Successful treatment of rheumatoid arthritis complicated by anti-Jo-1 antibody-positive myopathy with abatacept: A case report

Abstract

Abatacept (ABT) is effective in the treatment of rheumatoid arthritis (RA).　However, there is no consensus regarding the treatment of patients with RA and idiopathic inflammatory myopathy (IIM).　Here, we describe the case of a 55-year-old Japanese female with a 5-year history of RA who developed anti-Jo1 antibody-positive IIM.　She developed myalgia and dyspnea while receiving a combination therapy of methotrexate and a Janus kinase inhibitor for RA.　Chest computed tomography imaging revealed bilateral middle-to-lower lung frosted shadows.　Magnetic resonance imaging of the lower limbs showed a high short tau inversion recovery signal in the bilateral thigh muscle groups.　Needle electromyography revealed myogenic changes in the proximal muscles of both the upper and lower extremities.　Symmetric proximal muscle weakness, elevated serum muscle enzymes, and the presence of anti-Jo1 antibodies were noted.　The diagnosis of IIM was made according to the European Alliance of Associations for Rheumatology diagnostic criteria.　The myositis symptoms stabilized with glucocorticoids; however, RA worsened during steroid tapering.　After ABT initiation, RA clinical symptoms and functional outcomes improved and myositis remained in remission.　In conclusion, ABT may be an effective treatment option for patients with RA and IIM.　

Introduction

Rheumatoid arthritis (RA) is a chronic, symmetrical, inflammatory autoimmune disease¹⁾.　Abatacept (ABT), a fusion protein composed of the extracellular domain of cytotoxic T-lymphocyte antigen 4 and the Fc region of human immunoglobulin (Ig) G1, is a biologic selectively designed to inhibit T-cell costimulation and is currently approved as a second-line treatment for RA^2,3).　Several recent case series and clinical trials have also reported the efficacy of ABT for treatment of idiopathic inflammatory myopathy (IIM)^4-6).　IIM, a group of chronic autoimmune conditions primarily affecting the proximal muscles, includes dermatomyositis, polymyositis, and inclusion body myositis.　In rare cases, RA can be complicated by IIM^7,8); however, there is no consensus regarding treatment in these cases.　Herein, we describe the rare case of a 55-year-old female with RA complicated by anti-Jo-1 antibody-positive myopathy who was successfully treated with ABT.

Case Presentation

A 55-year-old female was admitted to our hospital for interstitial pneumonia.　Five years before admission, the patient had presented with polyarthritis and was diagnosed with RA by her primary care physician after testing positive for rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) antibodies.　After diagnosis, treatment with methotrexate (6 mg/week) was initiated.　Subsequently, she was treated with two biologics (etanercept: a fusion protein composed of the two subunits of the extracellular domain of TNFRII and the Fc region of human IgG1; and tocilizumab: a humanized IgG1 monoclonal antibody directed against the human IL-6 receptor), which did not successfully control her RA disease activity.　Thus, she was switched to 4 mg/day of oral baricitinib approximately 3.5 years before hospitalization.　After induction of baricitinib treatment, RA disease activity went into remission.　The patient developed a fever and cough two weeks before admission.　She visited a local physician, who noted an abnormal lung shadow on chest radiography.　Interstitial or bacterial pneumonia was suspected, and the patient was admitted to our department.　At admission, she had a temperature of 38.1°C, heart rate of 92 beats/min, blood pressure of 122/76 mmHg, and SpO₂ of 93% on room air.　The physical examination revealed fine crackles at the dorsal aspects of both lower lungs.　No joint swelling or tenderness was observed; however, grasping pain in the proximal muscles was noted.　The manual muscle strength test revealed weakness in the proximal muscles, including the deltoids (2/2), biceps (4/4), iliopsoas (3/3), gluteus medius (4/4), quadriceps (4/4), and hamstrings (4/4).　She had normal deep tendon reflexes in all four limbs and no ataxia or sensory disturbances.　No skin rash was observed.　The Disease Activity Score (DAS)-28 C-reactive protein (CRP) level was found to be 2.52, indicating low RA disease activity.　Laboratory findings (Table 1) revealed elevated serum levels of creatine kinase (CK), lactate dehydrogenase, and KL-6.　Autoantibody titers were also elevated, with elevated antinuclear, anti-Sjögren’s-syndrome-related antigen A, anti-CCP, and RF antibodies.　She was suspected of having IIM due to muscle weakness, elevated serum CK levels, and interstitial pneumonia, and was evaluated for myositis-specific antibodies.　The patient was strongly positive for anti-aminoacyl tRNA synthetase (ARS) and anti-Jo-1 antibodies.　A 12-lead electrocardiogram and transthoracic echocardiography revealed no abnormalities.　The chest radiography results can be seen in Fig. 1A.　Chest computed tomography (CT) imaging revealed bilateral middle-to-lower lung frosted shadows (Fig. 1B).　Radiography of the hands revealed bilateral destruction of the wrist bones and narrowing of the joint cleft (Fig. 2).　Magnetic resonance imaging of the lower limbs showed a high short tau inversion recovery signal in the bilateral thigh muscle groups (Fig. 3).　Needle electromyography revealed myogenic changes in the proximal muscles of both the upper and lower extremities.　Thus, the patient was diagnosed with IIM based on the European Alliance of Associations for Rheumatology (EULAR)/American College of Rheumatology (ACR) classification criteria⁹⁾.　The patient’s clinical course after admission is illustrated in Fig. 4.　Methotrexate and baricitinib were discontinued immediately after admission due to the possibility of drug-induced interstitial and bacterial pneumonia.　Glucocorticoid pulse therapy (methylprednisolone 1000 mg/day) was administered intravenously for the first 3 days after admission, followed by 50 mg/day (1.0 mg/kg body weight) of oral prednisolone (PSL) to treat IIM and RA.　On admission day 4, 2 mg/day of oral tacrolimus was initiated, which was increased to 3 mg/day on day 23.　The PSL dose was gradually reduced, and the patient was discharged 26 days after admission.　However, on day 82, bilateral pain in the wrist joints developed due to an exacerbation of RA activity.　The DAS28- CRP level at that time was 3.18, indicating moderate activity.　Thus, 500 mg/4 weeks of intravenous ABT was initiated for intensified RA treatment.　After the introduction of ABT therapy and despite a reduction in the PSL dose, her arthralgia disappeared.　The DAS28-CRP level was 1.11 at day 83 after ABT introduction, and she was considered to be in remission.　Subsequent chest X-ray and CT showed improvement in interstitial pneumonia.　Currently, the patient continues to attend outpatient clinics; the PSL dose has been reduced to 5.0 mg/day, and there has been no relapse of myalgia or interstitial pneumonia.

