Anti-citrullinated Protein Antibody-positive Arthralgia Associated with an L110P-E148Q Double Heterozygote: A Case-based Review

Abstract

A 42-year-old woman with positive anti-citrullinated protein antibody (ACPA) and rheumatoid factor (RF) levels exhibited arthralgia, but she did not fulfill the criteria for rheumatoid arthritis (RA). Subsequently, the patient exhibited episodic monoarthritis with a remarkable response to colchicine. An analysis of the MEFV gene identified heterozygous variants, L110P and E148Q, thus indicating a colchicine-responsive autoinflammatory condition. The patient was later diagnosed with RA and achieved remission with abatacept and colchicine. This case illustrates that ACPA-positive arthralgia evolves into RA through an autoinflammatory mechanism, thereby underscoring the diagnostic difficulties arising from the convergence of both autoimmune and autoinflammatory characteristics.

Introduction

Autoinflammatory disorders, such as familial Mediterranean fever (FMF), are defined by recurring fever episodes lasting up to three days, accompanied by abdominal pain, chest pain, arthritis, and erysipelas-like erythema, typically observed in the lower extremities. These diseases are distinct from autoimmune disorders, such as rheumatoid arthritis (RA) and infectious diseases (1). FMF is a monogenic autoinflammatory disorder resulting from autosomal recessive variants of the MEFV gene, which encodes pyrin, leading to exacerbated inflammation through the activation of the inflammasome and increased production of interleukin (IL)-1β (1,2). While FMF may coexist with rheumatic disorders, the occurrence of FMF alongside positive anti-cyclic citrullinated peptide antibodies (ACPA), which are specific to RA, is uncommon (3,4). Previous research has described several FMF patients with arthritis exhibiting positive results for ACPA, but all individuals tested negative for rheumatoid factor (RF) (5). We present a complex case of a patient diagnosed with ACPA- and RF-positive arthritis who initially did not meet the criteria for RA, but was ultimately diagnosed with RA after experiencing episodes of periodic monoarthritis and showing MEFV gene variants.

Case Report

A 42-year-old woman presented to a local rheumatology clinic complaining of pain in the left wrist, both elbows, both knees, and both Achilles tendons (one year before the initial visit to our hospital). Swelling and tenderness were noted over the entire right index finger and around the Achilles tendon; however, no localized swelling in the joint was evident. Laboratory findings at that time were: ACPA 776.1 U/mL (reference range ＜4.5 U/mL), RF 169 IU/mL (reference range ≤15 IU/mL), C-reactive protein (CRP) ＜0.05 mg/dL (reference range ≤0.30 mg/dL), and erythrocyte sedimentation rate (ESR) 2 mm/h. Under a provisional diagnosis of ACPA-positive arthralgia or spondyloarthritis, nonsteroidal anti-inflammatory drugs (NSAIDs) were administered for two months but proved to be ineffective. The clinic then empirically prescribed 1,000 mg/day of sulfasalazine, which relieved the symptoms; however, the patient requested further examination and was thus referred to our hospital.

At the initial visit (Day 1), the patient complained of pain in both finger joints and Achilles tendons, none of which showed either any apparent swelling or tenderness. Ultrasonography did not reveal any thickening of the synovium, increased blood flow signals in the finger joints, or increased blood flow signals around the Achilles tendon. Table 1 presents test data collected during the first visit to our hospital. No notable new findings were detected except for elevated RF levels and marginally reduced complement levels. At the initial visit, although the patient exhibited elevated levels of ACPA and RF, they did not fulfill the 2010 American College of Rheumatology/European Alliance of Associations for Rheumatology diagnostic criteria for RA, as there was an absence of clinically evident synovitis based on both the physical examination and ultrasound findings. Her human leukocyte antigen types were A2/A24(9) and B7/B62(15). Chest computed tomography revealed no significant findings, including interstitial pneumonia or hilar adenopathy. The patient had no notable family history of autoimmune or inflammatory disorders. The patient was diagnosed with ACPA-positive arthralgia. Treatment with sulfasalazine was continued, and mild pain in the joints and Achilles tendons fluctuated between improvement and exacerbation.

