Indian Journal of Rheumatology

REVIEW ARTICLE
Year
: 2017  |  Volume : 12  |  Issue : 6  |  Page : 189--193

Fibroblastic rheumatism


Jyoti Ranjan Parida 
 Department of Immunology and Rheumatology, IMS and SUM Hospital, Bhubaneswar, Odisha, India

Correspondence Address:
Jyoti Ranjan Parida
Department of Immunology and Rheumatology, IMS and SUM Hospital, Bhubaneswar, Odisha
India

Abstract

Fibroblastic rheumatism (FR) is a rare dermoarthopathy reported from different parts of the world since 1980. Although the exact cause is unknown, few reports implicate infection may be a triggering event. Patients usually present with multiple skin nodules and polyarthropathy with progressive skin contractures. Laboratory parameters including acute phase reactants are usually normal. The confirmatory diagnosis is based on histopathologic study of skin nodules, which demonstrate fibroblastic proliferation, thickened collagen fibers, dermal fibrosis, and decreased number of elastic fibers. Immunoreactivity for b-catenin, smooth muscle actin, and the monoclonal antibody HHF35 show myofibroblastic differentiation. Treatments with oral prednisolone and other disease-modifying drugs such as methotrexate, infliximab, and interferon have been tried with variable success. In general, skin lesions respond more aptly than joint symptoms indicating that skin fibroblast is more amenable to treatment than synovial fibroblasts. Awareness regarding this orphan disease among clinicians and pathologists will help in more reporting of such cases and finding out optimal treatment regimen.



How to cite this article:
Parida JR. Fibroblastic rheumatism.Indian J Rheumatol 2017;12:189-193


How to cite this URL:
Parida JR. Fibroblastic rheumatism. Indian J Rheumatol [serial online] 2017 [cited 2019 Dec 15 ];12:189-193
Available from: http://www.indianjrheumatol.com/text.asp?2017/12/6/189/219082


Full Text



 Introduction



Fibroblastic rheumatism (FR) was first described in 1980 from France by Chaouat et al.[1] and thereafter only a few dozens of cases have been reported in literature in the past four decades. FR is characterized by sudden onset of multiple cutaneous nodules with polyarthritis and sometimes skin contractures.[2] The diagnosis is made by biopsy of cutaneous nodules, which shows myofibroblastic proliferation in a background matrix of collagen and decrease in elastic fibers.[3] Although the skin nodules regress after treatment, joint deformity persists.[4] FR should be included in the differential diagnosis of any patient presenting with polyarthritis with multiple skin nodules.

 Epidemiology



The exact prevalence of FR is unknown considering its unawareness among physicians. Although cases have been reported worldwide most cases have been detected among Caucasians.[1],[2],[3],[4] The age onset ranges from 8 to 68 years without any gender predilection. Till date, around nine cases have been reported in children.[5] Only one adult case has been reported from India by our group in 2011,[6] and no cases reported thereafter to the best of to our knowledge. We attribute this to the lack of awareness of this condition among physicians and pathologists.

 Pathogenesis



The exact cause and pathogenesis of FR are unknown. Histopathological studies suggest that FR occurs due to fibroblastic proliferation rather than increased collagen synthesis. The fibroblasts have a greater proliferative ratein vitro as well as reduced secretion of collagen and noncollagenous proteins in FR.[7] This finding is in contradiction to systemic sclerosis, where increased dermal collagen synthesis is observed.

Under which condition the dermal fibroblasts are converted to myofibroblasts is yet to be elucidated. Both exogenous and endogenous factors have been implicated. Many case reports suggest infection as a possible trigger and different infections such as upper respiratory infection,[8] hepatitis C,[5] and Streptococcus[5] have been attributed based on their temporal association. In one child, FR symptoms appeared within 1–2 weeks of hepatitis B infection.[9] Only one case described in a patient suffering from lupus [10] and another case found to have lung adenocarcinoma [7] on autopsy. However, these data are insufficient to attribute malignancy or connective tissue disease as a possible trigger or disease association.