Table 1.

Laboratory findings on admission.

TSH, thyroid stimulating hormone; RF, rheumatoid factor; Ig, immunoglobulin; ANA, antinuclear antibodies; CCP, cyclic citrullinated peptide; Abs, antibodies; RNP, ribonucleoprotein; SSA, Sjögren's-syndrome-related antigen A; SSB, Sjögren's-syndrome-related antigen B; ARS, aminoacyl-tRNA synthetase; MDA5, melanoma differentiation-associated gene 5; TIF1γ, transcription intermediary factor 1-γ; ds-DNA, double strand deoxyribonucleic acid; Sm, smith; MPO-ANCA, myeloperoxidase-anti-neutrophil cytoplasmic antibodies; PR3-ANCA, proteinase 3-anti-neutrophil cytoplasmic antibodies; HPF, High power field; HBs-Ag, hepatitis B virus surface antigen; HCV, hepatitis C virus; CMV, cytomegalovirus.

Fig. 1.

Chest radiography and computed tomography findings.

(A) Chest radiography findings.　There are infiltrative shadows in the bilateral lower lungs.　(B) Chest computed tomography imaging findings.　There is enhancement of interstitial shadows on the dorsal surfaces of both lungs.　

Fig. 2.

Bilateral hand radiography findings.

There is bony destruction in the bilateral wrist joints and subluxation of the metacarpophalangeal joint of the left thumb.

Fig. 3.

Magnetic resonance imaging findings.

Magnetic resonance imaging shows a high signal intensity on short tau inversion recovery in the bilateral thigh muscles, suggesting inflammation.　Coronal and horizontal images of the bilateral lower thighs are shown.

Fig. 4.

Clinical course of the 55-year-old female patient after diagnosis of idiopathic inflammatory myopathy.

The patient’s symptoms (muscle weakness and myalgia) gradually improved after administration of glucocorticoids and tacrolimus.　However, bilateral wrist arthralgia developed during the course of the disease.　After concomitant abatacept treatment, the arthralgia disappeared.

CK, creatine kinase; CRP, C-reactive protein; DAS, Disease Activity Score; IV, intravenous; mPSL, methylprednisolone; PSL, prednisolone; TAC, tacrolimus.

Discussion

ABT inhibits T-cell activation by binding to CD80/CD86 ligands on the surface of antigen-presenting cells and competing with CD28 expressed by T-cells.　In addition, ABT has important indirect effects on the inflammatory cascade, inhibiting cytokine and autoantibody production^10,11).　These mechanisms suggest that ABT may be effective for the treatment of RA as it inhibits T-lymphocyte costimulation^3,12).　