Table 1.

Laboratory Findings.

Peripheral blood			Reference range	Serological tests			Reference range
Red blood cells	5.18×1012	/L	3.86-4.92	C-reactive protein	0.01	mg/dL	<0.14
Hemoglobin	14.3	g/dL	11.6-14.8	Erythrocyte sedimentation rate	1	mm/h	3-15
Hematocrit	45.4	%	35.1-44.4	IgG	1,069	mg/dL	820-1,740
White blood cells	4.1×109	/L	3.3-8.6	IgA	108	mg/dL	90-400
Neutrophils	63.6	%	38.3-71.7	IgM	87	mg/dL	52-270
Eosinophils	2.9	%	0.2-7.3	CH50	26	U/mL	30-45
Basophils	0.5	%	0.2-2.0	Anti-nuclear antibodies	<×40		<40
Monocytes	7.8	%	2.7-7.6	ACPA	776.1	U/mL	<4.5
Lymphocytes	25.2	%	21.3-50.2	Rheumatoid factor	112	IU/mL	<15
Platelets	189×109	/L	158-348	Anti-SSA antibodies	<1.0	U/mL	<10.0
Blood chemistry				Anti-SSB antibodies	<1.0	U/mL	<10.0
Total protein	6.1	g/dL	6.5-8.2	Anti-smooth muscle antibodies	<×20		<20
Total bilirubin	0.4	mg/dL	0.4-1.5	Matrix metalloproteinase-3	46.3	mg/mL	17.3-59.7
Aspartate aminotransferase	19	U/L	13-30	Urinalysis
Alanine aminotransferase	10	U/L	7-23	pH	7.0		4.5-7.5
Lactate dehydrogenase	142	U/L	124-222	Protein	Negative		Negative
Alkaline phosphatase	42	U/L	38-113	Glucose	Negative		Negative
Gamma-glutamyl transpeptidase	9	U/L	9-32	Occult blood	Negative		Negative
Creatine kinase	73	U/L	41-153	White blood cells	<1	/HPF
Total cholesterol	195	mg/dL	142-248	Red blood cells	<1	/HPF
Blood urea nitrogen	12.2	mg/dL	8.0-20.0
Creatinine	0.59	mg/dL	0.46-0.79

Anti-SSA antibodies: anti-Sjögren’s syndrome type A antibodies, Anti-SSB antibodies: anti-Sjögren’s syndrome type B antibodies, ACPA: anti-cyclic citrullinated peptide antibodies, CH50: 50% hemolytic complement activity, Ig: immunoglobulin

Two years after the initial visit (Day 674), the patient complained of bilateral coxalgia, and ultrasonography revealed synovial thickening and joint effusion in the same areas. We then started methotrexate 8 mg/week in combination with folic acid. Since the start of the new treatment, both the joint and Achilles tendon pain have markedly improved. However, on Day 745, drug-induced liver injury was identified (alanine aminotransferase level, 66 U/L; aspartate aminotransferase level, 138 U/L). The dosage of methotrexate had to be adjusted to a range of 4-6 mg/week.

Around Day 940, the patient developed periodic severe monoarticular pain accompanied by sudden swelling and heat that she had not experienced previously. The pain was not localized, arose in the shoulder, knee, or ankle, and disappeared within 1 or 2 days. Colchicine (1 mg/day) was administered for diagnostic and therapeutic purposes for these newly occurring, periodic episodes of severe monoarticular pain, which had lasted 1-2 days before resolving spontaneously. Colchicine has shown significant efficacy; following its initiation, these acute attacks resolved and no longer recur. This therapeutic response pertained specifically to these acute autoinflammatory flares and did not inhibit the onset of the persistent polyarthritis characteristics of RA. An analysis of MEFV identified heterozygous variants at L110P and E148Q. Therefore, we added and maintained colchicine at 1 mg/day as regular oral therapy.