Many cytokines may play a role in transdifferentiation of fibroblasts to myofibroblasts. Transforming growth factor-beta and granulocyte macrophage-colony-stimulating factor are known to induce this phenotypic switch.[11] Successful use of anti-tumor necrosis factor (TNF) and infliximab in one patient [12] indicates TNF-alpha may have a pathogenic role by modulating fibroblast function. Although the exact mechanism of tissue injury in FR is unclear, myofibroblasts are thought to have synthetic, phagocytic, and contractile properties.[13] Factors responsible for transdifferentiation of synovial fibroblasts also stimulate the secretion of matrix metalloproteinases and/or promote collagen phagocytosis by myofibroblasts, leading to joint destruction.[13]

There is a debate in the literature whether to include FR as a non-Langerhans histiocytosis or fibromatosis. In the initial case reports, histopathological specimen showed dermal fibrosis with interspersed histiocytes suggesting classifying FR under non-Langerhans histiocytosis.[14] However later, most immunohistochemical studies showed that most of the spindle-shaped cells in FR were stained with anti-smooth muscle actin (SMA) and anti-calponin antibodies and negative for most histiocytic markers such as CD163 and FXIIIa, suggesting that they should be better classified as fibromatoses.[15]

 Clinical Feature



FR is characterized by the presence of cutaneous nodules and joint symptoms. However, there are two case reports of FR only presenting with cutaneous manifestation without any joint involvement even after long-term follow–up.[16],[17] Systemic or visceral involvement is not reported yet.

The cutaneous nodules are essential to the diagnosis and may precede or follow the musculoskeletal features by weeks to months. These nodules are usually solid, pink, or flesh colored and range from 5 to 20 mm in diameter.[1],[2],[3],[4] They are present in upper and lower extremities with a predilection for periarticular areas such as hands, elbows, knees, ears, and neck. They tend to resolve in 6–24 months with or without treatment.[17] Other cutaneous features are reported in various case reports and include sclerodactyly (76%), thickened palmar fascia (44%), erythematous plaques or papules (28%), and Raynaud phenomenon (36%).[18]

Joint involvement may manifest in any stage of the disease and is many times heralded by the edema of the affected joints. They consist of sudden onset symmetric polyarthritis/polyarthralgia, usually affecting small distal joints of both upper and lower extremities. There are case reports of arthritis affecting large joints (knees, hips, shoulders, and elbows). Initially, FR mostly presents as joint stiffness without any joint destruction. With progression of the disease, articular movement of affected joints becomes markedly restricted and painful and is associated with flexion contractures of the fingers.

 Laboratory Diagnosis



Laboratory investigation

Blood investigations are usually unremarkable in FR. Complete blood count and acute phase reactants are normal, and this helps in differentiating from inflammatory arthritis. All the autoantibodies including rheumatoid factor, anticitrullinated antibody, and antinuclear antibody are absent. These laboratory tests are useful to rule out other diagnoses such as inflammatory arthritis or other connective tissue disorders.

 Histopathology



Biopsy from the cutaneous nodule is unique and diagnostic of FR. Both histopathology and immunohistochemical studies should be ordered. Histopathological studies of this nodule show that epidermis is essentially normal. Dermis shows proliferation of spindle-shaped cells focally arranged in a storiform pattern, thickened collagen fibers, and dermal fibrosis.[18] Weigert–Unna–Taenzer and Orcerin staining reveals marked decrease in elastic fibers. Inflammatory infiltrate is scarce, and sometimes there may be mild perivascular lymphohistiocytic infiltrate. Subcutaneous tissue may show similar changes, but aponeurosis and muscle are usually unaffected.[15]

Data from synovial biopsy are only available from few cases.[19],[20] There is mild-to-moderate synovial cell hyperplasia, with a morphologically normal lining cell layer. Within the synovium, a marked proliferation of fibroblasts in a matrix of vascular granulation tissue is observed without much inflammatory infiltrate. These proliferating cells exhibit the ultrastructural features of myofibroblasts such as indented nuclei, intracytoplasmic vesicles containing collagen fibers, linear arrays of filaments, and well-developed and cystic rough endoplasmic reticulum.