The mechanism underlying IIM development is not fully understood; however, several histopathological studies have suggested that IIM is a T-cell-mediated disease^13,14).　Therefore, ABT is also expected to be effective for the treatment of IIM.　Indeed, several case series and clinical trials have reported the efficacy of ABT for the treatment of IIM^4-6).　Tjärnlund et al. conducted a pilot study evaluating the efficacy of ABT in 20 patients with treatment-refractory IIM and reported that half of the patients showed a clinically meaningful and statistically significant improvement without serious side effects⁶⁾, suggesting that ABT can be effective and safe in this patient population.　

Few cases of concurrent RA and anti-Jo-1 antibody-positive myopathy have been reported in the literature^7,8).　In our case, RF and anti-CCP antibodies were both positive, and radiographic examinations of the hands revealed bony erosion consistent with RA¹⁵⁾.　Joint damage is generally less common with anti-Jo-1 antibody myopathy^16-18).　Furthermore, Matsushita et al. reported a higher prevalence of interstitial pneumonia in patients with RA and ARS antibodies¹⁹⁾, which is consistent with our clinical findings.　This patient had no muscle symptoms for a long period after the RA diagnosis, and the joint symptoms did not parallel the course of the myopathy.　Based on these findings, we concluded that the patient’s joint symptoms were related to RA.　Interstitial lung disease (ILD) is a relatively common complication of RA²⁰⁾, occurring in 2% to 8% of cases^21-24).　Many drugs commonly used in the treatment of RA have been associated with de novo and/or exacerbation of ILD²⁵⁾.　Furthermore, neither the ACR nor the EULAR guidelines^26,27) provide specific treatment recommendations for these patients.　However, in the British guideline²⁸⁾, ABT and rituximab, a chimeric monoclonal antibody that eliminates B-lymphocytes by binding to the lymphocyte antigen molecule CD20, are recommended as biological therapies in RA-ILD.　Several retrospective cohort studies showed that ABT is as effective as Janus kinase inhibitor for RA-ILD^29,30).　This patient developed IIM with ILD despite being on methotrexate and Janus kinase inhibitor combination therapy.　Therefore, ABT was selected as a potentially effective treatment for both IIM and RA-ILD, and the treatment was successful.

Effective treatments for patients with the rare combination of RA and IIM are unknown.　Despite the glucocorticoid dose reduction, the patient exhibited improvement in joint symptoms after initiation of ABT.　Moreover, there were no increases in her serum CK level or muscle weakness.　Therefore, ABT may be an effective agent for treatment of patients with RA and IIM, though long-term follow-up is necessary.　

In conclusion, we describe the case of a 55-year-old female with RA complicated by anti-Jo-1 antibody-positive myopathy who was successfully treated with ABT.　Thus, ABT may be an effective treatment option for patients with RA and IIM.　A larger study is needed to confirm the efficacy of ABT in this patient population.

Informed consent

Informed consent was obtained from the patient.　

