosphamide, an important improvement was achieved, and notably no serious side effect was observed.

Introduction

Immune-mediated necrotizing myopathy (IMNM) is an autoimmune myopathy characterized by severe proximal weakness, myofiber necrosis, and marked elevation of serum creatine kinase (CK). ¹

Histologically, inflammatory cell infiltrates are usually absent or minimal. Anti-signal recognition particle (SRP) and anti-3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGCR) are the 2 known pathogenic autoantibodies in IMNM. ²

The IMNM is usually idiopathic and to our knowledge its occurrence as an association with rheumatoid arthritis (RA) has never been mentioned. Herein, we report the case of a young woman with RA who developed a severe form of anti-SRP IMNM. The patient responded favorably to a therapeutic scheme combining rituximab and cyclophosphamide.

Case Description

We report a 32-year-old woman with a history of pulmonary tuberculosis in 2010 presented in August 2022 to the rheumatology department with the complaint of polyarthralgia. The workup at this time has led to a diagnosis of RA according to 2010 ACR-EULAR diagnostic criteria for RA.

The relevant results were the positivity of anti-cyclic citrullinated peptide antibodies (anti-CCP2) at 341 U/mL, rheumatoid factor, and antinuclear antibodies at 1:640 with speckled pattern. Aspartate transaminase and alanine transaminase were, respectively, slightly elevated at 61.5 and 76.3 IU/L.

However, the patient did not follow any therapy and was not seen until February 2023 with the apparition of a subacute weakness and muscle pain of all limbs.

The patient became wheelchair-dependent after 2 weeks from the onset of the weakness. A concomitant dosage of serum CK was increased at 1990 IU/L (mid-February 2023).

The physical examination revealed intense generalized myalgia with a bilateral, symmetrical, and predominantly proximal weakness of the upper and lower limbs at 1/5 according to Medical Research Council (MRC) scale.

Severe axial weakness (transition from lying to sitting position was not possible) and neck flexors weakness (3/5 according to MRC scale) were also observed.

Notably, no skin changes were present during this examination. Laboratory studies (late February 2023) revealed elevated erythrocyte sedimentation rate (47 mm/h), serum CK (rise to 9000 IU/L), lactate dehydrogenase (2007 U/L), and transaminases (aspartate transaminase 1064.3 IU/L, alanine transaminase 578.8 IU/L). Serum ionogram and full blood count were normal.

Electromyography study demonstrated a typical pattern of irritable myopathy in proximal muscles. A muscle biopsy (from the left biceps) revealed widespread myonecrosis, regeneration, and myophagocytosis. No inflammatory lymphocytic infiltrate was present (Figure 1).

Figure 1.

Histopathology of the muscle biopsy. Upper left: overview showing globally preserved muscle tissue, without obvious inflammation (hematoxylin and eosin staining, transverse section). Bottom left: at closer magnification, one necrotic fiber (star) and one regenerating fiber (arrowhead) (hematoxylin and eosin staining, oblique section). Upper right: macrophages invading 2 necrotic muscle fibers (CD68 immunostaining, longitudinal section). Bottom right: only a few T lymphocytes are focally present (CD3 immunostaining, transverse section).

At this stage, the diagnosis of necrotizing myopathy was confirmed; however, its etiology remained unclear. The history did not find any drug or toxic exposure and particularly no statin use. Nonetheless, the association with RA has led us to prioritize an immune-mediated etiology of the necrotizing myopathy.

Meanwhile, at the end of the third day of hospitalization, her myopathy worsened with the occurrence of mild dysphagia and dyspnea.

Therefore, we decided to give the patient steroids pulse (methylprednisolone 1 g/d for 5 consecutive days), which contributed to the regression of dysphagia and dyspnea. However, motor weakness did not improve.

Workup for infectious etiologies was negative for human immunodeficiency virus, human T-lymphotropic virus type 1, and hepatitis virus panel. A line blot Myositis Specific (11 Autoantibody Panel) revealed positivity for anti-SRP antibodies. Assessment for anti-HMGCR antibodies was not performed. Computed tomography of the thorax and abdomen in addition to an echocardiogram was unremarkable.