Around Day 1,050, the patient manifested enduring symmetrical polyarthritis of the fingers, wrists, and shoulders. Swelling was confirmed in eight joints (bilateral proximal interphalangeal, metacarpophalangeal (MP), and metatarsophalangeal joints), and tenderness was noted in 10 joints. Despite the absence of official calculations for disease activity scores, such as the simplified disease activity index/clinical disease activity index, these findings, along with her elevated levels of ACPA and RF, now fulfilled the 2010 ACR/EULAR categorization criteria for RA for the first time in her clinical course (6). No apparent erosion of the bones was noted on the hand and foot X-rays conducted at the time of RA diagnosis. On Day 1,102, ultrasonography of the right MP joints revealed synovial thickening, although without joint effusion or power Doppler signals (Figure A). A subsequent MRI evaluation of the hand confirmed bone erosion at the distal end of the right third metacarpal bone on T2*-weighted images (Figure B). The intravenous infusion of abatacept and a short course of prednisolone were added to colchicine treatment. By Day 1,158, pain in all joints had resolved, joint swelling was no longer present, and the administration of corticosteroids was discontinued.

Figure.

Imaging findings of the hand on Day 1,102. (A) Ultrasound of the right metacarpophalangeal (MP) joints showing synovial thickening (arrowhead), but no joint effusion or power Doppler signals. (B) T2*-weighted magnetic resonance imaging (MRI) of the right hand, indicating bone erosion at the distal end of the third metacarpal bone (arrow).

Search strategy

We performed a thorough search of PubMed and Ichushi Web for studies published until May 27, 2025. The search technique employed combinations of the following terms: (“Familial Mediterranean Fever”) AND (“anti-cyclic citrullinated peptide antibody” OR “anti-CCP”). Language constraints were not imposed on the dataset. We incorporated case reports, case series, and original articles documenting patients diagnosed with both FMF and ACPA-positive. Conference abstracts, editorials, and review articles that lacked original case data were excluded (Supplementary material). Two authors independently evaluated the titles and abstracts, and subsequently retrieved pertinent full-text papers. References of the included articles were manually examined for pertinent supplementary publications. A PRISMA-style flowchart was not created because of the nature of this case-based review; nonetheless, the selection process is detailed in the Discussion section.

Discussion

We obtained nine articles via PubMed, three from Ichushi Web, and two through reference searches. Following the elimination of one duplicate document, one conference abstract, one review article, and three unrelated documents, we selected eight articles, comprising five case-control studies and three case reports. The data from the retrieved articles are summarized in Table 2 (4,5,7-12).

Table 2.

Literature Review of Familial Mediterranean Fever Patients with Anti-cyclic Citrullinated Peptides Antibodies.

Reference	Country	Number of patients (n)	Age (years)	Sex (M/F)	WBC (×103/mm3)	ESR (mm/h)	CRP (mg/dL)	RF levels (IU/mL)	ACPA levels (U/mL)	ACPA positivity rate (%)	Arthritis (%)	Other concomitant manifestations	Gene mutation
(7)	Turkey	83	30.6±10.7	30/53	7.9±2.4	18.1±16.4	NA	2.1±12.7	14.8±21.1	14.4 (>20 U/mL)	44.6	Abdominal pain: 81.9% Pleuritis: 19.3%	Positivity rate: 92.8% (homozygous 31.1%, heterozygous 68.9%)
(8)	Turkey	49	26.9±6.2	24/25	NA	11.9±7.1	0.6±0.3	10.0±1.3	NA	0 (>25 U/mL)	46.9	NA	NA
(9)	Turkey	1	48	F	NA	71.0	3.0	412.0	NA	100 (Cut off value: NA)	100	Fever, abdominal pain	M694V homozygous
(5)	Turkey	55	33.6±13.5	22/33	7.7±2.1	15.5±15.1	0.6±0.5	8.9±0.8	10.4±14.0	14.5 (>20 U/mL)	36.4	NA	NA
(10)	Turkey	50	31.5 (range: 18-62)	12/38	NA	11 (range: 2-50)	0.4 (range: 0.1-6.4)	NA (positivity rate: 4%, >20 IU/mL)	NA	0 (>12 U/mL)	56.0	Fever: 88% Abdominal pain: 98% Chest pain: 56% Arthralgia: 86% Amyloidosis: 6%	NA
(11)	Turkey	126	11.0±4.0	60/66	NA	20.0±15.0	3.0±12.8	NA	0.97 (IQR: 0.70-1.39)	0 (>20 U/mL)	41.3	Fever: 78.6% Abdominal pain: 73.8% Arthralgia: 41.3%	Positivity rate: 87.3% (M694V homozygous 23.6%, M694V heterozygous 34.5%, other 41.9%)
(12)	Japan	1	51	F	9.2	54.0	0.5	120.0	1,720.0	100 (>4.5 U/mL)	100	Fever	Heterozygous mutations (E148Q/G304R/P369S/R408Q)
(4)	Japan	1	42	F	NA	NA	0.4	64.0	11.2	100 (Cut off value: NA)	100	No fever	R304R homozygous
This case	Japan	1	42	F	4.1	1.0	<0.1	112.0	776.1	100 (>4.5 U/mL)	0	No fever	Heterozygous mutations (E148Q/L110P)