References

• 1.   Kolarz K, Targońska-Stępniak B, Majdan M. [Early reumatoid arthritis]. Wiad Lek, 71:1061-1065, 2018.
• 2.   Fernández-Díaz C, Atienza-Mateo B, Castañeda S, et al. Abatacept in monotherapy vs combined in interstitial lung disease of rheumatoid arthritis-multicentre study of 263 Caucasian patients. Rheumatology (Oxford), 61:299-308, 2021.
• 3.   Ostör AJ. Abatacept: a T-cell co-stimulation modulator for the treatment of rheumatoid arthritis. Clin Rheumatol, 27:1343-1353, 2008.
• 4.   Çağlayan M, Işik H, Oktayoglu P. A Case of Refractory Polymyositis Successfully Treated With Abatacept Monotherapy. Arch Rheumatol, 35:618-622, 2020.
• 5.   Kerola AM, Kauppi MJ. Abatacept as a successful therapy for myositis—a case-based review. Clin Rheumatol, 34:609-612, 2015.
• 6.   Tjärnlund A, Tang Q, Wick C, et al. Abatacept in the treatment of adult dermatomyositis and polymyositis: a randomised, phase IIb treatment delayed-start trial. Ann Rheum Dis, 77:55-62, 2018.
• 7.   Mohammed MJ, Hashim HT, Al-Obaidi AD, Al Shammari A. A novel overlap syndrome: Rheumatoid arthritis, Sjogren’s syndrome, antiphospholipid syndrome, and dermatomyositis. Clin Case Rep, 11:e7274, 2023.
• 8.   Weerasinghe WS, Jayasinghe C. Overlapping rheumatoid arthritis and antisynthetase syndrome with secondary Sjögren’s syndrome: a case report and review of the literature. J Med Case Rep, 16:132, 2022.
• 9.   Lundberg IE, Tjärnlund A, Bottai M, et al. 2017 European League Against Rheumatism/American College of Rheumatology classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups. Ann Rheum Dis, 76:1955-1964, 2017.
• 10.   Hossen MM, Ma Y, Yin Z, et al. Current understanding of CTLA-4: from mechanism to autoimmune diseases. Front Immunol, 14:1198365, 2023.
• 11.   Rowshanravan B, Halliday N, Sansom DM. CTLA-4: a moving target in immunotherapy. Blood, 131:58-67, 2018.
• 12.   Kremer JM, Westhovens R, Leon M, et al. Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N Engl J Med, 349:1907-1915, 2003.
• 13.   Venalis P, Lundberg IE. Immune mechanisms in polymyositis and dermatomyositis and potential targets for therapy. Rheumatology (Oxford), 53:397-405, 2014.
• 14.   Zong M, Lundberg IE. Pathogenesis, classification and treatment of inflammatory myopathies. Nat Rev Rheumatol, 7:297-306, 2011.
• 15.   Schett G, Gravallese E. Bone erosion in rheumatoid arthritis: mechanisms, diagnosis and treatment. Nat Rev Rheumatol, 8:656-664, 2012.
• 16.   Oddis CV, Medsger TA, Jr., Cooperstein LA. A subluxing arthropathy associated with the anti-Jo-1 antibody in polymyositis/dermatomyositis. Arthritis Rheum, 33:1640-1645, 1990.
• 17.   Meyer O, Charlanne H, Cherin P, et al. Subluxing arthropathy: an unusual manifestation of the antisynthetase syndrome. Ann Rheum Dis, 68:152-153, 2009.
• 18.   Mumm GE, McKown KM, Bell CL. Antisynthetase syndrome presenting as rheumatoid-like polyarthritis. J Clin Rheumatol, 16:307-312, 2010.
• 19.   Matsushita M, Tamura N, Ogasawara M, Tada K, Yamaji K, Takasaki Y. The Association of Anti-Aminoacyl-Transfer Ribonucleic Acid Synthetase Antibodies in Patients With Rheumatoid Arthritis and Interstitial Lung Disease. Arch Rheumatol, 33:26-32, 2018.
• 20.   Kelly CA, Saravanan V, Nisar M, et al. Rheumatoid arthritis-related interstitial lung disease: associations, prognostic factors and physiological and radiological characteristics—a large multicentre UK study. Rheumatology (Oxford), 53:1676-1682, 2014.
• 21.   Kiely P, Busby AD, Nikiphorou E, et al. Is incident rheumatoid arthritis interstitial lung disease associated with methotrexate treatment? Results from a multivariate analysis in the ERAS and ERAN inception cohorts. BMJ Open, 9:e028466, 2019.
• 22.   Raimundo K, Solomon JJ, Olson AL, et al. Rheumatoid Arthritis-Interstitial Lung Disease in the United States: Prevalence, Incidence, and Healthcare Costs and Mortality. J Rheumatol, 46:360-369, 2019.
• 23.   Hyldgaard C, Hilberg O, Pedersen AB, et al. A population-based cohort study of rheumatoid arthritis-associated interstitial lung disease: comorbidity and mortality. Ann Rheum Dis, 76:1700-1706, 2017.
• 24.   Restrepo JF, del Rincón I, Battafarano DF, Haas RW, Doria M, Escalante A. Clinical and laboratory factors associated with interstitial lung disease in rheumatoid arthritis. Clin Rheumatol, 34:1529-1536, 2015.
• 25.   Roubille C, Haraoui B. Interstitial lung diseases induced or exacerbated by DMARDS and biologic agents in rheumatoid arthritis: a systematic literature review. Semin Arthritis Rheum, 43:613-626, 2014.
• 26.   Smolen JS, Landew RBM, Bijlsma JWJ, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis, 79:685-699, 2020.
• 27.   Singh JA, Saag KG, Bridges SL, Jr., et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Rheumatol, 68:1-26, 2016.
• 28.   Holroyd CR, Seth R, Bukhari M, et al. The British Society for Rheumatology biologic DMARD safety guidelines in inflammatory arthritis. Rheumatology (Oxford), 58:e3-e42, 2019.
• 29.   Tardella M, Di Carlo M, Carotti M, Ceccarelli L, Giovagnoni A, Salaffi F. A retrospective study of the efficacy of JAK inhibitors or abatacept on rheumatoid arthritis-interstitial lung disease. Inflammopharmacology, 30:705-712, 2022.
• 30.   Tsujii A, Isoda K, Yoshimura M, et al. Janus kinase inhibitors vs. abatacept about safety and efficacy for patients with rheumatoid arthritis-associated interstitial lung disease: a retrospective nested case-control study. BMC Rheumatol, 8:4, 2024.