Although this kind of overlap syndrome is rare, don't get lucky!

*Only for medical professionals to read and reference, come and learn, don’t panic when you encounter it! Rheumatology and immunology doctors can always practice their skills in the daily diagnosis and treatment of intractable diseases
.

They are like Sherlock Holmes, who constantly shed their cocoons in the misty cases, seek the truth in clues, and use their solid knowledge and rich clinical experience to solve problems for all kinds of patients
.

However, there are still too many unknowns in the field of rheumatic immune diseases, and the more we see and learn, the more unknowns we have.
We also need to continue to learn and recharge
.

In this issue, we will focus on a very rare disease-Rhupus syndrome
.

Is this name a bit strange? It is actually caused by the overlap of our common rheumatism-rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE)
.

Professor Cui Yang from Guangdong Provincial People's Hospital will share a diagnosis and treatment case of Rhupus syndrome for us.
The opportunity is precious, come and learn together! Basic information of the case data: female, 42 years old
.

Main complaint: Repeated symmetrical polyarticular swelling and pain and facial erythema for 5 years
.

History of present illness: 5 years ago, the patient had symmetrical polyarticular swelling and pain with no obvious cause, involving bilateral metacarpophalangeal joints (MCP), proximal interphalangeal joints (PIP), shoulder joints and knee joints, accompanied by morning stiffness, and facial erythema , Light allergy
.

In early 2016, he was admitted to our hospital
.

Past history: history of hyperthyroidism, taking levothyroxine sodium after turning to hypothyroidism 6 years ago
.

Personal history, history of marriage and childbirth, history of menstruation, history of marriage and childbirth, and family history are not special
.

Physical examination: butterfly erythema on face, 2nd, 3rd, 4th MCP and 2nd and 3rd PIP of both hands, shoulder and knee joint tenderness and swelling (S++, T++); lungs with clear breath sounds, constant heart rate, no edema in both lower limbs, The superficial lymph nodes are not palpable and swollen
.

Auxiliary examination: rheumatoid factor (RF) 544 IU/ml ↑, anti-cyclic citrullinated peptide (CCP) antibody 171.
8 RU/ml ↑, glucose-6-phosphate isomerase (GPI) 0.
58 mg/L ↑, erythrocyte sedimentation Rate (ESR) 78mm/h ↑; anti-nuclear antibody ANA 1:1000+ (homogeneous type), anti-ds-DNA 71.
71 IU/ml ↑, anti-cardiolipin antibody IgG (ACA-IgG) positive, anti-SSA/Ro60 and Anti-U1-nRNP positive; complement C3 980mg/L, complement C4 111mg/L ↓
.

Hand MR prompts: changes in synovitis of wrist, second and third metacarpophalangeal joints, and a little effusion
.

Diagnosis: Rhupus syndrome (RA overlapping SLE, see Table 1 for diagnosis basis and disease evaluation)
.

Table 1: Diagnosis details and condition assessment of this patient ACR: American Academy of Rheumatology; EULAR: European Society for Antirheumatic Diseases; DAS28: 28 joint disease activity, common methods for assessing disease activity in RA patients; SLEDAI: systemic erythema Lupus disease activity score; treatment process and effect: 1.
Prednisone 50 mg qd + hydroxychloroquine (HCQ) 200 mg bid + methotrexate (MTX) 15 mg qw.
During regular follow-up, the prednisone dose is regularly reduced and the treatment is maintained for 6 months After the patient’s symptoms were relieved, the DAS28 score decreased to 3.
2 points, and the SLEDAI score decreased to 4 points; 2.
In May 2020, the patient’s symptoms recurred, manifested as arthritis and rash recurrence, and fluoride (LEF) 20 mg qd was added After half a year of treatment, the condition did not alleviate; 3.
In October 2020, he switched to abatacept 150 mg qw.
After half a year of treatment, the DAS28 score and SLEDAI score decreased significantly, the anti-CCP antibody and RF titers decreased, and the patient’s symptoms basically disappeared (Table 2)
.

Table 2: Auxiliary examination results and disease activity scores of patients before and after the use of abatacept.
Experts comment that overlap syndrome is a very complex and difficult group of diseases in the clinic.
Patients have two or more connective tissue diseases (CTD) at the same time.
Clinical manifestations, difficult to diagnose and difficult to treat
.