Note: Age, WBC, ESR, CRP, RF levels, and ACPA levels are given as mean±SD. Other values are given as median (range) or median (IQR).

ACPA: anti-cyclic citrullinated peptide antibodies, CRP: C-reactive protein, ESR: erythrocyte sedimentation rate, F: female, IQR: interquartile range, M: male, NA: not available, RF: rheumatoid factor, SD: standard definition, WBC: white blood cell

The case reports detailed three instances of FMF and RA, characterized by elevated RF levels and positive ACPA. These patients fulfilled the diagnostic criteria for RA (4,9,12). In our case, despite elevated ACPA and RF levels, no indications of arthritis were noted, thus leading to a diagnosis of ACPA-positive arthralgia in the patient. The symptoms improved slightly with sulfasalazine treatment, but the patient's pain improved significantly with the transition to methotrexate. During treatment, new, previously unobserved, episodic, and severe monoarthritis emerged. Colchicine proved particularly effective for these exacerbations, and a genetic analysis revealed variants of the MEFV gene. Subsequently, edema and pain developed in various joints, resulting in a definitive diagnosis of RA (6). Alongside colchicine therapy, treatment with the biological agent abatacept was initiated, leading to the elimination of joint symptoms and remission. This case exemplifies a complicated course of illness marked by the simultaneous presence of autoimmune and autoinflammatory disorders along with gradual advances in both the diagnosis and therapy. We selected abatacept, a T-cell co-stimulation modulator, for the treatment of RA. Owing to the intricate interaction of autoinflammatory and autoimmune characteristics, together with the pivotal function of T-cells in the pathology of RA, abatacept was deemed an appropriate choice. It was selected instead of tumor necrosis factor (TNF) or IL-6 inhibitors to avoid potential paradoxical effects occasionally documented in autoinflammatory situations; however, evidence for this is limited (13). Recent studies have documented paradoxical inflammatory or autoimmune reactions during TNF-α or IL-6 inhibition, such as psoriasis-like lesions or granulomatous inflammation, even in autoinflammatory disorders such as FMF and Behçet's disease (14,15). These reactions are thought to stem from dysregulated type I interferon and inflammasome activation, potentially intensifying autoinflammatory predispositions. Furthermore, TNF-α and IL-6 inhibitors have demonstrated inconsistent efficacy in FMF, although IL-1 inhibition is recognized as the best-validated biological intervention (13,16-18). Based on these findings, abatacept was deemed a safer and mechanistically unique alternative for addressing T-cell co-stimulation and adaptive immunological activation, whereas colchicine was retained for the management of the autoinflammatory aspect.