 Immunohistochemistry



Immunohistochemical study of the fibroblast-like cells or spindle cells revealed that they were positive for nuclear and cytoplasmic b-catenin, anti-SMA, HHF35, and anti-calponin antibodies suggesting myofibroblastic differentiation. They are usually negative for most histiocytic markers such as CD1a, CD34, CD68, CD163, factor XIIIa, or S100 proteins.[5],[15],[18]

 Radiology



Radiography results are usually normal in the initial stages, but erosions and demineralization may occur as the disease progress. Accordingly, X-ray of hand and feet may be normal in initial stage whereas magnetic resonance imaging (MRI) may demonstrate early synovitis, tenosynovitis as well as early erosions. With progress of the disease, X-ray can demonstrate demineralization, joint space narrowing, and/or erosive changes.

In an interesting observation by Rety et al.,[21] two-third of X-rays done within first 4 months of disease onset were normal whereas rest showed only demineralization or soft tissue swelling. In most patients, destructive arthropathy of the hand developed 1 year after the onset of joint symptoms.

 Differential Diagnosis



Clinically, FR has to be distinguished from other causes of dermoarthopathies that present with skin nodules and polyarthritis or polyarthralgia [Table 1]. In adults, it has to be differentiated from multicentric reticulohistiocytosis (MRH), rheumatoid arthritis (RA), progressive nodular fibrosis (PNF), and nodular scleroderma, whereas, in children, this can mimic juvenile hyaline fibromatosis (JHF).{Table 1}

MRH is the closest differential diagnosis of FR. Early onset erosive arthritis, mucosal involvement, and typical periungual distribution of skin nodules (coral bead appearance) suggest a diagnosis of MRH.[22] Histopathology shows lipid-laden histiocytes and multinucleated giant cells with ground-glass cytoplasm in MRH in contrast to fibroblastic proliferation in FR.

RA when associated with rheumatoid nodules or methotrexate (MTX) nodulosis may be confused with FR. However, sparing of distal interphalangeal (DIP), typical location of rheumatoid nodules on extensor surfaces, and characteristic deformities in RA can distinguish it clinically from FR.[23] Further positive serology (RF and anti-cyclic citrullinated peptide antibody) and elevated erythrocyte sedimentation rate and C-reactive protein favor a diagnosis of RA. Histologically, RA nodules show a shell of fibrous tissue surrounding a center of fibrinoid necrosis and intervening cellular palisade.

PNF [24] is another condition only presenting as cutaneous nodules, and there is no joint involvement. Skin nodules are not restricted to para-articular areas, and biopsy shows nodular proliferation of plump fibroblasts in the dermis together with thickened collagen bundles.

Nodular scleroderma [25] is a variant of scleroderma, which may be observed in the context of both, localized sclerosis (i.e., morphea) and systemic sclerosis. Patient usually presents with skin nodules over neck, back, and abdomen. This may be associated with other features of scleroderma such as Raynaud's, sclerodactyly, telangiectasia, polyarthralgia, or erosive arthritis involving DIPs. Skin nodules have a distinct histology, with hyalinized thickened collagen bundles, tightly bound eccrine glands, and lack of fibroblastic proliferation.

JHF [26] is the main differential diagnosis in children and is a rare autosomal recessive disease due to germline mutations in the capillary morphogenesis gene-2. Children with JHF also present joint contractures, bone erosion, and cutaneous nodules, which may mimic FR. Onset in infancy and early childhood, location of the skin lesions on the trunk, gingival hypertrophy, and lack of sclerodactyly favor JHF. Histopathology shows a characteristic deposition of an amorphous Periodic acid–Schiff-positive hyaline substance besides fibroblast and myofibroblast proliferation.

 Treatment



Early diagnosis and treatment of FR is crucial to avoid permanent joint deformity and disability. Many anti-inflammatory and disease-modifying antirheumatic drugs (DMARDs) such as prednisone,[7] colchicine, interferon alpha,[27] penicillamine, MTX,[8] hydroxychloroquine,[28] acetylsalicylate, and nonsteroidal anti-inflammatory drugs, infliximab [12] have been tried in the past having variable results. As inflammatory component is much less than fibroblastic component in histopathology, improvement in joint symptoms with these agents is partial and often poor. In spite of treatment, rheumatologic features may progress to disabling condition with flexion contractures. Cutaneous nodules tend to improve faster, but it is uncertain whether this is related to the treatment, as spontaneous remission is known.