Common overlapping diseases include various combinations of SLE, RA, idiopathic inflammatory myositis (IIM), systemic sclerosis (SSc) and Sjogren’s syndrome (SS) [1]
.

The overlap of RA and SLE, also known as Rhupus syndrome, is a rare overlap syndrome in clinical practice, and lacks uniform and effective classification standards, follow-up and treatment strategies
.

From a single disease point of view, RA is an autoimmune disease with erosive arthritis as the main clinical manifestation.
Joint involvement is obvious and the disability rate is high; while SLE is characterized by systemic multiple organ damage, skin and joints.
Even important organs (such as kidneys and heart) will be severely affected
.

When the two diseases overlap, the clinical manifestations are mainly erosive arthritis, and generally tend to follow the pattern of RA progression, while SLE-related manifestations are usually mild, mainly hematological abnormalities and skin and kidney involvement [2 ]
.

From the point of view of pathogenic mechanism, SLE and RA are fundamentally different
.

For example, RA is mainly related to Th1 immune response, while SLE is mainly related to Th2 immune response
.

At present, studies have begun to explore this, trying to explain how overlap occurs from different perspectives, such as common genetic background, T cell polarization related to immune aging, and hormonal factors [2]
.

In addition to clinical manifestations, the biological characteristics of Rhupus syndrome are also different from single diseases
.

Compared with SLE patients with only non-erosive arthritis, patients with Rhupus syndrome have more significant increases in CRP and ESR levels, and higher positive rates and titer of RF and anti-CCP antibodies, while there is no significant increase compared with RA patients Differences or reductions; in terms of SLE-related biomarkers, patients with Rhupus syndrome are positive for ANAs and anti-ds-DNA antibodies, and the positive rate is similar to that of SLE patients, while the positive rate of anti-ds-DNA antibodies for RA patients Lower [2]
.

The clinical manifestations of this patient not only met the RA diagnostic criteria established by ACR/EULAR in 2009, but also met the SLE diagnostic criteria updated by ACR/EULAR in 2019 [3-4]
.

Not only has high titers of RF and anti-CCP antibodies, but ANA and anti-ds-DNA antibodies are also positive, and the level of complement is decreased.
After diagnosis, RA and SLE overlap
.

Among them, RA disease activity is severe, and SLE disease activity is assessed as moderate
.

How should we treat such rare cases in clinical practice? How to balance the two diseases? Hormones and disease-improving anti-rheumatic drugs (DMARDs), such as MTX, sulfasalazine, azathioprine and LEF, are commonly used drugs to relieve arthritis and joint damage in clinical practice
.

In general, the treatment of hormones, HCQ combined with other DMARDs has a certain effect on RA and SLE, and can be tried in the clinic to treat Rhupus syndrome
.

With the popularity of biological agents in the field of rheumatic immune diseases, many researchers have turned their attention to these new drugs, trying to find biological agents that can effectively treat Rhupus syndrome
.

Abatacept is a CTLA4-Fc fusion protein that inhibits T cell activation by regulating T cell costimulatory signals
.

At present, abatacept is mainly used in the treatment of RA, and it has been proven to effectively reduce the patient's disease activity and slow the progression of joint damage
.

Its efficacy studies on SLE patients are relatively limited, and existing studies have proved that Abatacept can relieve the musculoskeletal symptoms of SLE patients [5]
.

In 2018, the SLE treatment guidelines issued by the Latin American Lupus Research Group and the Pan American Anti-Rheumatic Alliance (GLADEL-PANLAR) pointed out that for SLE patients with musculoskeletal symptoms, abatacept can be added to the conventional therapy (Figure 1) [ 6]
.

Figure 1: Recommendations for the treatment of SLE issued by the GLADEL-PANLAR guidelines in 2018 ABT: Abatacept, SOC: conventional treatments, such as hormones (GCs), antimalarials (AMs), IS: a retrospective study of immunosuppressants Six patients with Rhupus syndrome (all with refractory arthritis and non-life-threatening organ damage) were enrolled, and their condition was not effectively relieved under the treatment of traditional DMARDs such as MTX, tacrolimus and cyclosporine
.