At this point, the diagnosis of anti-SRP IMNM associated with RA was made. Given the severity of the weakness in our patient and the poor response to steroids, she received 1 g rituximab twice (15 days apart) additionally to 1 g cyclophosphamide every 4 weeks. Prednisolone at 1 mg/kg daily was maintained for 6 weeks followed by a slowly tapering until a maintenance dose of 10 mg daily.

Anti-infectious prophylaxis regimen containing acyclovir, trimethoprim-sulfamethoxazole, and folic acid was added. A rehabilitation program was initiated and maintained during the subsequent months.

We noticed a gradual and steady improvement of muscle strength during the following months alongside to the decrease of serum CK. No adverse events, especially no serious infections, were observed.

At 7 months from the onset of the therapeutic protocol (September 2023), the muscle strength significantly recovered in addition to the normalization of serum level of CK. Hence, the patient became able to walk alone and to perform her daily activities without assistance.

A switch toward methotrexate was then envisioned to both prevent relapses of IMNM and control RA activity. Rehabilitation program was pursued due to the persistence of a mild residual weakness.

Discussion

Most IMNMs are associated with anti-SRP or anti-HMGCR-specific autoantibodies, despite 20% of patients with IMNM are seronegative. ³

Patients with anti-SRP myopathy are usually younger with more severe presentations compared with those with anti-HMGCR myopathy. ¹

Akin to our patient, IMNM presents as a subacute, severe, proximal muscle weakness associated with a significantly elevated serum CK.

A period of asymptomatic rise of serum CK, lasting months, may predate the weakness. ⁴

Notably, our patient had slightly elevated transaminase 6 months before the occurrence of weakness. Although serum CK was not evaluated at this period, the elevation of transaminase (without any hepatic or cardiac disease) may indicate a muscular origin. Therefore, an asymptomatic hyperCKaemia may have predated the weakness by 6 months in our patient.

Cardiac involvement was thought to be prevalent in anti-SRP myopathy; however, recent literature has only revealed this manifestation in small proportion of patients. Nonetheless, cardiac evaluation should be realized systematically given its prognostic value. ⁴

Other extramuscular manifestations such as interstitial lung disease (ILD) and skin involvement occur rarely in anti-SRP IMNM and are usually mild. ¹

Our patient did not present myocardial involvement nor ILD. Nonetheless, she developed several worse prognostic features such as profound proximal and axial weakness, dysphagia, respiratory insufficiency, and association with connective tissue disease (CTD).

There is an extremely rare literature reporting association between CTD and anti-SRP IMNM.

In this setting, a recent study described 6 patients with anti-SRP IMNM overlap Sjogren’s syndrome (SS) of 30 patients with anti-SRP IMNM. ⁵

Muscle biopsies analysis in RA-related myopathies usually reveals several nonspecific muscle fiber damages and the presence of inflammatory deposits. ⁶

To our knowledge, there is no reported case of an association between RA and anti-SRP IMNM.

Interestingly, one report of a patient with RA developed anti-SRP IMNM.

However, the authors of this case concluded that leflunomide, rather than RA, provoked IMNM in their patient. Leflunomide is used in the treatment for RA and has been shown to induce autoimmune diseases, including autoimmune hepatitis and polymyositis. ²

The lapse of time separating the occurrence of RA and IMNM in our patient did not exceed 6 months, thus indicating a highly probable link between the 2 conditions.

A flare of autoimmunity likely underpinned the expression of the 2 diseases and hence makes the hypothesis of their coincidence unlikely.

Management of IMNM is currently not standardized but treatment must be both initiated early and aggressive to avoid disability related to muscle atrophy. ¹

Given the severe and subacute presentation of myopathy in our patient, we favored an association of rituximab and cyclophosphamide which allowed a significant clinical improvement with serum CK normalization after 7 months from the beginning of the therapeutic scheme.

Importantly, no serious infection was reported attesting the tolerability of the protocol in our patient.

Due to the high potential risk of relapses, we switched to methotrexate which is an effective and less expensive option (than rituximab) for both IMNM and RA.

Conclusion

Our report indicates that anti-SRP IMNM may be associated with RA and thus clinicians should be aware of this combination especially if a patient with RA presents with a severe subacute myopathy.

The implications of an early diagnosis are of utmost importance avoiding irreversible disability by means of an aggressive immunosuppressive therapy.

The combination of rituximab-cyclophosphamide was both effective and tolerated allowing the patient to regain her autonomy without any significant side effect.