MTX causes a dose-dependent inhibition of the proliferation of cultured human synovial fibroblasts [29] and prevents the development of synovial fibrosis in RA. It has both antiproliferative and apoptosis-inducing effects. Low-dose oral MTX 10 mg/week was first used to treat FR in 1996 with good clinical response.[8] It was highly effective in reducing the symptoms of joint pain, morning stiffness, and synovitis. Skin nodules completely disappeared within 2 months of treatment. Subsequently, it was tried in many patients with dose range varies from 10 to 25 mg/week and had a variable clinical response. We suggest that this difference may be related to different dosing schedules and FR may need a little higher dose of MTX than inflammatory arthritis like RA.

Interferon-alfa has been shown to reduce fibroblasts and myofibroblasts in hypertrophic scars [30] and likely has similar effects on fibroblasts in FR. There are case reports of effectiveness of interferon alpha in FR [27] Although the cutaneous nodule resolved, joint symptoms persisted. This may be related to differential antiproliferative effect of interferon-alfa on dermal fibroblast (more sensitive) than synovial fibroblast (resistant). One case report of effectiveness of infliximab [12] in FR suggests TNF-alpha having a pathogenic role in changing fibroblast function, and this has to prove in future studies.

As functional disability with flexion contractures remains the main long-term morbidity, role of physical therapy is crucial in maintaining joint function. One report suggests dramatic improvement with intensive physical therapy (3 times/week) without any use of pharmacological treatment.[4] After a 2-year follow-up with weekly regular physical therapy, pain subsided, the functional impairment continuously improved, and some delicacy in the fingers movements was recovered. Follow-up MRI did not reveal any erosion or significant synovitis.

 Conclusion



FR is a rarely reported condition and remains unfamiliar to most physicians. FR should be suspected and included in differential diagnosis of any patient presented with symmetrical polyarthritis, para-articular skin nodules, and flexion contracture of fingers and toes. Histopathological and immunohistochemical study of skin nodules showing fibroblastic proliferation with a decrease in elastic fibers is diagnostic of the condition. Hence, regular physical therapy with the judicious use of DMARDs and anti-inflammatory agents should be offered to all patients of FR with joint symptoms. Cutaneous nodules may resolve spontaneously.