After 12 weeks of treatment with abatacept, the RA-related clinical disease activity index (CDAI) and SLE disease activity score (SLEDAI) were significantly decreased (P values ​​were 0.
028 and 0.
039, respectively), and were maintained until the 24th week
.

In addition, the patient's health assessment questionnaire-disability index (HAQ-DI), CRP and anti-ds-DNA antibody levels were significantly improved from baseline at 24 weeks, and all patients achieved a good or moderate EULAR response (Figure 2) [7]
.

This suggests that abatacept may be effective in the treatment of patients with Rhupus syndrome and has a certain inhibitory effect on the production of autoantibodies
.

 Figure 2: Changes in clinical indicators and laboratory tests of each enrolled patient after receiving abatacept treatment (*P<0.
05).
Therefore, in the treatment exploration of this patient, we used conventional therapies-hormones, HCQ, In the case of poor response to traditional immunosuppressive therapy, abatacept was switched to treatment and achieved good results: the disease activity of RA and SLE were significantly reduced-the disease activity of RA was reduced from the severity before treatment (DAS28: 5.
5 ) Decreased to mild (2.
9), while SLE disease activity decreased from moderate (SLEDAI: 10) to almost no activity (2), autoantibodies such as anti-CCP antibodies, RF, ANA, and anti-ds-DNA antibodies decreased.
Symptoms such as joint swelling and pain and facial erythema were relieved significantly
.

This is a positive and beneficial exploration of the biological treatment of Rhupus syndrome
.

Expert Profile Professor Cui Yang, Chief Physician and Professor of Department of Rheumatology, Guangdong Provincial People's Hospital Member of the Academic Group, Standing Member of the Second Rheumatology Committee of the Cross-Strait Medical and Health Exchange Association.
Deputy Chairman of the Committee Academic Committee Member of National Drug Clinical Trial Institution of Guangdong Provincial People's Hospital Once served as the young and middle-aged member of the Chinese Medical Association Rheumatology Branch presided over and undertook 8 national and provincial topics, published nearly 30 papers, participated in the compilation of national textbooks and translated books References of "Rheumatology", "Kelly's Rheumatology", "Infection and Immune Diseases" (Associate Editor)[1].
Iaccarino L, Gatto M, Bettio S, et al.
Overlap connective tissue disease syndrome[J].
Autoimmun Rev.
2013, 12(3):363-73.
[2].
Antonini L, Le Mauff B, Marcelli C, et al.
Rhupus: a systematic literature review[J].
Autoimmun Rev.
2020, 19(9) :102612.
[3].
Aletaha D, Neogi T, Silman AJ, et al.
2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative[J].
Arthritis Rheum.
2010, 62(9) :2569-81.
[4].
Aringer M, Costenbader K, Daikh D, et al.
2019 European League Against Rheumatism/American College of Rheumatology Classification Criteria for Systemic Lupus Erythematosus[J].
Arthritis Rheumatol.
2019, 71(9):1400-1412.
[5].
Merrill JT, Burgos-Vargas R, Westhovens R, et al.
The efficacy and safety of abatacept in patients with non-life-threatening manifestations of systemic lupus erythematosus: results of a twelve-month, multicenter, exploratory, phase IIb, randomized, double-blind, placebo-controlled trial[J].
Arthritis Rheum.
2010, 62:3077–87.
[6].
Pons-Estel BA, Bonfa E, Soriano ER, et al.
First Latin American clinical practice guidelines for the treatment of systemic lupus erythematosus: Latin American Group for the Study of Lupus (GLADEL, Grupo Latino Americano de Estudio del Lupus)-Pan-American League of Associations of Rheumatology (PANLAR)[J].
Ann Rheum Dis.
2018, 77(11):1549-1557.
[7].
Ikeda K, Sanayama Y, Makita S, et al.
Efficacy of abatacept for arthritis in patients with an overlap syndrome between rheumatoid arthritis and systemic lupus erythematosus[J].
Clin Dev Immunol.
2013, 2013:697525.
*This This article is only used to provide scientific information to medical and health professionals, and does not represent the platform's position
.