The episodic characteristics of monoarthritis may indicate a diagnosis of palindromic rheumatism, frequently regarded as a precursor to rheumatoid arthritis. The pronounced and constant reaction of these particular episodes to colchicine, together with the existence of MEFV variants, prompted us to contemplate a concurrent autoinflammatory process linked to the identified MEFV variants rather than solely palindromic rheumatism. This underscores the diagnostic difficulty in distinguishing these episodic arthritides, particularly in ACPA-positive individuals. Alternative etiologies of acute monoarthritis, including crystal-induced arthritis, were evaluated. Despite the absence of a synovial fluid analysis, the migratory pattern of arthritis, the lack of characteristic radiographic evidence for chondrocalcinosis, and the swift response to colchicine instead of NSAIDs rendered crystal-induced arthritis in this case as improbable.

A case-control study revealed a significant incidence of ACPA and elevated antibody titers among FMF subjects with arthritis (5). On the other hand, several other studies have reported no ACPA in any case and no differences in antibody levels between control groups and patients, irrespective of the presence of arthritis (8,10,11). However, in studies that included cases with positive ACPA, the overall positivity rate was only approximately 14%, indicating that ACPA is uncommon in FMF (5,7). Studies detailing these cases were conducted in Turkey, and evidence regarding the prevalence of ACPA in FMF in Japan is lacking. FMF has been documented to coexist with other rheumatic disorders (3), and previous studies have indicated the potential coexistence of FMF and RA (4,9,12). Nonetheless, in the present instance, despite the initially elevated levels of RF and ACPA, no indications of arthritis were detected throughout the follow-up period. This unusual progression poses a problem for clinical assessment. In our case, colchicine was administered as a rescue therapy for pain and proved to be highly effective, leading us to conduct a MEFV gene analysis and identify heterozygous variants at L110P and E148Q. The diagnosis of FMF was deemed to fulfill the minor criteria of the Tel-Hashomer criteria established by Livneh et al. (19) and the diagnostic criteria of the Eurofever/PRINTO criteria (20), which encompass genetic abnormalities. According to the Tel-Hashomer criteria, our patient was categorized as having an “incomplete attack” phenotype. The patient met one minor criterion: recurrent monoarthritis that was responsive to colchicine. The attacks were deemed to be “incomplete” due to their afebrile nature and short duration (1-2 days). The patient satisfied the Eurofever/PRINTO requirements owing to the presence of a suitable MEFV gene variant in conjunction with colchicine effectiveness and a short attack duration.

The E148Q variant in exon 2 is the predominant variant of unknown significance (VUS), and recent guidelines have indicated that heterozygous E148Q variants do not support a diagnosis of FMF (1). In contrast, L110P is a variant located in exon 2 which has been identified in both Turkish and Spanish patients with FMF (21). A surveillance study of FMF gene variants in Japanese patients revealed that E148Q-L110P variants were present in 5.6% of the subjects (22). Concerning the E148Q-L110P gene variants and their clinical manifestations, 50% of patients with FMF possessing these variants exhibited either no fever or only slight fever. Moreover, only 16.7% of the patients exhibit arthritis (23). A study examining the characteristics of FMF patients with multiple VUS variants revealed that, in contrast to patients with a single VUS variant, those with multiple VUS variants exhibited markedly lower responsiveness to colchicine treatment (88.9% vs. 96.7%; p=0.037). Furthermore, the presence of multiple VUS variants was significantly and independently correlated with colchicine resistance (odds ratio, 4.42; 95% confidence interval 1.08-18.1; p=0.038) (24). This study indicated a statistical tendency; however, not all people with multiple VUSs exhibited colchicine resistance. The favorable response in our patient, whose phenotype was defined by afebrile transient monoarthritis, may be ascribed to her specific L110P-E148Q genotype, which may not present the same resistance risk as other VUSs. Migita et al. categorized FMF into typical and atypical types according to the Tel-Hashomer criteria. Typical FMF patients display episodes of common symptoms, such as peritonitis, pleuritis, monoarticular arthritis, or fever, as defined by the Tel-Hashomer criteria. In contrast, atypical FMF patients show “incomplete” attacks. An episode is considered to be incomplete if it differs from the definition of a typical episode in one or two of the following characteristics: body temperature below 38°C; episode duration either shorter than 12 hours or longer than 3 days, but not shorter than 6 hours or exceeding one week; absence of peritonitis signs during abdominal episodes or localized signs; or atypical distribution of arthritis (25). Table 3 shows the characteristics of typical and atypical FMF (19,25). The classification of this case as having an “atypical” phenotype, as delineated by these criteria, was predicated on these characteristics, with the symptoms of the episodes (afebrile, short-duration monoarthritis) also deemed to be atypical in comparison to classic FMF presentations. Although several studies have indicated that the E148Q-L110P genotype may correlate with a milder phenotype, including the absence of fever (23), the pathogenic implications of these variants, especially E148Q, are still controversial. Therefore, these genetic findings must be regarded with caution as possible factors contributing to an autoinflammatory tendency rather than as primary causes.