More insight regarding origin and pathogenesis of this condition is needed to identify additional targeted therapies. Increase awareness regarding this condition is needed among both clinicians and pathologists for early diagnosis and treatment.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Chaouat Y, Aron-Brunetiere R, Faures B, Binet O, Ginet C, Aubart D. Unenou- velleentite. Le rhumatismefibroblastique. A propos d'une observation. Rev Rhum Mal Osteoartic 1980;47:345-51.
2Romas E, Finlay M, Woodruff T. The arthropathy of fibroblastic rheumatism. Arthritis Rheum 1997;40:183-7.
3Fam AG, Hanna W, Mak V, Assaad D. Fibroblastic rheumatism: Clinical and histologic evolution of cutaneous manifestations. J Rheumatol 1998;25:2261-6.
4Courties A, Guégan S, Miquel A, Duriez P, Berenbaum F, Sellam J, et al. Fibroblastic rheumatism: Immunosuppressive therapy is not always required. Joint Bone Spine 2014;81:178-9.
5Jurado SA, Alvin GK, Selim MA, Pipkin CA, Kress D, Jamora MJ, et al. Fibroblastic rheumatism: A report of 4 cases with potential therapeutic implications. J Am Acad Dermatol 2012;66:959-65.
6Parida JR, Agarwal V, Krishnani N. An unusual case of polyarthritis, skin nodules and patchy skin thickening: Fibroblastic rheumatism. Int J Rheum Dis 2012;15:e12-4.
7Lacour JP, Maquart FX, Bellon G, Gillery P, Lepeytre P, Ziegler G, et al. Fibroblastic rheumatism: Clinical, histological, immunohistological, ultrastructural and biochemical study of a case. Br J Dermatol 1993;128:194-202.
8Vittecoq O, Mejjad O, da Silva F, Joly P, Thomine E, Lauret P, et al. Preliminary experience with low-dose methotrexate in fibroblastic rheumatism. Arthritis Rheum 1996;39:2070-3.
9Lee JM, Sundel RP, Liang MG. Fibroblastic rheumatism: Case report and review of the literature. Pediatr Dermatol 2002;19:532-5.
10Shen YJ, Chen GS, Chen JY, Wu CS. Fibroblastic rheumatism in a female of systemic lupus erythematosus. Dermatol Sinica 2006;24:135-39.
11Desmoulière A, Geinoz A, Gabbiani F, Gabbiani G. Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Biol 1993;122:103-11.
12Romiti R, Levy Neto M, Menta Simonsen Nico M. Response of fibroblastic rheumatism to infliximab. Dermatol Res Pract 2009;2009:715729.
13Gabbiani G. The biology of the myofibroblast. Kidney Int 1992;41:530-2.
14Zelger B, Burgdorf W. Fibroblastic rheumatism: A variant of non-langerhans cell histiocytoses? Pediatr Dermatol 2003;20:461-2.
15Kluger N, Dumas-Tesici A, Hamel D, Brousse N, Fraitag S. Fibroblastic rheumatism: Fibromatosis rather than non-langerhans cell histiocytosis. J Cutan Pathol 2010;37:587-92.
16Colonna L, Barbieri C, Di Lella G, Zambruno G, Annessi G, Puddu P, et al. Fibroblastic rheumatism: A case without rheumatological symptoms. Acta Derm Venereol 2002;82:200-3.
17Cabral R, Brinca A, Cardoso JC, Reis JP, Tellechea O, Figueiredo A, et al. Fibroblastic rheumatism – A case report. Acta Reumatol Port 2013;38:128-30
18Marconi IM, Rivitti-Machado MC, Sotto MN, Nico MM. Fibroblastic rheumatism. Clin Exp Dermatol 2009;34:29-32.
19Crouzet J, Amouroux J, Duterque M, Halmagrand N, Beraneck L, Guillien P, et al. Fibroblastic rheumatism. A case with study of synovial histology. Rev Rhum Mal Osteoartic 1982;49:469-72.
20Taccari E, Teodori S, Zoppini A. Fibroblastic rheumatism of the elderly. Histopathological, ultrastructural data and problems of differential diagnosis. Rev Rhum Mal Osteoartic 1987;54:463-7.
21Réty F, Tayebjee OA, Servettaz A, Godmer P, Le Van An JC, Laredo JD, et al. Radiological bone lesions in fibroblastic rheumatism; case report. Presse Med 2007;36:432-6.
22Tajirian AL, Malik MK, Robinson-Bostom L, Lally EV. Multicentric reticulohistiocytosis. Clin Dermatol 2006;24:486-92.
23Jacob J, Sartoris D, Kursunoglu S, Pate D, Pineda CJ, Braun RM, et al. Distal interphalangeal joint involvement in rheumatoid arthritis. Arthritis Rheum 1986;29:10-5.
24Bauer EA, Uitto J, Santa Cruz D, Turner ML. Progressive nodular fibrosis of the skin: Altered procollagen and collagenase expression by cultured fibroblasts. J Invest Dermatol 1986;87:210-6.
25Srisuttiyakorn C, Aunhachoke K. Scleroderma with nodular scleroderma. Case Rep Dermatol 2016;8:303-10.
26Thomas JE, Moossavi M, Mehregan DR, McFalda WL, Mahon MJ. Juvenile hyaline fibromatosis: A case report and review of the literature. Int J Dermatol 2004;43:785-9.
27Ostlere LS, Stevens HP, Jarmulowicz M, Higgens C, Black C, Rustin MH, et al. Fibroblastic rheumatism. Clin Exp Dermatol 1994;19:268-70.
28Schiavon F, Punzi L, Todesco S. Fibroblastic rheumatism: A fifteen-year followup study. Arthritis Rheum 1998;41:759-60.
29Cutolo M, Sulli A, Pizzorni C, Seriolo B, Straub RH. Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis. Ann Rheum Dis 2001;60:729-35.
30Nedelec B, Shankowsky H, Scott PG, Ghahary A, Tredget EE. Myofibroblasts and apoptosis in human hypertrophic scars: The effect of interferon-alpha2b. Surgery 2001;130:798-808.