Table 3.

Comparison of Typical and Atypical Cases of FMF.

		Typical FMF	Atypical FMF
Fever	Duration	12-72 h	Within a few hours or lasting more than 4 days
	Temperature	≥38°C	Sometimes <38°C
Serositis		Non-localized	Localized
		Common	Less common
Arthritis		Monoarthritis	Polyarthritis
Myalgia (ratio)		Low	High
MEFV mutations		exon 10 (M694I)	exon 1 (E84K)
			exon 2 (E148Q, E148Q-L110P)
			exon 3 (P369S-R408Q)
			exon 5 (S503C)

FMF: familial Mediterranean fever

RA and FMF are categorized as autoimmune and autoinflammatory diseases, respectively, but they share a common underlying mechanism characterized by aberrant activation of the innate immune system via the inflammasome. In both conditions, the overproduction of IL-1β through the activation of Nod-like receptor protein 3 (NLRP3) or pyrin inflammasome is an important factor contributing to pathophysiology (26). The NLRP3 activation pathway induced by ACPA in RA (involving integrin, Panx-1, and two-pore domain weak inwardly rectifying K⁺ channel 2) and the regulatory mechanism of the pyrin inflammasome in FMF share the characteristic that the cytoskeleton (microtubules) and ion channels are crucial for signal transduction (27). Colchicine, an FMF medication, inhibits the pyroptosis inflammasome through RhoA signaling, highlighting the critical role of cytoskeletal dynamics in regulating inflammasome activity. The signal transduction of ACPA in RA is mediated by integrin, a cell adhesion protein, and is associated with cytoskeletal remodeling, suggesting the potential presence of analogous mechanisms in the signal transduction pathways of both diseases (27,28). Clarifying the mechanisms by which ACPA stimulates the NLRP3 inflammasome will enhance our understanding of the RA etiology and emphasize its contributions to FMF, an autoinflammatory disease. These findings may facilitate the identification of shared therapeutic targets for both diseases and the formulation of novel treatment methods.

Conclusion

This case illustrates an uncommon case of a patient with positive results for ACPA and RF, who advanced to RA following a course of colchicine-responsive recurrent arthritis associated with MEFV variants. In patients with ACPA-positive arthralgia, the presence of symptoms atypical for RA, such as intermittent or migratory arthritis, necessitates caution when diagnosing RA. Differentiation from autoinflammatory diseases, particularly through MEFV gene testing, should therefore be performed. The clinical progression in this case substantiates the concept that autoimmune mechanisms in RA and autoinflammatory processes in FMF may interact via a shared pathophysiological foundation involving inflammasome activation. Instances of coexisting FMF and RA are uncommon, and treatment protocols for such patients are currently lacking. Elucidating the link between these two entities, currently categorized as distinct diseases, will enhance our understanding of the pathophysiology involved and may facilitate in the identification of novel therapeutic targets in the future.

Written informed consent for the publication of this case report and genetic analysis was obtained from the patient.

The authors state that they have no Conflict of Interest (COI).

Supplementary Material

Appendix 1

Searches were conducted in PubMed and Ichushi Web. Search results were merged prior to screening.